Improving in Vivo Efficacy of Bioactive Molecules

Hindawi
Journal of Oncology
Volume 2017, Article ID 7351976, 34 pages
https://doi.org/10.1155/2017/7351976
Review Article
Improving In Vivo Efficacy of Bioactive Molecules:
An Overview of Potentially Antitumor Phytochemicals and
Currently Available Lipid-Based Delivery Systems
Lamia Mouhid,1 Marta Corzo-Martínez,2 Carlos Torres,2 Luis Vázquez,2

Guillermo Reglero,1,2 Tiziana Fornari,2 and Ana Ramírez de Molina1
1
Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
2
Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL),
Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
Correspondence should be addressed to Ana Ramı́rez de Molina; [email protected]
Received 29 December 2016; Accepted 6 March 2017; Published 7 May 2017
Academic Editor: Akira Hara
Copyright © 2017 Lamia Mouhid et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer
treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds
which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or
development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in
the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant
products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays.
However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons,
mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their
bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive
compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association
with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive
supplements for cancer treatment based on the improvement of their bioavailability goes through this association.
1. Introduction However, despite their promising benefits in vitro, results

from several studies highlight a low Phy bioactivity in vivo
The conventional treatments against cancer are nowadays
replaced by new approaches such as hormone therapy, bio- [5], mainly attributed to their poor water solubility, rapid
logical therapy, and stem cell transplantation. In addition metabolism, and short half-live and even causing gastroin-
to these proposals, new chemical compounds are tested, testinal irritation. These factors lead to low and variable
focusing on founding antitumoral agents with high speci- oral bioavailability and nonreproducible absorption, which
ficity response and low toxic side effects and warding off gives rise to therapeutic concentrations that are difficult to
resistance development. In this sense, phytochemicals (Phy) achieve, high intra- and intersubject variability, and lack of
have received increasing attention due to their high potency dose proportionality [6], offering significant limitations or
and low toxicity compared with common chemotherapeu- challenges to the cancer therapy with Phy.
tic agents [1] and with pharmacological properties acting Therefore, to increase the Phy applicability, developing
through specific molecular targets [2–4]. Thus, Phy are con- formulation strategies that overcome limited oral bioavail-
sidered as nonnutritive compounds found in plants and safe ability of Phy is needed. In this sense, the association of Phy
for human intake [2] and with promising applications since to delivery systems or carriers composed of diverse materials
their consumption is integrated within diet components. has been proposed [7]. Particularly, in the last decade,
2 Journal of Oncology
association with lipids, usually referred to as lipid-based other chemical groups. One of the most studied phenolic
delivery systems, gained much interest as they are nontoxic, compounds is the ellagic acid, as described in Table 1.
biodegradable, and highly biocompatible and show great ver- (ii) Flavonoids. Although they are not considered as
satility. In this respect, lipid formulations can be modified in essential dietary factors, they represent 60% of dietary pol-
various ways to meet a wide range of product stability require- yphenols [2, 13] and are starting to be considered the key
ments (molecular weight and physicochemical properties), between prevention and treatment of chronical diseases
disease conditions and route of administration, and existing and diet. Chemically, the flavonoid skeleton consists of two
commercial formulations for topical, oral, pulmonary, or phenyl rings joined by a linear three-carbon bridge [15].
parenteral product delivery [8, 9]. Table 1 summarizes those studied against cancer. Genistein,
In these frameworks, the present work summarizes the (−)-epigallocatechin-3-gallate (EGCG), and quercetin are the
existing dietary Phy with promising anticarcinogenic prop- flavonoids more frequently tested in clinical trials against
erties and Phy-based therapies that are being currently tumors. Genistein have been extensively studied as prospec-
evaluated in vitro, in vivo, and in clinical trials as efficient tive antitumor molecules in the treatment of prostate cancer.
approaches for the prevention and treatment of cancer and Meanwhile, EGCG has also been largely studied in exper-
their bioavailability. Likewise, it also summarizes the delivery imental studies against different types of tumors, even in
systems currently used to enhance the clinical use of Phy by clinical trials, particularly against prostate or cervical injuries.
increasing their oral bioavailability and by promoting their Quercetin was tested, in addition, against tumors related to
safe and targeted activity, mainly emphasizing the lipid-based the digestive tract, such as bowel, colon, or pancreas.
delivery systems. Within flavonoids, proanthocyanidins are also under-
lined as effective naturally occurring compounds in grape
2. Dietary Phytochemicals Possessing seeds or pine bark with antitumorigenic effects. They take
Anticancer Properties the form of oligomers or polymers (+) catechin and (−) epi-
catechin, and the carried-out in vivo studies have remarked
In the last years, several studies have amply demonstrated the preventive and effective action against UV-induced skin
that tumor development could be highly associated with tumors but also showed the inhibition of lung metastasis
diet habits [10, 11]. In this sense, current researches on and mammary and prostate cancer [16]. Concerning clinical
new approaches for cancer treatment are focused on the studies, the is just one concluded trial which studied the
study of three axes: dietary patterns, specific foods, and safe positive chemoprevention proanthocyanidin effect on breast
and bioavailable dietary compounds [12]. Among the latter, cancer [17].
Phy derived from diet might be considered as promising (iii) Stilbenes constitute a large family within polyphenols
preventive and therapeutic alternative agents against cancer. and have numerous implications in plant disease resistance
According to their chemical structure, Phy can be mainly and human health (including antitumoral activity). Stilbenes
classified into four groups: polyphenols, terpenes, organosul- have a 1,2-diphenylethylene core and belong to a small
fur compounds, and phytosterols. The following provides a group of phenylpropanoids and only a few plants spices can
description of Phy belonging to the mentioned structural synthetize them. They are produced in response to a biotic
categories that have shown potential anticancer properties in or abiotic stress [18]. The most largely studied is resveratrol,
in vitro studies, as the first step to evaluate their enhanced which is produced in plants in response to mechanical
activities, and in in vivo models, as the second step of injuries. It is reported to be efficient against gastrointestinal
efficacy evaluation and determination of molecular action tumors in clinical trials, and in vivo tests were carried out in
and targets. Phy tested in preclinical and clinical studies breast, ovarian, lung, or skin tumors (Table 1).
conducted with human cancer patients to validate their in (iv) Curcuminoids are derived from curcumin, and they
vivo therapeutic effect are also listed. are obtained from turmeric (Curcuma longa). Curcumin
belongs to diarylheptanoid series and is characterized by
2.1. Polyphenols. Antitumor benefits of polyphenols have 1,3-diketones and two methoxylated phenols [19]. Curcumin
been widely described. Polyphenols constitute one of the is largely used as medicinal and food ingredient in Asia,
major constituents of plants and are abundant in our diet. especially in India. Within cancer therapies, it has been tested
The occurrence in plant matrix is very variable, going from in several in vivo tumor models and even in clinical trials
simple phenolic molecules to complex associations (highly (Table 1).
polymerized compounds). They are usually classified into
different groups according to their structure and number of 2.2. Terpenes. Another important group of phytochemicals
rings, highlighting phenolic acids, flavonoids, stilbenes, and is that constituted by terpenoids or terpenes, which is the
curcuminoids, which are described below and compiled in most abundant and structurally diverse group synthetized by
Table 1. plants. Terpenes show a wide range of physiological func-
(i) Phenolic acids represent 30% of total dietary polyphe- tions, many of them related to the plant defense system, and
nols [13] and they are the major constituents of phenolic they are often components of essential oils and resins [20].
compounds. They usually include hydroxybenzoic acids and Terpenes are synthesized from two to five carbon building
hydroxycinnamic acids [14], where one of the positions of the blocks based upon the isoprene unit. Depending on the num-
aromatic benzoic o cinnamic ring is occupied by a hydroxyl ber of blocks, they can be classified as monoterpenes (C10),
group and the remaining four positions are available for sesquiterpenes (C15), diterpenes (C20), triterpenes (C30),
Table 1: Polyphenols studied in experimental in vitro tests, in vivo models, and clinical trials.
Cancer targets in vivo References cancer
Journal of Oncology
Polyphenols Phytochemical Main source Clinical trials Chemical structure

and in vitro targets/clinical trials
Prostate O
HO O
Pancreas
Pomegranate, berries, Prostate [161–165]/ HO OH
Phenolic acids Ellagic acid Bladder
grapes Follicular lymphoma [166, 167]
Breast O OH
Colon O
Prostate HO
HO
Renal carcinoma
Prostate O OH
Breast HO
(−)-Epigallocatechin- Green tea Papilloma cervical [168–174]/
Laryngeal carcinoma O
3-gallate (EGCG) (Camellia sinensis) Breast [175–178]
Non-small cell lung HO HO
Prostate O
Colon
HO
Pancreas HO
Bone marrow Prostate O
HO
Prostate Bone
[179–183]/
Genistein Soybean Breast Endometrial
[184–187]
Cervical Breast OH O OH
Colon Bladder
Hepatocellular carcinoma
Oral squamous OH
carcinoma
Cabbages, celery, HO O
Prostate OH
Luteolin broccoli, onion leaves, — [188–193]
Breast
Flavonoids parsley
Thyroid
OH O
Colorectal
Cervical
Lung
Prostate
Breast O
OH
Ovary
HO O O
Thistle Colon Upper gastrointestinal [194–198]/ O
Silymarin
(Silybum marianum) Lung Leukemia [199, 200] OH
OH
Bladder
OH O
Skin
Prostate
3
4
Table 1: Continued.
Cancer targets in vivo References cancer
Polyphenols Phytochemical Main source Clinical trials Chemical structure
and in vitro targets/clinical trials
Pancreas Large bowel OH
Breast Ovary OH
Capers, lovage leaves, Cervical Pancreas [201–206]/ HO O
Quercetin
apple Colon Prostate [207–209]
Prostate Thrombotic OH
Lung Colorectal OH O
Breast
Colorectal
OH
Hepatic melanoma
Lung Colorectal HO
[38, 39, 210–217]/
Stilbenes Resveratrol Grape, berries Pancreas Colon [218–222]
Prostate Gastrointestinal tumors
Skin OH
Bladder
Ovarian
Pancreas
Prostate
Ovarian
Melanoma Pancreas
Head and neck squamous Colorectal O OH
cell carcinoma Colon O CH3
H3 C O
Curcuminoids Curcumin Curcuma longa L. Leukemia [40, 41, 223–230]/
Liver
Hepatoma [96, 231–238] HO OH
Pancreas
Gastric Breast
Glioblastoma Head and neck
Lung
Breast
Cervical
Colorectal
Clinical trials carried out considering phytochemicals as dietary complements or drugs (therapy) in cancer patients.
For the experimental studies, in vivo studies are in italic characters.
Chemical structures were obtained by using ChemDraw Professional 15.0 software.
Journal of Oncology
Journal of Oncology 5
tetraterpenes (C40), and polyterpenes [21]. Their potential phytosterols, among which 𝛽-sitosterol, campesterol, and
antitumor properties have been described in several works sitostanol are the major ones [30].
[22], as shown in Table 2. 𝛽-Sitosterol is the most abundant phytosterol and
(i) Carotenoids are the most abundant tetraterpenes, and although it is well known for its cholesterol lowering action
in natural samples they could be found free or esterified by [31], several in vitro and in vivo evidences suggest it possesses
fatty acids, the degree of esterification being related to the preventive effects against cancer (Table 2). Campesterol and
hydroxyl groups. They also are characterized by the presence sitostanol, however, have not shown any effect on tumor
of 11 or 12 conjugated carbon double bounds [23]. All of them growth [32].
represent variants or degradation derivatives of 𝛽-carotene, Within terpenes, triterpenoids (squalene) play a deter-
which is found in carrot (Daucus carota). Antitumor activity minant role as they are considered common precursors of
of the acyclic tetraterpene lycopene has been largely studied steroids, including phytosterols. Triterpenoids exist in free
in both in vivo and clinical trials, especially conducted form or combined with sugar into glycosides. The free form
with prostate tumors (Table 2). Besides lycopene, astaxanthin shares the same chemical properties as phytosterol so long
may exert antitumor activity through its antioxidant and as they can be dissolved in organic solvents but insoluble
immunomodulatory characteristics in tumors such as colon in water [33]. In the last years, triterpenoids have demon-
and hepatic carcinomas, as shown in Table 2. strated antitumor efficacy against breast, leukemia, multiple
(ii) Noncarotenoids are not derived from carotenes. This myeloma, and non-small cell lung carcinomas, specially
group of terpenes includes carnosol, a phenolic diterpene affecting cell proliferation [34, 35]. Some triterpenes are
largely studied in cancer and associated with bioactivity of already tested in Phase I clinical trials [36], with beneficial
rosemary (Table 2). For carnosol, there are in vivo positive effects, even if some authors defend their combination with
studies against colon, prostate, and skin tumors and no other triterpenoids, Phy, or synthetic drugs.
clinical studies proposed. In general, in vitro and in vivo assays conducted with
dietary Phy (Tables 1 and 2) showed tumorigenesis inhibi-
2.3. Organosulfur Compounds. Organosulfur compounds are tion or potential chemopreventive effects. However, a high
Phy with one or more carbon-sulfur bonds in their structure variability in anticancer effects was observed among different
and a thioketal-linked glucose molecule (S-glycosides). They patients during clinical trials, which is one of the major
are classified into two groups: glucosinolates and thiosulfi- limitations of the Phy-based therapy in the clinical practice.
nates [24]. Glucosinolates are sulfur-containing plant sec-
ondary metabolites that usually exist in cruciferous plants
and are hydrolyzed by specific enzymes (myrosinases) to 3. In Vivo and Clinical
release biologically active sulfurated aglycones, known as Bioactivity of Phytochemicals
isothiocyanates [2, 25]. Glucosinolates and their hydrolysis
products exhibit direct and indirect antioxidant effects by Although Phy hold part of their biological activity in vivo,
scavenging harmful radicals and modulation of detoxifica- as said above, their activity in this context is lower than
tion enzymes, such as glutathione S-transferase [26]. Thus, observed for the same compound in the in vitro evaluation
consumption of cruciferous plants, such as cabbage and broc- phase. An obvious reason for the “loss” of activity is the
coli, is believed to promote health and to reduce the risk lack of pharmacokinetic optimization or compatibility [37].
of cancer development [27]. Among isothiocyanates, sul- One of the main factors that influences pharmacokinetics
foraphane, produced from the glucosinolate glucoraphanin, of the tested bioactive compound is its tissue bioavailability,
has been largely studied as chemopreventive agent in different which is defined by the Food and Drug Administration as
tumors in vivo, and it is the unique organosulfur compound “the rate and extent to which the active ingredient or active
that has been tested in a clinical trial as antitumorigenic agent moiety is absorbed from a drug product, reach plasma and
[28] (Table 2). body tissues and becomes available at the site of action in an
Thiosulfinates (allyl sulfides), such as diallyl sulfide unchanged form”. Thus, bioavailability should be considered
(DAS), diallyl disulfide (DADS), and diallyl trisulfide when the efficacy of dietary Phy is evaluated in vivo in
(DATS), are mainly present in garlic and onion (Allium animal models and/or human clinical trials. The impact of
family) [25]. Among them, DADS, an oil-soluble organo- bioavailability is especially pronounced when the bioactive
sulfur compound, has been described as the major one compound is intended for oral use, whereby gastrointestinal
responsible for therapeutic properties against prostate and (GI) absorption constitutes the primary barrier between an
colon in in vitro models and gastric, breast, and leukemia in active ingredient and systemic circulation. In the present
in vivo models (Table 2). review, we focus on oral bioavailability as the major phar-
macokinetic aspect for the clinical application of orally
2.4. Phytosterols. Phytosterols are lipid-like compounds and delivered dietary Phy with high bioefficacy as anticancer
essential for maintaining permeability and fluidity on cell agents. In this respect, factors affecting GI absorption and
plant permeability. Vegetable oils are the main source of oral bioavailability of main dietary Phy will be addressed.
dietary phytosterols. They occur in various structural forms
(as steryl glucosides, acetylated steryl glucosides, esters, 3.1. Oral Bioavailability of Dietary Phytochemicals. Oral route
or alcohols) [29], each of them existing in different com- is generally considered the easiest and most convenient
partments of the plant cell. There are approximately 200 method for the delivery of drugs and dietary bioactive
6
Table 2: Terpenes, organosulfur, and phytosterols commonly studied in cancer therapy.

References cancer
Cancer targets in
Family Phytochemical Main source Clinical trials targets/clinical Chemical structure
vivo and in vitro
trials
Terpenes
Prostate
Colon
H3 C
Breast CH3 CH3
Tomato H3 C CH3
Lung [239–242]/
Lycopene (tetraterpene) (Lycopersicon Prostate
Cervical [243, 244] H3 C CH3
esculentum) CH3
CH3 CH3
Breast
Laryngeal
Liver carcinoma
Hepatic
Oral carcinoma OH
Green microalgae
Fibrosarcoma O
Astaxanthin (Haematococcus — [245–251] O
Skin
Carotenoids pluvialis) HO
Bladder
Colon
Laryngeal
Non-small cell
lung
Gastric cancer
Prostate
[252–256]/
𝛽-Elemene Ginger, celery Brain Glioma
[257]
Breast
Cervical
Colon
Ovarian
Melanoma
Glioblastoma
Colon OH
Sage (Salvia Prostate
HO
carnosa), Skin O
Noncarotenoid Carnosol (diterpene) Rosemary Breast — [258–263]
(Rosmarinus O
Ovarian
officinalis) Intestinal H
Melanoma
Journal of Oncology
Journal of Oncology
Table 2: Continued.
References cancer
Cancer targets in
Family Phytochemical Main source Clinical trials targets/clinical Chemical structure
vivo and in vitro
trials
Organosulfur
Skin
Gastrointestinal-
colon
O
Prostate [42, 95, 264–267]/
Sulforaphane Brassica vegetables Breast [268] S
Pancreas H3 C NCS
Breast
Bladder
Thiosulfinates Ovary
Mammary
Gastric
Breast
Leukemia
H2 C
S S
Diallyl disulfide Allyl vegetables Neuroblastoma — [43, 44, 269–273] CH2
Prostate
Colon
Thyroid
Phytosterols
Colon CH3
H3 C CH3
Breast H3 C H
Phytosterols Vegetal oils — [274–278] CH3
𝛽-Sitosterol Stomach H3 C H
Prostate H H
Fibrosarcoma HO
Clinical trials carried out considering phytochemicals as dietary complements or drugs (therapy) in cancer patients.
For the experimental studies, in vivo studies are in italic characters.
Chemical structures were obtained by using ChemDraw Professional 15.0 software.
7
Exogenous factors: physicochemical properties and pharmacokinetics of active compound and physiological, biochemical, and
biological barriers
Oral
Short systemic circulation time

Poor water solubility and stability Stomach
ease of oxidation, hydrolysis, and
PHY precipitation and degradation isomerization
during gastric digestion severely Absorption
limiting application
Distribution Kidney
Blo
o
Small intestine Excretion
ds
Poor permeability and absorption
tre
due to inefficient transportation, large
am
Absorption Rapid elimination
molecular weight, high hydrogen-
fast systemic clearance from
bonding, low lipophilicity, and others
plasma with a short elimination
Urine half-life, lower than the relative
biological activity
Extensive metabolism
by intestinal microorganisms
and in enterocyte by enzymes Large Liver
intestine Metabolism Extensive metabolism
in hepatocytes
Excretion
Feces
Endogenous factors: individual age and gender, mucosal mass, gastric emptying, genetics, and diseases
Coingested compounds or foods
Figure 1: Determinant factors of the oral bioavailability of bioactive compounds, including phytochemicals.
compounds due to properties such as noninvasiveness, cost- (iv) Endogenous factors, as the individual age and gender,
effectiveness, and being less prone to side effects, such as mucosal mass, gastric emptying, genetics, and dis-
injection-site reactions [9]. In fact, although in some of the in eases [46]
vivo studies and clinical trials listed in Tables 1 and 2 Phy were
administered by intraperitoneal or intratumoral injection (v) Amount of coingested compounds or foods
and topical route [38–44], in most of the cases, they were
orally administered (by gavage, diet supplementation, water A compound which can exist in a stable form to survive
suspension, or capsules). the GI environment and that has optimum physicochemical
However, as commented above, the suitability of this properties to penetrate the GI wall is most likely to possess
administration route depends on the oral bioavailability of acceptable oral bioavailability. Most of Phy, however, have
the active ingredient, which, as summarized in Figure 1, is the shown physicochemical properties that lead to a poor water
result of the synergistic effect of the following factors: solubility and stability in the GI environment and poor
permeability. These include complex structure, size, high
(i) Physicochemical properties of Phy, which determine molecular weight, high lipophilicity, compound H-bonding
their water solubility and stability inside the GI tract to solvent, intramolecular H-bonding, intermolecular H-
bonding, crystal packing, crystallinity, polymorphic forms,
(ii) Physiological barriers, including the chemical (e.g., ionic charge status, isoelectric point (pI), and salt form
pH) and biological environment (e.g., microbiota) [47]. In addition to physicochemical properties limiting
inside the GI tract, which also have a significant influ- their GI absorption, Phy are usually subjected to extensive
ence on Phy stability during digestion and absorption metabolism in the enterocyte and hepatocyte and/or quickly
[45] eliminated in the urine [48]. All these factors result in a
(iii) Biochemical barriers (including biodistribution), bio- poor and variable bioavailability, which leads to therapeutic
logical barrier (GI wall permeability), and pharma- concentrations that are difficult to achieve, nonreproducible
cokinetics (metabolism and clearance) of the active absorption, variable efficacy intra- and intersubject during
ingredient clinical trials, and lack of dose proportionality. This explains
the lower in vivo bioactivity and nonreproducible data glucoraphanin (active sulforaphane) in plasma and urine
obtained in previous studies (Table 2) [6, 49]. Bioavailability [57], although it has not been evaluated in specific organs
studies of the major dietary Phy are described below. levels.
3.1.1. Bioavailability Studies of the Major (iv) Phytosterols. Phytosterol structure is similar to that
of cholesterol but each phytosterol has an additional side
Dietary Phytochemicals
chain, which confers dissimilarities in their absorption. Low
(i) Polyphenols. Most of the studies focus on bioavailability bioavailability of phytosterols is reported in human plasma
related to levels of the polyphenol present in blood or urine after intake. Before absorption starts, the esters are split in
[50], but few of them determine the bioavailability in target the duodenum, increasing their hydrophobicity and reducing
tissues, which can be more determinant for affirming their their absorption at the same time. In addition, it has been
application for a specific illness. After intestinal hydrolysis, described that they poorly reesterify in the enterocytes,
polyphenols are conjugated by glucuronidation (addition of explaining their poor absorption and their subsequently low
glucuronic acid), methylation (addition of a methyl group), concentration in the blood circulation [58, 59].
or sulfurylation (addition of a sulfo-group), which often facil-
itate their urinary elimination. Thus, they are well absorbed 4. Use of Lipid-Based Delivery Systems to
on tissues where they are metabolized (bowel and liver) [51, Increase the Clinical Efficacy of Antitumor
52], but their bioavailability in target tissues is low because of Phytochemicals Administered Orally
their rapid clearance from the body.
Nevertheless, there is a study that reveals that once sulfate The development of crystalline solid formulations by mod-
and glucuronide conjugates of resveratrol are circulating in ifying physicochemical properties, as salt formation and
plasma (with an expected low bioavailability), their sub- micronization (particle size reduction), was initially adopted
sequent hydrolysis releases free resveratrol which can be to amend the poor water solubility of Phy [60]. However,
captured by those cells with specific membrane receptors, the low wettability and handling difficulties of reduced size
increasing thus its bioavailability in specific tissues [53]. formulations as well as the aggregation of nanocrystals inside
These conjugations may also depend on factors described the body and the impossibility of salt formation from neutral
in Section 3.1 such as age and gender, genetics and dis- compounds limit the use of these approaches [61]. Amor-
eases, and protein-binding in tissues and blood. Moreover, phous formulations, including solid solutions (active com-
independently of the mechanistic processing of flavonoids, pound immobilized in polymer) and self-dispersing solid
some authors have also described the preventive efficacy of solutions (with surfactants), have been also applied; however,
flavonoids (resveratrol) as dependent on the type of diet. the questionable physical stability of product (possibility of
In this sense, it has been demonstrated that low doses of crystallization of drug or polymer) limited their use [62].
resveratrol were able to reduce colon tumor progression Over the last years, new formulation strategies to increase
better than high doses in subjects exposed to a high fat diet. the clinical efficacy of poor water-soluble active compounds
[54]. have been developed. Figure 2 shows the new ones, specif-
ically those developed for oral administration of active
(ii) Terpenes. Clinical relevancies of terpenes depend on their compounds (in italic). In addition, polymer-based delivery
presence in target organs. Terpenes have a high lipophilic systems (PBDS) have also been popularly adopted to increase
behavior, and therefore they depend on their solubility in the clinical efficacy of some Phy, as observed in Table 4 [63,
the aqueous phase of the gut lumen. Thus, it has been 64]. To a lesser extent, inclusion complexes with cyclodex-
observed that bioavailability of terpenes is related upon their trins and its derivatives as well as inorganic, hybrid, and other
incorporation to a lipid phase either during digestion or novel nanocarriers are being currently used (Table 4).
during food processing, making the presence of a quantity of Furthermore, it is worth mentioning that, in recent years,
fat necessary for their absorption [20]. Lycopene, one of the an increased interest has been focused on the incorporation
major carotenoids described for its anticarcinogenic poten- of poorly water-soluble compounds into lipid-based delivery
tial, has been demonstrated to enhance its bioavailability systems (LBDS). Association with lipid-based delivery sys-
when they are integrated in a chylomicron [55]. tems has been shown to be one the most powerful strategies
for the formulation of poorly water-soluble active compounds
(iii) Organosulfur Compounds. Studies related to organosulfur [8, 9], as they show several advantages compared to other
compounds are frequently carried out in combination with carriers, including
other Phy or drugs. Indeed, few experimental data determine
(i) higher degree of biodegradability and biocompatibil-
their bioavailability, and urine levels after uptake of Brussels
ity;
or broccoli sprouts [56] are the unique parameter usually
measured. (ii) higher degree of versatility: lipid formulations can
But as they are increasingly consumed due to their be modified in various ways to suit the stability
potential antitumoral effects, a new variety with genetic requirements (molecular weight and physicochemical
variations has been proposed increasing thus the expression properties) and toxicity and efficacy of the active
of transcription factors involved in glucosinolate biosynthe- agent as well as the route of administration and cost;
sis. The resulting broccoli could deliver a larger amount of (iii) high and enhanced loading capacity;
Polymeric micelles (PM)

Polymer-based Polymeric nanoparticles (PNP)
Polymer-bioactive conjugates
delivery systems
Dendrimers
Biopolymer-based nanocarriers
Liposomes
Phospholipid complexes
Vesicle systems Transfersomes
Ethosomes
Niosomes
Lipid-based
Solid lipid nanoparticles (SLNs)
delivery systems Lipid particulate
clinical efficacy of phytochemicals
Nanostructured lipid carriers (NLCs)

(Nano)carriers use to increase the
systems
Lipid-bioactive conjugates
Micro- and nanoemulsions
Emulsions Nanosuspensions
Self-emulsifying delivery systems (SEDSs)
Molecular
Inclusion complexes with cyclodextrins
complexes
Gold nanoparticles
Inorganic Mesoporous silica nanoparticles
nanocarriers Magnetic nanoparticles
Nanotubes
Hybrid nanocarriers
Lipid and polymeric nanocapsules

Other novel Liquid crystals
nanocarriers Polymersomes
Nanofibers
Figure 2: Types of (nano)carriers used to increase bioefficacy of phytochemicals. Those developed for oral administration of active
compounds are in italic characters.
(iv) pharmaceutical stability; (i) Screening and preselection of lipid excipients, mainly
(v) release of the active compound in controlled and considering their solubility, dissolution/dispersion
targeted way; properties, digestibility, and absorption. Other factors
are irritancy, toxicity, purity, chemical stability (reg-
(vi) simple preparation methods and easy scale produc- ulatory issues), capsule compatibility, melting point
tion; (depending on the fatty acid composition), and cost
(vii) low risk of side effects (nontoxic).
(ii) Identification of the suitable formulation technique
The present work reviews the novel LBDS (vesicle and lipid for the intended dosage form. Often solid form, devel-
particulate systems and emulsions) as recorded in Figure 2, oped mainly by adsorption on solid carriers [66],
describing the formulation approaches and mechanism of spray drying [67], lyophilization [68], melt extrusion
action. Furthermore, the LBDS combined with Phy in vitro [69], and nanoparticle technology [62], is preferred
and in vivo studies are also listed. over liquid and semisolid forms, which offer low sta-
bility, irreversible drug/excipient precipitation, large
4.1. Formulation Approaches for Oral Lipid-Based Delivery volume of dose, and difficulty of handling and porta-
Systems. LBDS can be obtained by blending excipients such bility
as pure triglyceride oils, mixed glycerides, lipophilic surfac-
(iii) Testing the formulation in appropriate animal models
tants, hydrophilic surfactants, and water-soluble cosolvents,
to predict the in vivo behavior (bioavailability, phar-
which determine the absorption process [65]. Thus, in order
macokinetics, and intestinal lymphatic absorption)
to maximize the success in lipid-Phy formulation develop-
ment and commercialization, it is precise to consider the (iv) Optimization of the formulation based on the Phy
following aspects: loading and dissolution profile.
(I) Gastric digestion
Stomach
Nondispersed oil
(II) Intestinal digestion Gastric lipase

Gall bladder
Oil droplets
Micelles of BS/PL
endogenous
Pancreas
Bile duct
Small intestine
Mixed micelle
Panc. colipase
Small intestine Micelle
Panc. lipase
D D
D
Oil D Vesicles D
droplet
D D
D D
(III) Lipid and active agent absorption
(A) (B) (C) (D) (E)
(A) (C)
(B)
Lipoprotein
Liver Lymph node
Systemic circulation
Figure 3: Mode of action of lipid-based delivery systems designed for the efficient oral administration of phytochemicals. (A) Allowing
paracellular transport by opening tight junction; (B) facilitating transcellular absorption due to increased membrane fluidity; (C) promotion
of phagocytosis via specialized microfold cells (M cells) of Peyer’s patches; (D) increased intracellular concentration and residence time by
surfactants due to inhibition of P-gp and/or CYP450; (E) lipid stimulation of lipoprotein/chylomicron production.
4.2. Mode of Action of Oral Lipid-Based Delivery Systems. The in stomach and the enzymatic and/or chemical degradation
goal of any oral LBDS is to enhance the GI absorption and oral within the GI tract [1, 5, 6, 70].
bioavailability of the active compound. Their mode of action (II) Once in the small intestine, lipid excipients stimulate
involves the alteration of the following physiological effects. bile flow and pancreatic juices excretion [71]. Pancreatic
(I) After oral administration of the lipid-Phy formulation lipase hydrolyzes triglycerols (TG) into free fatty acids (FFA),
and once in the aqueous environment of the stomach, gastric monoglyceride (MG), and diglyceride (DG), which, along
lipase initiates the digestion of formulation lipids. Simul- with bile salts and phospholipids (PL) from gallbladder, form
taneously, peristaltic movements of the stomach facilitate vesicles, micelles, and mixed micelles (Figure 3(II)). These
dispersion of lipid excipients into small droplets (Figure 3(I)). colloidal structures favor solubilization and transportation
This accelerates the solubilization process of Phy in the lipid of Phy until absorption area protecting it from microbiota
base and keeps the Phy in solution for prolonged period, metabolism and enzymatic degradation, prolonging its res-
avoiding its precipitation and protecting it from the low pH idence time, and leading to the uniform distribution of Phy
in the GI tract, which minimizes irritation of gut wall due to including vesicle systems, lipid particulate systems, and
direct contact with Phy [1, 72]. emulsions. Among the vesicle systems, liposomes and phos-
(III) Formation of colloidal systems (vesicles, micelles, pholipid complexes are the most frequently used.
and mixed micelles) that significantly enhances the intestinal
absorption of lipid digestion products and Phy as follows: (i) Liposomes. Liposomes are the most common and well-
(i) Changing Phy uptake by interacting with transport investigated nanocarriers for targeted drug/active delivery.
processes of enterocyte. These include mucoadhesion (inter- The use of liposomes to deliver phytochemicals began
action with mucin to increase membrane fluidity), paracel- in the 1980s as an approach to overcome limitations of
lular transport by modulating tight junctions, and promo- clinical application of these compounds [1]. Conventional
tion of receptor-mediated transport processes (endocytosis, liposomes consist in small spherical vesicles, which present
transcytosis, and phagocytosis) via M cells of Peyer’s patches a simple bilayer membrane enclosing aqueous spaces. The
and other mucosa-associated lymphoid tissues (MALT) lipids mainly used are phospholipids, so that, in an aqueous
(Figure 3(III)(A)–(C)). medium, the hydrophobic tails tend to gather together, while
(ii) Inhibiting efflux transporter P-glycoprotein (P- the hydrophilic heads are exposed towards water, thereby
gp) and metabolism by cytochrome P450 (CYP450) or forming the round-shape vesicles. Amphiphilic nature of
cytochrome 3A (CYP-3A) isozymes (Figure 3(III)(D)). This these systems makes them capable of encapsulating from
increases the intracellular concentration and residence time hydrophilic agents, which can be located within the aqueous
of Phy in enterocyte. core, to hydrophobic substances, which can be embedded
(iii) Enhancing Phy transport to the systemic circulation into the inner fatty acid layers [82–85].
via intestinal lymphatic system [73–75]. Lipid metabolites Liposomes are highly biocompatible and possess self-
stimulate lipoprotein/chylomicron production, which react assembly capacity. They are considered pharmacologically
with Phy molecules enhancing its intestinal lymphatic trans- inactive with minimal toxicity [82–85], although they are not
port (Figure 3(III)(E)). This avoids the first-pass hepatic as immunologically inert as previously suggested [86]. Like-
metabolism, which provides resistance to metabolic pro- wise, conventional liposomes have been shown to increase
cesses, leading to changes in Phy disposition and, finally, in oral bioavailability and bioefficacy of loaded agents by
its pharmacokinetic properties [70, 75].
(i) improving their water solubility and stability;
All of this leads to an enhanced absorption, oral bioavail-
ability, and bioefficacy of Phy, which should allow applying (ii) avoiding their early precipitation and intestinal and
an accurate oral dosage to obtain reproducible results in hepatic degradation;
clinical assays (reduced inter- and intrasubject variability) (iii) leading to drug concentration in tumoral tissues. This
and enhance, thus, the clinical use of Phy therapy. is because liposomes are preferentially delivered and
(IV) In addition of increasing water solubility, absorption, passively accumulate here due to the high interstitial
and oral bioavailability, lipid-based delivery systems have pressure, enhanced vascular permeability and reten-
been shown to tion, and the lack of functional lymphatic drainage of
solid tumors (passive targeting effect) [87, 88];
(i) reduce the effect of coingested food on pharmacoki-
netics of the bioactive molecule [70]; (iv) minimizing side effects.
(ii) increase Phy pharmaceutical stability and lengthen its However, conventional liposomes show some disadvantages
systemic circulation time [76]; that limit their applicability. These include poor stability in
(iii) release Phy slowly over an extended duration (days the systemic circulation and high recognition by reticuloen-
or months) after a single administration (sustained dothelial system (RES), which leads to short circulation time
release) [77]; (short shelf life) and low encapsulation efficacy expulsion of
loaded molecules by intermembrane transfer [89].
(iv) enhance penetration into tumoral matrices, promot- Over the last years, structural and physicochemical prop-
ing more reliable Phy access, and enhance blood- erties of liposomes have been modified to develop different
brain barrier permeability [78, 79]; types of liposomal delivery systems, called nanostructured
(v) modulate the biodistribution of incorporated liposomes, which do not show the drawbacks of the conven-
molecules, which leads to targeted effects and, hence, tional ones [90] (Figure 4). Among them, we find the PEGy-
reduced side effects [1]; lated liposomes, which are modified by adding polyethylene
(vi) overcome multidrug resistance [80]; glycol (PEG) to the surface. This confers steric stabilization
and, hence, higher stability in vivo. Structural modification
(vii) enhance efficiency of codelivery of active ingredients can also consist in the attachment of different types of
and therapeutic agents [81]. ligands (e.g., antibodies, peptides, and carbohydrates) to the
surface or to the terminal end of the attached PEG chains.
4.3. Types of the Main Oral Lipid-Based Delivery Systems and These systems, which are called ligand-targeted liposomes,
Their Applications are used for specific (active or physicochemical) targeting
[91, 92]. Finally, to develop more efficient drug delivery
4.3.1. Vesicle Systems. As indicated in Figure 2, lipid-based systems, multifunctional liposomal formulations, also called
delivery systems can be classified in three categories, theranostic liposomes, have been recently developed. These
(A) Conventional liposome (D) Theranostic liposome

Hydrophobic
drug
Targeting ligand
Positively
charged lipid +
Negatively
charged lipid −
Hydrophobic Functionalized
Imaging agent
drug
Polyethylene
glycol (PEG) PEG
Small molecule
Carbohydrate
Peptide
Antibody
Protein
(B) PEGylated liposome (C) Ligand-targeted liposome
Figure 4: Schematic representation of the different types of liposomal drug delivery systems: (A) conventional liposome; (B) PEGylated
liposome; (C) ligand-targeted liposome; (D) theranostic liposome (reprinted from Frontiers in Pharmacology, 6, article 286, 1–12. Advances
and Challenges of Liposome Assisted Drug Delivery, by Sercombe et al. [87], with permission from the authors).
carriers usually consist of the nanoparticle, the therapeutic (ii) Phospholipid-Phytochemical Complexes (Phytosomes).
agent, an imaging component, and one or more targeting Several plant bioactive compounds and extracts, mainly con-
ligands which enhance their accumulation in pathological stituted by polyphenols and terpenoids, are conjugated with
sites and promotes organelle-specific delivery. In this sense, naturally occurring phospholipids, as phosphatidylcholine
theranostic liposomes can be used as therapeutic and diag- (PC), in a ratio of 1 : 1 or 1 : 2 (w : w). This formulation strategy
nostic tool at the same time [87, 91]. leads to the formation of the patented complexes called
The stability in vitro and in vivo of nanostructured Phytosomes. Like liposomes, structure of these complexes
liposomes as well as the release profile of the loaded agent consists in spherical vesicles with a bilayer membrane of
is determined by the liposome surface charge, particle size, phospholipids, in which the hydrophilic heads are exposed
lipid composition, and number of lamellae and the nature of towards the aqueous medium, while the hydrophobic tails
polymers and ligands attached to their surface [85, 93]. remain together in the inner layer. Unlike liposomes, the
Nanostructured liposomes have been adopted in recent active agent is not located within the aqueous core, but it
years for the efficient oral delivery of several Phy with poor binds to the polar end of phospholipid through weak chem-
water solubility and stability in the gastric environment ical bonds, and the nonpolar portion of the phospholipid
(Table 5). Thus, for instance, vinorelbine, a chemotherapeutic remains free [96, 97]. Phy-loaded phytosomes are highly
obtained by semisynthesis from alkaloids extracted from the biocompatible and bioavailable as compared to unloaded
rosy periwinkle (Catharanthus roseus), has been loaded into Phy. Incorporation into phytosomes increases the enterocyte
a cholesterol-polyethylene glycol (cho-PEG) coated liposome cell membrane permeability of Phy and, hence, the amount
with the purpose of increasing circulating half-life and reaching the systemic circulation. Likewise, phytosomes offer
reducing severe side effects of this agent [94]. Likewise, N- a controlled and sustained Phy release pattern, which leads to
trimethyl chitosan chloride- (TMC-) coated liposomes for a longer action time and, therefore, to the need of a reduced
the oral delivery of curcumin were found to be a promising Phy dose [96, 97].
strategy to reduce toxicity and increase therapeutic index Silybin was the first bioactive compound marketed as
[88]. Phytosome formulation. Phospholipid complexation signif-
Moreover, brucine, an alkaloid isolated from Strychnos icantly increased the water solubility and liver protection of
nux-vomica L. (Loganiaceae), produced impressive dose- silybin, which resulted in an increase of its oral bioavailability
dependent antitumor effects by causing apoptosis. However, and pharmacological activity [98]. In a comparative phar-
brucine was characterized by a narrow therapeutic index, macokinetic study using an equimolar dose of silybin and
and high doses of brucine cause severe central nervous its complex, the plasma 𝐶max of silybin after four hours was
system toxicity. Brucine-loaded stealth liposomes enhanced <35 ng/mL, whereas, for the silybin complex, it was 112 ng/mL
antitumor activity and decreased distribution to the brain [99]. Similarly, quercetin loaded-phytosome showed a water
[95], which, therefore, considerably improved its therapeutic solubility 12-fold higher than free-form quercetin. However,
index. complexation did not affect its antioxidant activity [100].
higher control release and specific delivery of the loaded

agent, which minimizes side effects [109]. LNPs show other
benefits as compared to other systems, including ease of
Solid lipids
preparation and high scale production and sterilization [110,
+ 111], excellent physical stability, and chemical versatility.
Solid lipids
Liquid lipids Moreover, incorporation into the nanoparticle matrix can
protect molecules from light, moisture, chemical degrada-
tion, and oxidation [109] and favor their penetration through
mucus barrier due to nanosize [103, 112–114].
SLNs NLCs
(i) Solid Lipid Nanoparticles (SLNs). Despite all these advan-
tages, applicability of SLNs presents several limitations such
Lipid monolayer enclosing a Lipid monolayer enclosing a
as the growth of matrix lipid particles, high water content,
solid lipid core of solid lipids solid lipid core of solid and
ease of gelation, and unpredictable polymorphic transitions,
liquid lipids
resulting in poor loading capacity [115–117]. In general,
Figure 5: Structure of solid lipid nanoparticles (SLNs) versus drug molecules stay in between the fatty acid chains or
nanostructured lipid carriers (NLCs). as amorphous clusters in crystal imperfections within SLN
matrix. However, during SLN storage time, a transition of
lipids to a low-energetic form can occur, giving rise to a
perfect crystalline structure with very little space for the
Ginkgo biloba L. and green tea extracts have been also drug molecules. This promote the expulsion of encapsulated
loaded into phytosomes. Ginkgo biloba L. phytosome was molecules, especially when SLN matrix is composed of a
supplied via oral to rats and, then, the pharmacokinetic highly purified lipid, which results in a nanoparticle low
profile of the major flavonoids of the extract (quercetin, incorporation capacity and a changing release profile with
kaempferol, and isorhamnetin) was evaluated by measuring storage time [103, 113].
their plasma 𝐶max , AUC0 , and 𝑇max . Pharmacokinetic param-
eters of the three flavonoids were significantly improved after (ii) Nanostructured Lipid Complexes (NLCs). To overcome
formulation, demonstrating that complexation with phos- SLNs drawbacks, NLCs have been developed as alternative
pholipids leads to a large increase in Phy oral bioavailability carrier systems. The presence of liquid lipids (oil) in the
[101]. Likewise, phytosome of green tea extract, principally solid matrix makes more imperfections to accommodate
represented by (−)-epigallocatechin 3-O-gallate, showed an more active molecules than SLNs, which reduces the active
enhanced absorption of catechins as compared to unloaded molecule expulsion and enhances the nanoparticle loading
green tea catechins [102]. capacity. Furthermore, the release and delivery of the active
compound can be easily modulated by changing the lipid
4.3.2. Lipid Particulate Systems: SLNs and NLCs. Generally, composition of matrix [113]. NLCs present a lower water
there are two types of lipid nanoparticles (LNPs), solid content than SLNs and no significant differences regarding
lipid nanoparticles (SLNs) and nanostructured lipid carriers biotoxicity have been observed [118].
(NLCs) [103]. Both SLNs and NLCs have spherical shape Table 5 shows in vitro/in vivo studies where SLNs and
and their average size usually ranges from 40 to 1000 nm. NLCs have been applied for the efficient oral delivery of
LNPs can be produced by several techniques such as high- antitumor Phy, mainly flavonoids, with limited therapeutic
pressure or high-speed homogenization, supercritical fluid potential [119]. Thus, for instance, Luo et al. [120, 121]
extraction of emulsions, solvent emulsification/evaporation, investigated the effect of loading puerarin, an isoflavonoid
spray drying, and ultrasonication [104–106]. derived from Radix Puerariae, into SLNs, including phar-
LNPs are composed of a lipid solid matrix lipid and sur- macokinetics, tissue distribution, and relative bioavailability
factants that provide stability [107]. SLN matrix is constituted in rats. When incorporated into the SLNs, puerarin was
by biocompatible, biodegradable, and GRAS solid lipids, rapidly absorbed and its relative oral bioavailability was
which are solid at room and body temperature (e.g., highly improved more than 3-fold as compared with that of the
purified triglycerides, partial glycerides, fatty acids, and puerarin suspensions. In addition, SLNs produced increased
steroids) [108]. The matrix of NCLs is also solid at room/body tissue concentrations in puerarin target organs, particularly
temperature; however, unlike SLNs, often it is composed of heart and brain. Likewise, triptolide, a diterpenoid epoxide
a mixture of solid and liquid lipids [101]. Figure 5 shows a isolated from Tripterygium wilfordii with anti-inflammatory,
scheme of these formulations, where structural differences anticystogenesis, and anticancer effects, showed enhanced
between both LNPs are observed. clinical efficacy and minimized side effects (irritation of the
In the last years, a great attention has been paid to LNPs gastrointestinal tract) after encapsulation into SLN [122]. This
as an interesting and cost-effective alternative to polymeric was attributed to the solubilization of triptolide during GI
nanoparticles, liposomes, and emulsions. LNPs are cheaper digestion by the SLN matrix and colloidal mixed micelles
and safer than polymeric carriers, as their production is an (Figure 4), avoiding its precipitation and degradation as well
organic solvent-free process [103]. Likewise, compared to as the GI irritation caused by insolubilized crystals. Moreover,
conventional liposomes, nanoparticle solid matrix allows a SLNs minimize direct contact of triptolide with the mucosal
surface and lead to a gradual release, avoiding high local and conditions, such as temperature, ionic strength, and com-
irritating concentrations. position (adding/removing molecules to/from the aqueous
Several Phy have been also loaded into NLCs in studies continuous phase), which may compromise their stability. In
focused on improving water solubility, enhancing GI absorp- addition, MEs formation requires the use of relatively large
tion and oral bioavailability, controlling release, increas- amounts of synthetic surfactants to achieve an efficient load-
ing stability, and lengthening circulation time by reducing ing capacity, especially when using triglycerides as dispersed
the recognition by the reticuloendothelial system (RES) oil phase [126].
(Table 5). The flavonoid silymarin has been used clinically Nanoemulsions (NEs), often also called miniemulsions,
to treat several hepatic disorders without a high efficiency. are systems with droplet-like structure. They are formed by
To improve oral absorption, silymarin-loaded NLCs were an oil phase, an aqueous phase, and a mixture of surfactants
developed [123]. These formulations showed fast in vitro and cosurfactants stabilizing droplets, whose average size
lipid digestion, suggesting that NLCs may facilitate the rapid is significantly (10-fold or so) smaller than that of droplets
silymarin absorption, and gave rise to relative silymarin present in conventional emulsions [126]. Like MEs, they
bioavailability 2.54- and 3.10-fold greater than that produced are optically transparent and show low viscosity. Moreover,
by marketed LEGALON and solid dispersion pellets, respec- although NEs do not form spontaneously and have been
tively. The ability of NLCs to enhance absorption was con- shown to be thermodynamically unstable, they show high
firmed in other studies using tripterine, a triterpenoid from kinetic stability, which can be for several years. As compared
the Celastraceae family, extracted from the Chinese herbal to MEs, these systems are much less sensitive to changes of
plant Tripterygium wilfordii [124]. More recently, various environmental conditions and require lower amounts of
novel and complex NLCs have emerged as carrier designed synthetic surfactants to be formed due to their higher loading
to achieve specific functions. For example, cell penetrating capacity [126].
peptide- (CPP-) coated NLCs loaded with tripterine notice- Application of MEs and NEs as carriers for the efficient
ably enhanced antitumor activity in vitro in prostate tumor oral administration of Phy is shown in Table 5. Hydroxysaf-
cells, as well as in prostate tumor-bearing mice [124]. Ionic flor yellow A (HSYA) is a flavonoid derived and isolated
complex loaded NLCs enhanced the encapsulation efficiency, from the safflower plant (Carthamus tinctorius L.) that has
improved lipophilicity, and produced sustained release in vivo been shown to possess antioxidant and anti-inflammatory
[95]. actions, antiplatelet aggregation, and antitumor properties as
well as antimyocardial injury effects [128, 129]. Unlike other
4.3.3. Emulsions flavonoids, water solubility of HSYA is high; however, it has
very poor permeability, which limits its GI absorption, oral
(i) Microemulsions and Nanoemulsions. Microemulsions bioavailability, and bioefficacy. Qi et al. [130] developed a
(MEs) are optically isotropic systems with special features, HSYA-loaded ME (w/o), which showed a bioavailability ca.
including an average particle size that ranges from 10 to 19-folds higher than that of the unloaded compound. MEs
100 nm; spontaneous formation, that is, without any energy have been also used to deliver poor water-soluble and sta-
input; thermodynamic stability; optical transparence or slight ble Phy, such as elemenes (sesquiterpene). Elemene-loaded
opalescence; and low viscosity and allergenicity. All this emulsions have been used clinically as antitumor agents.
makes them very attractive delivery systems [125]. However, due to their poor stability and water solubility, the
MEs are constituted by an oil phase, an aqueous phase, a oral bioavailability of these emulsions was only 18.8%. An o/w
surfactant, and, probably, a cosurfactant [126]. When there elemene-loaded ME was then prepared [131]. This showed
are similar amounts of oil and water, a bicontinuous ME high entrapment efficiency of 99.81% and significantly higher
is usually formed, in which both phases form continuous stability than a normal emulsion, which led to a relative
domains separated by surfactant-stabilized interfaces. Other- bioavailability 1.63-fold greater than that of the conventional
wise, when amounts of oil and water are not similar, MEs with emulsion (Table 5).
droplet-like structure are formed, which can be water-in-oil
(w/o) or oil-in-water (o/w) MEs depending on the major (ii) Self-Emulsifying Delivery Systems. A further and very suc-
compound. cessful approach to overcome problems associated with poor
Like other promising carriers, MEs have been shown to water solubility of Phy is self-emulsifying delivery systems
improve oral delivery of bioactive compound by (i) enhanc- (SEDSs), self-microemulsifying delivery systems (SMEDSs),
ing stability and permeability, (ii) allowing a controlled and and self-nanoemulsifying delivery systems (SNEDSs). These
sustained release, and (iii) improving GI absorption and oral systems consist in isotropic mixtures, which include a large
bioavailability via the lymphatic transport pathway [1, 127]. In variety of liquid or waxy excipients available, ranging
this respect, it has been found that this absorption pathway from oils through biological lipids (natural/synthetic oil)
can be significantly favored by w/o MEs as compared to and hydrophobic and hydrophilic surfactants to water-sol-
o/w MEs. In addition, due to their special features, MEs uble cosolvents, generally regarded as safe (GRAS) status
offer further advantages, such as ease of preparation, high [132]. Moreover, additives like 𝛼-tocopherol, 𝛽-carotene, and
capacity to solubilize hydrophilic, and lipophilic compounds propyl gallate can be added to prevent the oxidation of
and long-term stability. SEDSs-Phy formulations [133].
Despite their numerous advantages, MEs present some Unlike all the previously described lipid formulations,
limitations. They are sensitive to changes of environmental these systems have a unique property: they remain in
a preformulation state until ingestion. Upon dilution in these studies are summarized in Table 5. Thus, for instance,
aqueous physiological fluids of GI tract and with the gentle the self-double emulsifying formulation of Hydroxysafflor
agitation provided by peristaltic movements, SEDSs are able yellow A (HSYA) was developed using phospholipid dis-
to spread readily and self-emulsify spontaneously, forming solved in Labrafac, Lipophile WL1349, Tween 80, and oleic
fine o/w emulsions (50 nm > droplet size > 250 nm), that acid. The formulation results in 20-fold increase in 𝐶max and
keep the active agent in solubilized form [134–136]. SEDDS 35-fold rise in AUC value of Phy as compared to the aqueous
formulations (oil, 40–80% (HLB < 12), 20–60%) commonly solution [143, 144]. The SMEDS of gentiopicrin obtained from
give rise to opaque dispersions with particle sizes >250 nm, the roots of gentians was formulated using phospholipids
while SMEDS formulations (oil, 40–80% (HLB > 11), 20–40%; in Labrasol as oil phase and Cremophor EL and Transcutol
hydrophilic cosolvents, 0–40%) disperse into smaller droplets P as other excipients. The SMEDS of gentiopicrin with
with particle sizes between 50 and 250 nm, leading to opti- phospholipids enhanced the relative bioavailability of Phy
cally clear or slightly opalescent microemulsions. SNEDS to 703.62% as compared to gentiopicrin alone. Similarly,
formulations (oil, <20% (HLB > 11), 20–50%; hydrophilic the phospholipid complex of morin (MPC) was developed
cosolvents, 20–50%) further disperse in GI fluids, giving rise as SNEDS using Labrafil M1944 CS, Cremophor RH 40,
to nanoemulsions with a droplet size less than 50 nm and and Transcutol P as excipients which exhibited a significant
completely transparent [9, 62]. increase in 𝐶max , 𝑇max , and relative oral bioavailability (6.23-
The reduction in emulsion particle size of these formu- fold) as compared to the morin suspension [145]. Likewise,
lations once in the GI tract increases the surface area of lutein formulated as SNEDDS demonstrated having imme-
particles, which, in turn, provides higher interfacial surface diate dissolution (within 5 min) as compared to commercial
area and a very low interfacial tension. This provides SEDSs product of lutein (Eyelac) where there is no dissolution
with a high capacity to solubilize the loaded Phy in the GI within specific time [146]. Many other studies have been car-
tract and to enhance its release and absorption and oral ried out to enhance oral bioavailability and therapeutic effect
bioavailability [136–138]. It should be noted that droplet size of other plant active compounds, including apigenin, berber-
of o/w emulsions formed after self-emulsification inside the ine hydrochloride (BBH), puerarin, hesperidin, quercetin,
body and, hence, capacity of SEDSs to act as efficient Phy curcumin, baicalin, oleanolic acid, vinpocetine, nobiletin,
carriers is highly determined by the excipient combination oridonin, and silymarin.
used in the formulation of these systems. Therefore, selection
of excipients is a quite challenging task that should be 5. Other Approaches to Increase Bioefficacy of
considered. Antitumor Phytochemicals
Besides improving oral bioavailability of poor water-
soluble Phy, SEDSs show multiple advantages. Among them 5.1. Oral Codelivery of Phytochemicals and Chemotherapeutic
are the following: Drugs. Combined cancer therapy consisting in (i) the com-
(i) Formulation surfactants increasing the intestinal per- bined application of some of the most common types of can-
meability, which decreases surface tension and facili- cer treatment, including surgery, radiotherapy, chemother-
tates formulation contact with intestinal mucus [139] apy, targeted therapy, and immunotherapy or (ii) the coad-
ministration of different chemotherapy drugs, is often more
(ii) SEDSs protecting loaded Phy against enzymatic effective. The rationale for combination chemotherapy is
degradation and avoid its first-pass hepatic metabo- to use drugs that work by different mechanisms, thereby
lism decreasing the likelihood that resistant cancer cells will
(iii) SEDSs providing higher loading capacity than con- develop. Moreover, when drugs with different effects are
ventional lipid solutions combined, each drug can be used at its optimal dose, without
(iv) Thermodynamic stability intolerable side effects [147].
(v) Ease of manufacture and scale-up. These advantages Following the same rationale, it is believed that codelivery
make SEDS unique when compared to other drug of antitumor drugs and plant bioactive compounds could
delivery systems like solid dispersions, liposomes, improve therapeutic effects by targeting diverse molecular
nanoparticles, and so forth [140–142] targets, reducing toxicity, overcoming drug resistance, and
facilitating the use of lower and safer doses [1]. Thus, as
(vi) Ease of administration and versatility of dosage form, observed in Table 3, there are many in vitro and in vivo studies
in either liquid or solid form. Liquid dosage forms as well as some clinical trials focused on demonstrating the
can be administered in soft or hard gelatin capsules potential synergistic effect when codelivering phytochem-
but these have shown some drawbacks, such as high icals, mainly polyphenols, and first line chemotherapeutic
production costs, low drug compatibility and stability, agents [148, 149].
drug leakage and precipitation, capsule ageing, and Codelivery strategy is, however, usually limited by low
need of a large quantity of surfactants (30–60%), water solubility, poor oral bioavailability, undesirable phar-
which can induce GI irritation. These disadvantages macokinetic characteristics, and side effects [1]. In this sense,
are overcome by formulating SEDS as solid forms by incorporation of two or more molecules (Phy + Phy or
extrusion/spheronization methods [72]. Phy + drug) in one nanocarrier seems to be a promising
The delivery of poorly water-soluble Phy using SEDSs has way to increase the bioefficacy of codelivery method. It
been extensively studied during the past decade and many of has demonstrated to (i) improve water solubility and oral
Journal of Oncology
Table 3: Phytochemicals combined with first-line antitumor drugs and their study in clinical trials. Nanocarriers used to enhance bioefficacy of codelivery are also shown.
Phytochemical Codelivered antitumor agent In vitro/in vivo Clinical trial Phase of study Ref.
5-Fluorouracil Colon — — [279]
Ellagic acid Vinorelbine — Hormone refractory prostate cancer Completed [167]
𝛼-Difluoromethylornithine Colon — — [280]
Tamoxifen + sulindac Lung — — [281]
(−)-Epigallocatechin-3-gallate (EGCG)
Sulindac Intestinal — — [281]
Tamoxifen Breast — — [282]
Pancreas
Gemcitabine hydrochloride Breast Completed [283–285]
Osteosarcoma
Decitabine — Pediatric solid tumors, leukemia Recruiting [286]
Decitabine — Non-small cell lung Completed [287]
Kidney cancer
Interleukin-2 (high-dose) — Completed [288]
Melanoma
5-Fluorouracil Colon — — [289]
Prostate
Lung
Docetaxel — — [290]
Genistein Breast
Pancreas
Prostate
Lung [290]
Doxorubicin — —
Breast
Pancreas
Ovarian
Prostate
Cisplatin Lung — — [290, 291]
Breast
Pancreas
Erlotinib — Pancreas Completed [292]
Erlotinib + gemcitabine Pancreas Pancreas Completed [293, 294]
Luteolin Celecoxib Breast — — [295]
17
18
Table 3: Continued.
Phytochemical Codelivered antitumor agent In vitro/in vivo Clinical trial Phase of study Ref.
Docetaxel Prostate — — [296]
Esophageal
5-Fluorouracil Colorectal — — [297–299]
Quercetin Liver
Sulindac Colorectal Colon Completed [300]
Tamoxifen Breast — — [301]
Paclitaxel Liver — — [302]
Rapamycin Breast — — [303]
Doxorubicin Breast — — [304]
Resveratrol Temozolomide Glioma — — [305]
5-Fluorouracil Colon [306]
Mitomycin Colorectal — — [307]
Irinotecan Colorectal Colorectal Active [308, 309]
Folfox Colon Active [310]
Sulindac Lung Colorectal Completed [224, 311]
Capecitabine Rectal Active [311]
5-Fluorouracil Colorectal — — [312]
Curcumin
Dasatinib Colon — — [313]
Paclitaxel Breast [314]
Celecoxib Colon [315]
Gemcitabine Lung — — [316]
Genistein Prostate — — [317]
Lycopene Docetaxel Prostate Adenocarcinoma of the prostate Active [318, 319]
Journal of Oncology
Table 4: Overview of nonlipid formulations, which have been designed to administer phytochemicals by oral route.
Lipid-based formulation
Active ingredient Effect of formulation Ref.
Type Subcategory
Overcome multidrug resistance and increased
Curcumin [320]
a
PLGA -NPs oral bioavailability in vivo.
In vitro sustained release and enhanced
Silymarin [321]
cytotoxicity.
Curcumin Hydroxypropyl cellulose NPs Temperature-dependent release in vitro. [322]
Puerarin
Curcumin PBDS
Increased in vitro oral bioavailability and reduced [323,
Resveratrol Dendrimers
side effects. 324]
Genistein
Podophyllotoxin
Improved water solubility, stability, and
Hyaluronic acid conjugate [325]
Curcumin antitumoral activity in vitro.
Higher water solubility, stability, and cytotoxicity
Alginate conjugate [326]
in vitro.
Rutin CD inclusion 𝛼-CD, 𝛽-CD, HP-𝛽-CD, and Improved water solubility and stability, increasing [327]
3-EGCG complexes DM-𝛽-CDb the oral bioavailability and bioefficacy. [328]
Silymarin (Silybum
Inorganic Sustained release and enhanced oral [321]
marianum) Porous silica nanoparticles (PSN)
nanocarriers bioavailability in vivo.
Silybin meglumine [329]
TCCc - liposomes Improved absorption and oral bioavailability and [330]
Resveratrol reduced side effects in vivo In vitro controlled
DQA-PEG1930 -DSPEa liposomes [153]
release and in vivo enhanced targeting and
Hybrid nanocarriers Dextran-sulfate-SLNs reduced side effects [331]
Vincristine
PLGA-PEG-R7a NPs Overcome multidrug resistance. [332]
Tripterine CPPa -NLCs Enhanced in vitro and in vivo antitumor activity. [118]
Silymarin Liquid crystalline nanocarrier [333]
Sustained release.
Other novel Folate-modified lipid
Quercetin Improved water solubility, oral bioavailability, and [334]
nanocarriers nanocapsules biological activity (active targeting-liver) in vivo.
Tetrandrine Lipid nanocapsules [335]
a
PLGA: poly(lactic-co-glycolic acid); PEG: polyethylene glycol; R7 is a cell-penetrating peptide; DQA: dequalinium; DSPE: polyethylene glycol-
distearoylphosphatidylethanolamine; R7 is a cell-penetrating peptide (CPP).
b
𝛼/𝛽-CD: alpha/beta-cyclodextrin; HP-𝛽-CD: hydroxypropyl-𝛽-cyclodextrin; DM-𝛽-CD: dimethyl-𝛽-cyclodextrin.
c
TCC: N-trimethyl chitosan chloride-coated.
bioavailability; (ii) suppress drug resistance, by inhibiting Likewise, in recent years, topical delivery of bioactive
transporter mediated efflux; (iii) delay adaptation processes; compounds has also drawn great attention owing to its
(iv) retard cells mutations; (v) produce synergistic therapeutic advantages over other administration routes and outstanding
effect through the simultaneous delivery of multiple agents to contribution in improving local action [151] or systemic
the action site; and (vi) minimize side effects [1, 150]. absorption, which can minimize the first-pass effect [152].
In this sense, few Phy described in Table 3 have been Nevertheless, this application also shows several barriers that
coencapsulated or coloaded in one oral nanocarrier. Querce- limit its use, including low skin permeation, short biological
tin + tamoxifen was administrated through PLGA nanoparti- half-life, presystemic metabolism, or systemic toxicity [1].
cles, while quercetin + paclitaxel was administrated through On the other hand, and to get over limitations of
parenteral and topical administration routes, application of
CQ-PM and curcumin + genistein through NLC.
nanocarriers has demonstrated to be also an efficient formu-
lation strategy. Table 6 shows and overviews the lipid and
5.2. Parenteral and Topical Administration of Phytochemicals nonlipid formulations specifically designed to parenteral and
as Alternative to the Oral Route. To overcome limitations in topical Phy administration. In case of the parenteral route,
the oral administration of poor water-soluble Phy, parental most of the investigations have focused on utilizing carriers
(intravenous and intraperitoneal) and topical (transdermal, to enhance antitumor efficiency through passive targeting
nasal, and ocular) administration routes can be used to or active targeting [153, 154], controlling drug release at the
increase dose precision and clinical efficacy. tumor site to minimize side effects [155, 156], or overcoming
Table 5: Overview of lipid-based delivery systems to administer phytochemicals by oral route.
Active ingredient Lipid-based formulation Effect of formulation Ref.

Reduced side effects and increased circulation half-life.
Vinorelbine [94]
Improved therapeutic effect in vivo.
Gypenoside Activated in vitro immune response in macrophages. [335]
Liposomes
Curcumin Improved pharmacokinetics and oral bioavailability in vivo. [329, 336]
3-EGCG Enhanced in vitro antitumor activity. [337]
Improved absorption and oral bioavailability, enhanced
Brucine [338, 339]
targeting, and reduced side effects in vivo.
Quercetin
Kaempferol [101]
Enhanced membrane permeability, sustained and controlled
Isorhamnetin release.
Phytosome
Silybin Enhanced absorption, oral bioavailability, and bioefficacy. [98, 99]
3-EGCG [102]
Quercetin [100]
𝛽-Elemene [131]
Increased water solubility and permeability and improved oral
Hydroxysafflor yellow A Microemulsions [130]
bioavailability.
Puerarin [127, 340]
Enhanced stability, oral bioavailability, and targeting effects in
Baicalin SEDS [134]
vitro and in vivo.
Curcumin [341]
Indirubin [88]
Hydroxysafflor yellow A [143, 144]
Gentiopicrin [341]
Lutein [342]
Apigenin [343]
Enhanced stability, oral bioavailability, and targeting effects in
Nobiletin SMEDS [137]
vitro and in vivo.
Oridonin [139]
Silymarin [140]
Puerarin [344]
Hesperidin [345]
Berberine hydrochloride
[346]
(BBH)
Morin [145]
Curcumin [347]
Lutein SNEDS Enhanced stability, oral bioavailability, and targeting effects in [146]
vitro and in vivo.
Oleanolic acid [348]
Vinpocetine [349]
Puerarin [120, 121]
Triptolide Improved absorption and oral bioavailability and reduced side [350]
SLNs
Cantharidin effects (irritation of GI mucous membrane) in vivo. [351]
Resveratrol [352]
Silymarin [123]
Increased absorption and oral bioavailability in vivo.
Tripterine NLCs
Enhanced in vitro and in vivo antitumor activity. [124]
Curcumin
multidrug resistance [157]. Parenteral nanocarriers include active compounds into nanocarriers aims to enhance skin
either lipid formulations (liposomes, SLNs, and NCLs) or permeation and stability, lengthen systemic circulating time,
polymer formulations (polymeric NPs and polymer-bioactive and minimize metabolic degradation and systemic toxic-
conjugates). For topical application, the incorporation of ity. Thus, for instance, MEs provide a safe, effective, and
Table 6: Overview of lipid and nonlipid formulations, which have been designed to administer phytochemicals by parental and topical routes.
Lipid-based formulation
Phytochemical Effect of formulation Admin. route Ref.
Type Subcategory
Curcumin LBDS NLCs Enhanced stability and brain targeting in Intraperitoneal [353]
Baicalein Tocol-NLCs vivo. [354]
Less irritating and toxic and enhanced
𝛽-Elemene bioavailability and antitumor efficacy in [355]
NLCs
vivo.
LBDS
Reduced toxicity and improved
Bufadienolides Intravenous [356]
pharmacokinetic profile in vivo.
Ionic-complex-based Sustained-release and protection against
Breviscapine [357]
NLCs liver enzyme degradation in vivo.
DQA-PEG2000 -DSPEa
Berberine Overcome multidrug resistance in vivo. [358]
liposomes
Quercetin [158]
Genistein MEs Increased permeation and skin retention. [159]
Chlorogenic acid Efficient systemic distribution in vivo. [160]
Resveratrol
Increased stability and anti-inflammatory
Curcumin PEGa liposomes Transdermal [359]
effects in vivo
Reduced toxicity and enhanced
Bufadienolides LBDS Poloxamer-liposomes [360]
antitumor efficacy in vivo.
Enhanced skin permeation in vitro and
Ligustrazine phosp. [152]
bioactivity in vivo.
Ethosomes
Enhanced anti-inflammatory effects in
Apigenin [361]
vivo.
Enhanced antitumor activity and brain
Curcumin NLCs Intranasal [362]
targeting in vitro.
Reduced irritation of eye mucous
Tetrandrine Charged SLNs Ocular [363]
membrane in vivo.
Inorganic Enhanced efficacy and reduced toxicity in Intratumoral
3-ECGC Gold NPs [155]
carriers vivo. injection
Dextran Controlled release and targeted effect
Curcumin [364]
sulfate-chitosan NPs against tumor cells in vitro.
In vivo anticancer effect on hepatic tumor
Curcumin Chitosan/PBCAb NPs Intravenous [365]
PBDS cells.
Higher in vivo liver targeting effect and in
Trans-resveratrol Chitosan-NPs
vitro cytotoxicity on hepatic cancer cells. [366–368]
Galactosylated Enhanced targeting and binding to the
Oridonin
chitosan NPs specific site of action (liver).
Polymeric micelles Achieving site-specific cell targeting and
Artemisinin Targeted polymeric enhancing intracellular drug [369]
micelles accumulation.
PBDS Cellular uptake, in vivo biodistribution, Intraperitoneal
Transferrin modified
Resveratrol and antitumor activity. Targeted therapy [370]
PEG-PLAc conjugate
of glioma.
Biotinylated chitosan Enhanced targeting and binding to the
Bufalin [371]
NPs specific site of action breast carcinoma.
In vitro and in vivo enhanced skin
Quercetin PBDS Lecithin-chitosan NPs Topical [371]
permeation.
a
PEG: polyethylene glycol; DQA: dequalinium; DSPE: polyethylene glycol-distearoylphosphatidylethanolamine.
b
PBCA: poly(butyl cyanoacrylate).
c
PLA: polylactic acid.
noninvasive means to topically deliver Phy such as quercetin [2] M. González-Vallinas, M. González-Castejón, A. Rodrı́guez-
[158], genistein [159], and chlorogenic acid and resveratrol Casado, and A. Ramı́rez de Molina, “Dietary phytochemicals
[160]. Other nanocarriers used for the topical delivery of Phy in cancer prevention and therapy: a complementary approach
include liposomes, ethosomes, NLCs, polymeric NPs, and with promising perspectives,” Nutrition Reviews, vol. 71, no. 9,
polymer-bioactive conjugates (Table 6). pp. 585–599, 2013.
[3] K. W. Lee, A. M. Bode, and Z. Dong, “Molecular targets of
phytochemicals for cancer prevention,” Nature Reviews Cancer,
6. Conclusions vol. 11, no. 3, pp. 211–218, 2011.
Phy are molecules obtained from natural plant species and in [4] R. H. Liu, “Potential synergy of phytochemicals in cancer
the last decades have shown their positive benefits in human prevention: mechanism of action,” The Journal of Nutrition, vol.
health, in prevention and treatment. 134, no. 12, pp. 3479S–3485S, 2004.
In the framework of cancer, polyphenols are the most [5] A. R. Bilia, B. Isacchi, C. Righeschi, C. Guccione, and M. C.
studied group of phytochemicals, in both the in vitro/in vivo Bergonzi, “Flavonoids loaded in nanocarriers: an opportunity
to increase oral bioavailability and bioefficacy,” Food and Nutri-
studies and clinical trials, with promising expectative, includ-
tion Sciences, vol. 5, no. 13, pp. 1212–1327, 2014.
ing the lack of side effects. Regarding terpenes, phytosterols,
[6] C. J. H. Porter and W. N. Charman, “In vitro assessment of oral
and organosulfur phytochemicals, they show hopeful results
lipid based formulations,” Advanced Drug Delivery Reviews, vol.
in breast, colon, and prostate models, although there are few
50, supplement 1, pp. S127–S147, 2001.
clinical trials that started to confirm their effects in human
[7] F. Aqil, R. Munagala, J. Jeyabalan, and M. V. Vadhanam,
models, compared with polyphenols.
“Bioavailability of phytochemicals and its enhancement by drug
The bioavailability of these compounds still adheres to delivery systems,” Cancer Letters, vol. 334, no. 1, pp. 133–141,
measure urine levels as a routine parameter, but many authors 2013.
defend the use of carriers to improve their availability in [8] S. Kalepu, M. Manthina, and V. Padavala, “Oral lipid-based drug
plasma and in targeted organs. This need is reflected in the delivery systems—an overview,” Acta Pharmaceutica Sinica B,
development of new delivery mechanisms, where lipid-based vol. 3, no. 6, pp. 361–372, 2013.
delivery systems are part of a strategy to increase the water [9] H. Shrestha, R. Bala, and S. Arora, “Lipid-based drug delivery
solubility and stability, prevent the rapid systemic clearance, systems,” Journal of Pharmaceutics, vol. 2014, Article ID 801820,
prevent the intestinal and hepatic metabolism, enhance the 10 pages, 2014.
bioavailability, and enhance the cancer cell targeting. The [10] T. M. Gibson, L. M. Ferrucci, J. A. Tangrea, and A. Schatzkin,
importance of measuring tissue levels of the chemopreventive “Epidemiological and clinical studies of nutrition,” in Anony-
agents would help to better understand the mode of action of mous Seminars in Oncology, pp. 282–296, Elsevier, Amsterdam,
the nanoparticles and phytochemicals and to avoid toxicity of Netherlands, 2010.
both. [11] T. Norat, C. Scoccianti, M.-C. Boutron-Ruault et al., “European
code against cancer 4th edition: diet and cancer,” Cancer
Epidemiology, vol. 39, supplement 1, pp. S56–S66, 2015.
Conflicts of Interest
[12] A. Umar, B. K. Dunn, and P. Greenwald, “Future directions in
All the authors declare that there are no conflicts of interest cancer prevention,” Nature Reviews Cancer, vol. 12, no. 12, pp.
regarding the publication of this paper. 835–848, 2012.
[13] S. Ramos, “Cancer chemoprevention and chemotherapy:
dietary polyphenols and signalling pathways,” Molecular Nutri-
Authors’ Contributions tion and Food Research, vol. 52, no. 5, pp. 507–526, 2008.
[14] W.-Y. Huang, Y.-Z. Cai, and Y. Zhang, “Natural phenolic
Lamia Mouhid and Marta Corzo-Martı́nez contributed
compounds from medicinal herbs and dietary plants: potential
equally to the manuscript.
use for cancer prevention,” Nutrition and Cancer, vol. 62, no. 1,
pp. 1–20, 2010.
Acknowledgments [15] T. Iwashina, “The structure and distribution of the flavonoids in
plants,” Journal of Plant Research, vol. 113, no. 1111, pp. 287–299,
This work has been supported by Ministerio de Economı́a 2000.
y Competitividad del Gobierno de España (MINECO, [16] V. Nandakumar, T. Singh, and S. K. Katiyar, “Multi-targeted pre-
Plan Nacional I+D+i AGL2013-48943-C2-2-R), Gobierno vention and therapy of cancer by proanthocyanidins,” Cancer
Regional de la Comunidad de Madrid (P2013/ABI-2728, Letters, vol. 269, no. 2, pp. 378–387, 2008.
ALIBIRD-CM), and EU Structural Funds. Marta Corzo- [17] City of Hope Medical Center and National Cancer Institute,
Martı́nez also thanks Ministerio de Economı́a y Competitivi- IH636 Grape Seed Extract in Preventing Breast Cancer in
dad (Spain) for her Juan de la Cierva contract. Postmenopausal Women at Risk of Developing Breast Cancer,
NCT00100893, 2015.
References [18] J. Chong, A. Poutaraud, and P. Hugueney, “Metabolism and
roles of stilbenes in plants,” Plant Science, vol. 177, no. 3, pp. 143–
[1] Y. Liu and N. Feng, “Nanocarriers for the delivery of active 155, 2009.
ingredients and fractions extracted from natural products used [19] E. Portes, C. Gardrat, and A. Castellan, “A comparative study
in traditional Chinese medicine (TCM),” Advances in Colloid on the antioxidant properties of tetrahydrocurcuminoids and
and Interface Science, vol. 221, pp. 60–76, 2015. curcuminoids,” Tetrahedron, vol. 63, no. 37, pp. 9092–9099, 2007.
[20] B. K. Tiwari, N. P. Brunton, and C. Brennan, Handbook of Plant [37] C. L. Stoner, A. Cleton, K. Johnson et al., “Integrated oral
Food Phytochemicals: Sources, Stability and Extraction, John bioavailability projection using in vitro screening data as a
Wiley & Sons, 2013. selection tool in drug discovery,” International Journal of Phar-
[21] T. Rabi and A. Bishayee, “Terpenoids and breast cancer chemo- maceutics, vol. 269, no. 1, pp. 241–249, 2004.
prevention,” Breast Cancer Research and Treatment, vol. 115, no. [38] C. Lee-Chang, M. Bodogai, A. Martin-Montalvo et al., “Inhi-
2, pp. 223–239, 2009. bition of breast cancer metastasis by resveratrol-mediated
[22] M. Huang, J.-J. Lu, M.-Q. Huang, J.-L. Bao, X.-P. Chen, and Y.-T. inactivation of tumor-evoked regulatory B cells,” Journal of
Wang, “Terpenoids: natural products for cancer therapy,” Expert Immunology, vol. 191, no. 8, pp. 4141–4151, 2013.
Opinion on Investigational Drugs, vol. 21, no. 12, pp. 1801–1818, [39] L. Tan, W. Wang, G. He et al., “Resveratrol inhibits ovarian
2012. tumor growth in an in vivo mouse model,” Cancer, vol. 122, no.
[23] E. Breitmaier, Terpenes, Flavors, Fragrances, Pharmaca, Pherom- 5, pp. 722–729, 2016.
ones, John Wiley & Sons, New York, NY, USA, 2006. [40] Y. G. Lin, A. B. Kunnumakkara, A. Nair et al., “Curcumin
inhibits tumor growth and angiogenesis in ovarian carcinoma
[24] A. K. Patra and J. Saxena, “Dietary phytochemicals as rumen
by targeting the nuclear factor-𝜅B pathway,” Clinical Cancer
modifiers: a review of the effects on microbial populations,”
Research, vol. 13, no. 11, pp. 3423–3430, 2007.
International Journal of General and Molecular Microbiology,
vol. 96, no. 4, pp. 363–375, 2009. [41] J. Odot, P. Albert, A. Carlier, M. Tarpin, J. Devy, and C.
Madoulet, “In vitro and in vivo anti-tumoral effect of curcumin
[25] P. M. Dewick, Medicinal Natural Products: A Biosynthetic
against melanoma cells,” International Journal of Cancer, vol. 111,
Approach, John Wiley & Sons, 2002.
no. 3, pp. 381–387, 2004.
[26] B. Holst and G. Williamson, “A critical review of the bioavail-
[42] N. P. Castro, C. M. Rangel, D. Salomon, K. Saylor, and Y. S. Kim,
ability of glucosinolates and related compounds,” Natural Prod-
“Sulforaphane suppresses the growth of triple-negative breast
uct Reports, vol. 21, no. 3, pp. 425–447, 2004.
cancer stem-like cells in vitro and in vivo,” Cancer Research, vol.
[27] J. V. Higdon, B. Delage, D. E. Williams, and R. H. Dashwood, 75, no. 15, article 912, 2015.
“Cruciferous vegetables and human cancer risk: epidemiologic [43] H. Tang, Y. Kong, J. Guo et al., “Diallyl disulfide suppresses
evidence and mechanistic basis,” Pharmacological Research, vol. proliferation and induces apoptosis in human gastric cancer
55, no. 3, pp. 224–236, 2007. through Wnt-1 signaling pathway by up-regulation of miR-200b
[28] F. Fuentes, X. Paredes-Gonzalez, and A. T. Kong, “Dietary and miR-22,” Cancer Letters, vol. 340, no. 1, pp. 72–81, 2013.
glucosinolates sulforaphane, phenethyl isothiocyanate, Indole- [44] H. Nakagawa, K. Tsuta, K. Kiuchi et al., “Growth inhibitory
3-Carbinol/3,3󸀠-Diindolylmethane: antioxidative stress/inflam- effects of diallyl disulfide on human breast cancer cell lines,”
mation, Nrf2, epigenetics/epigenomics and in vivo cancer Carcinogenesis, vol. 22, no. 6, pp. 891–897, 2001.
chemopreventive efficacy,” Current Pharmacology Reports, vol.
[45] S. S. Jambhekar, W. Foye, T. Lemke, and D. Williams, “Physico-
1, no. 3, pp. 179–196, 2015.
chemical and biopharmaceutical properties of drug substnaces
[29] R. A. Moreau, B. D. Whitaker, and K. B. Hicks, “Phytosterols, and pharmacokinetics,” Foyes Principles of Medicinal Chemistry,
phytostanols, and their conjugates in foods: structural diversity, pp. 61–105, 2008.
quantitative analysis, and health-promoting uses,” Progress in
[46] B. Holst and G. Williamson, “Nutrients and phytochemicals:
Lipid Research, vol. 41, no. 6, pp. 457–500, 2002.
from bioavailability to bioefficacy beyond antioxidants,” Cur-
[30] J. Smith and E. Charter, Functional Food Product Development, rent Opinion in Biotechnology, vol. 19, no. 2, pp. 73–82, 2008.
John Wiley & Sons, 2011. [47] C. A. Lipinski, “Drug-like properties and the causes of poor
[31] K. A. Varady, A. H. Houweling, and P. J. H. Jones, “Effect of solubility and poor permeability,” Journal of Pharmacological
plant sterols and exercise training on cholesterol absorption and Toxicological Methods, vol. 44, no. 1, pp. 235–249, 2000.
and synthesis in previously sedentary hypercholesterolemic [48] S. Prabhu, M. Ortega, and C. Ma, “Novel lipid-based formula-
subjects,” Translational Research, vol. 149, no. 1, pp. 22–30, 2007. tions enhancing the in vitro dissolution and permeability char-
[32] A. Downie, C. Fink, and A. B. Awad, “Effect of phytosterols acteristics of a poorly water-soluble model drug, piroxicam,”
on MDA-MB-231 human breast cancer cell growth,” The FASEB International Journal of Pharmaceutics, vol. 301, no. 1-2, pp. 209–
Journal, vol. 13, article A333, 1999. 216, 2005.
[33] X.-J. Yan, L.-H. Gong, F.-Y. Zheng, K.-J. Cheng, Z.-S. Chen, [49] J. Robinson, “Introduction: semi-solid formulations of oral drug
and Z. Shi, “Triterpenoids as reversal agents for anticancer drug delivery,” Bulletin Technique-Gattefosse, pp. 11–14, 1996.
resistance treatment,” Drug Discovery Today, vol. 19, no. 4, pp. [50] M. D’Archivio, C. Filesi, R. Varı̀, B. Scazzocchio, and R. Masella,
482–488, 2014. “Bioavailability of the polyphenols: status and controversies,”
[34] A. Bishayee, S. Ahmed, N. Brankov, and M. Perloff, “Triter- International Journal of Molecular Sciences, vol. 11, no. 4, pp.
penoids as potential agents for the chemoprevention and 1321–1342, 2010.
therapy of breast cancer,” Frontiers in Bioscience, vol. 16, no. 3, [51] A. Scalbert and G. Williamson, “Dietary intake and bioavail-
pp. 980–996, 2011. ability of polyphenols,” The Journal of Nutrition, vol. 130, no. 8,
[35] K. T. Liby, M. M. Yore, and M. B. Sporn, “Triterpenoids and pp. 2073S–2085S, 2000.
rexinoids as multifunctional agents for the prevention and [52] C. Manach, A. Scalbert, C. Morand, C. Rémésy, and L. Jiménez,
treatment of cancer,” Nature Reviews Cancer, vol. 7, no. 5, pp. “Polyphenols: food sources and bioavailability,” American Jour-
357–369, 2007. nal of Clinical Nutrition, vol. 79, no. 5, pp. 727–747, 2004.
[36] V. R. Yadav, S. Prasad, B. Sung, R. Kannappan, and B. B. Aggar- [53] K. R. Patel, C. Andreadi, R. G. Britton et al., “Sulfate metabo-
wal, “Targeting inflammatory pathways by triterpenoids for lites provide an intracellular pool for resveratrol generation
prevention and treatment of cancer,” Toxins, vol. 2, no. 10, pp. and induce autophagy with senescence,” Science Translational
2428–2466, 2010. Medicine, vol. 5, no. 205, p. 205ra133, 2013.
[54] H. Cai, E. Scott, A. Kholghi et al., “Cancer chemoprevention: [68] M. El-Badry and M. Fathy, “Enhancement of the dissolution
evidence of a nonlinear dose response for the protective effects and permeation rates of meloxicam by formation of its freeze-
of resveratrol in humans and mice,” Science Translational dried solid dispersions in polyvinylpyrrolidone K-30,” Drug
Medicine, vol. 7, no. 298, Article ID 298ra117, 2015. Development and Industrial Pharmacy, vol. 32, no. 2, pp. 141–
[55] Y. J. Chen, B. S. Inbaraj, Y. S. Pu, and B. H. Chen, “Development 150, 2006.
of lycopene micelle and lycopene chylomicron and a compari- [69] G. Verreck and M. E. Brewster, “Melt extrusion-based dosage
son of bioavailability,” Nanotechnology, vol. 25, no. 15, Article ID forms: excipients and processing conditions for pharmaceutical
155102, 2014. formulations,” Bulletin Technique Gattefossé, vol. 97, pp. 85–95,
[56] T. W. Kensler, J.-G. Chen, P. A. Egner et al., “Effects of glucosin- 2004.
olate-rich broccoli sprouts on urinary levels of aflatoxin-DNA [70] A. J. Humberstone and W. N. Charman, “Lipid-based vehicles
adducts and phenanthrene tetraols in a randomized clinical for the oral delivery of poorly water soluble drugs,” Advanced
trial in He Zuo Township, Qidong, People’s Republic of China,” Drug Delivery Reviews, vol. 25, no. 1, pp. 103–128, 1997.
Cancer Epidemiology Biomarkers and Prevention, vol. 14, no. 11 [71] B. N. Singh and K. H. Kim, “Drug delivery-oral route,” Encyclo-
I, pp. 2605–2613, 2005. pedia of Pharmaceutical Technology, vol. 1, 2002.
[57] T. Sivapalan, A. Melchini, M. Traka, S. Saha, and R. Mithen, [72] B. Chengaiah, M. Alagusundaram, S. Ramkanth, and C. M.
“Investigating the bioavailability of phytochemicals and miner- Chetty, “Self emulsifying drug delivery system: a novel approach
als from broccoli soups,” Proceedings of the Nutrition Society, vol. for drug delivery,” Research Journal of Pharmacy and Technol-
74, article E191, 2015. ogy, vol. 4, no. 2, pp. 175–181, 2011.
[58] Y. Sato, K. Nishikawa, K. Aikawa et al., “Side-chain structure [73] C. J. H. Porter, N. L. Trevaskis, and W. N. Charman, “Lipids
is critical for the transport of sterols from lysosomes to and lipid-based formulations: optimizing the oral delivery of
cytoplasm,” Biochimica et Biophysica Acta—Lipids and Lipid lipophilic drugs,” Nature Reviews Drug Discovery, vol. 6, no. 3,
Metabolism, vol. 1257, no. 1, pp. 38–46, 1995. pp. 231–248, 2007.
[59] S. Rozner and N. Garti, “The activity and absorption relation- [74] W. N. Charman, C. J. H. Porter, S. Mithani, and J. B. Dressman,
ship of cholesterol and phytosterols,” Colloids and Surfaces A: “Physicochemical and physiological mechanisms for the effects
Physicochemical and Engineering Aspects, vol. 282-283, pp. 435– of food on drug absorption: the role of lipids and pH,” Journal
456, 2006. of Pharmaceutical Sciences, vol. 86, no. 3, pp. 269–282, 1997.
[60] S.-M. Khoo, D. M. Shackleford, C. J. H. Porter, G. A. Edwards, [75] C. M. O’Driscoll, “Lipid-based formulations for intestinal lym-
and W. N. Charman, “Intestinal lymphatic transport of halo- phatic delivery,” European Journal of Pharmaceutical Sciences,
fantrine occurs after oral administration of a unit-dose lipid- vol. 15, no. 5, pp. 405–415, 2002.
based formulation to fasted dogs,” Pharmaceutical Research, vol. [76] A. Gabizon and D. Papahadjopoulos, “Liposome formulations
20, no. 9, pp. 1460–1465, 2003. with prolonged circulation time in blood and enhanced uptake
[61] E. S. Swenson, W. B. Milisen, and W. Curatolo, “Intestinal by tumors,” Proceedings of the National Academy of Sciences of
permeability enhancement: efficacy, acute local toxicity, and the United States of America, vol. 85, no. 18, pp. 6949–6953, 1988.
reversibility,” Pharmaceutical Research, vol. 11, no. 8, pp. 1132– [77] J. V. Natarajan, C. Nugraha, X. W. Ng, and S. Venkatraman,
1142, 1994. “Sustained-release from nanocarriers: a review,” Journal of
[62] S. Gupta, R. Kesarla, and A. Omri, “Formulation strategies Controlled Release, vol. 193, pp. 122–138, 2014.
to improve the bioavailability of poorly absorbed drugs with [78] V. Kakkar, A. K. Mishra, K. Chuttani, and I. P. Kaur, “Proof
special emphasis on self-emulsifying systems,” ISRN Pharma- of concept studies to confirm the delivery of curcumin loaded
ceutics, vol. 2013, Article ID 848043, 16 pages, 2013. solid lipid nanoparticles (C-SLNs) to brain,” International Jour-
[63] B. J. Aungst, “Novel formulation strategies for improving oral nal of Pharmaceutics, vol. 448, no. 2, pp. 354–359, 2013.
bioavailability of drugs with poor membrane permeation or [79] J. Kreuter, “Nanoparticulate systems for brain delivery of drugs,”
presystemic metabolism,” Journal of Pharmaceutical Sciences, Advanced Drug Delivery Reviews, vol. 47, no. 1, pp. 65–81, 2001.
vol. 82, no. 10, pp. 979–987, 1993. [80] S. Kunjachan, B. Rychlik, G. Storm, F. Kiessling, and T. Lam-
[64] B. D. Patel, R. V. Modi, N. A. Thakkar, A. A. Patel, and P. mers, “Multidrug resistance: physiological principles and
H. Thakkar, “Development and characterization of solid lipid nanomedical solutions,” Advanced Drug Delivery Reviews, vol.
nanoparticles for enhancement of oral bioavailability of Ralox- 65, no. 13-14, pp. 1852–1865, 2013.
ifene,” Journal of Pharmacy and Bioallied Sciences, vol. 4, no. 5, [81] S. Barui, S. Saha, G. Mondal, S. Haseena, and A. Chaudhuri,
pp. 14–16, 2012. “Simultaneous delivery of doxorubicin and curcumin encap-
[65] C. W. Pouton, “Lipid formulations for oral administration of sulated in liposomes of pegylated RGDK-lipopeptide to tumor
drugs: non-emulsifying, self-emulsifying and ’self-microemul- vasculature,” Biomaterials, vol. 35, no. 5, pp. 1643–1656, 2014.
sifying’ drug delivery systems,” European Journal of Pharmaceu- [82] G. A. Koning and G. Storm, “Targeted drug delivery systems
tical Sciences, vol. 11, no. 2, pp. S93–S98, 2000. for the intracellular delivery of macromolecular drugs,” Drug
[66] Y. Ito, T. Kusawake, M. Ishida, R. Tawa, N. Shibata, and K. Discovery Today, vol. 8, no. 11, pp. 482–483, 2003.
Takada, “Oral solid gentamicin preparation using emulsifier [83] J. M. Metselaar and G. Storm, “Liposomes in the treatment of
and adsorbent,” Journal of Controlled Release, vol. 105, no. 1-2, inflammatory disorders,” Expert Opinion on Drug Delivery, vol.
pp. 23–31, 2005. 2, no. 3, pp. 465–476, 2005.
[67] G. Nicolaos, S. Crauste-Manciet, R. Farinotti, and D. Brossard, [84] B.-S. Ding, T. Dziubla, V. V. Shuvaev, S. Muro, and V. R.
“Improvement of cefpodoxime proxetil oral absorption in rats Muzykantov, “Advanced drug delivery systems that target the
by an oil-in-water submicron emulsion,” International Journal vascular endothelium,” Molecular Interventions, vol. 6, no. 2, pp.
of Pharmaceutics, vol. 263, no. 1-2, pp. 165–171, 2003. 98–112, 2006.
[85] S. Hua and S. Y. Wu, “The use of lipid-based nanocarriers extracts, Ginkgo biloba extract phospholipid complexes and
for targeted pain therapies,” Frontiers in Pharmacology, vol. 4, Ginkgo biloba extract solid dispersions in rats,” Fitoterapia, vol.
article 143, 2013. 81, no. 8, pp. 1045–1052, 2010.
[86] J. Szebeni and S. M. Moghimi, “Liposome triggering of innate [102] P. Pietta, P. Simonetti, C. Gardana, A. Brusamolino, P. Moraz-
immune responses: a perspective on benefits and adverse zoni, and E. Bombardelli, “Relationship between rate and
reactions: biological recognition and interactions of liposomes,” extent of catechin absorption and plasma antioxidant status,”
Journal of Liposome Research, vol. 19, no. 2, pp. 85–90, 2009. Biochemistry and Molecular Biology International, vol. 46, no.
[87] L. Sercombe, T. Veerati, F. Moheimani, S. Y. Wu, A. K. Sood, 5, pp. 895–903, 1998.
and S. Hua, “Advances and challenges of liposome assisted drug [103] S. Das and A. Chaudhury, “Recent advances in lipid nanoparti-
delivery,” Frontiers in Pharmacology, vol. 6, article 286, 2015. cle formulations with solid matrix for oral drug delivery,” AAPS
[88] Z.-Q. Chen, Y. Liu, J.-H. Zhao, L. Wang, and N.-P. Feng, PharmSciTech, vol. 12, no. 1, pp. 62–76, 2011.
“Improved oral bioavailability of poorly water-soluble indiru- [104] P. Blasi, S. Giovagnoli, A. Schoubben, M. Ricci, and C. Rossi,
bin by a supersaturatable self-microemulsifying drug delivery “Solid lipid nanoparticles for targeted brain drug delivery,”
system,” International Journal of Nanomedicine, vol. 7, pp. 1115– Advanced Drug Delivery Reviews, vol. 59, no. 6, pp. 454–477,
1125, 2012. 2007.
[89] C. Dwivedi, R. Sahu, S. P. Tiwari, T. Satapathy, and A. Roy, “Role [105] M. Muchow, P. Maincent, and R. H. Müller, “Lipid nanoparticles
of liposome in novel drug delivery system,” Journal of Drug with a solid matrix (SLN, NLC, LDC) for oral drug delivery,”
Delivery and Therapeutics, vol. 4, pp. 116–129, 2014. Drug Development and Industrial Pharmacy, vol. 34, no. 12, pp.
[90] Y. Hu, F. Zeng, R. Ju, and W. Lu, “Advances in liposomal drug 1394–1405, 2008.
delivery system in the field of chemotherapy,” Clinical Oncology,
[106] H. Yuan, L.-F. Huang, Y.-Z. Du et al., “Solid lipid nanoparticles
vol. 1, article 1092, 2016.
prepared by solvent diffusion method in a nanoreactor system,”
[91] P. P. Deshpande, S. Biswas, and V. P. Torchilin, “Current trends Colloids and Surfaces B: Biointerfaces, vol. 61, no. 2, pp. 132–137,
in the use of liposomes for tumor targeting,” Nanomedicine, vol. 2008.
8, no. 9, pp. 1509–1528, 2013.
[107] A. A. Attama, M. A. Momoh, and P. F. Builders, Lipid Nanopar-
[92] M. Kanamala, W. R. Wilson, M. Yang, B. D. Palmer, and Z. ticulate Drug Delivery Systems: A Revolution in Dosage form
Wu, “Mechanisms and biomaterials in pH-responsive tumour Design and Development, INTECH Open Access, Rijeka, Croa-
targeted drug delivery: a review,” Biomaterials, vol. 85, pp. 152– tia, 2012.
167, 2016.
[108] J. M. Irache, I. Esparza, C. Gamazo, M. Agüeros, and S. Espuelas,
[93] N. Monteiro, A. Martins, R. L. Reis, and N. M. Neves, “Lipo-
“Nanomedicine: novel approaches in human and veterinary
somes in tissue engineering and regenerative medicine,” Journal
therapeutics,” Veterinary Parasitology, vol. 180, no. 1-2, pp. 47–
of the Royal Society Interface, vol. 11, no. 101, Article ID 20140459,
71, 2011.
2014.
[94] C. Li, J. Cui, C. Wang et al., “Encapsulation of vinorelbine into [109] S. Das, W. K. Ng, and R. B. H. Tan, “Are nanostructured lipid
cholesterol-polyethylene glycol coated vesicles: drug loading carriers (NLCs) better than solid lipid nanoparticles (SLNs):
and pharmacokinetic studies,” Journal of Pharmacy and Phar- development, characterizations and comparative evaluations
macology, vol. 63, no. 3, pp. 376–384, 2011. of clotrimazole-loaded SLNs and NLCs?” European Journal of
Pharmaceutical Sciences, vol. 47, no. 1, pp. 139–151, 2012.
[95] S.-H. Li, J. Fu, D. N. Watkins, R. K. Srivastava, and S. Shankar,
“Sulforaphane regulates self-renewal of pancreatic cancer stem [110] W. Mehnert and K. Mäder, “Solid lipid nanoparticles: pro-
cells through the modulation of Sonic hedgehog-GLI pathway,” duction, characterization and applications,” Advanced Drug
Molecular and Cellular Biochemistry, vol. 373, no. 1-2, pp. 217– Delivery Reviews, vol. 47, no. 2-3, pp. 165–196, 2001.
227, 2013. [111] C. Pardeshi, P. Rajput, V. Belgamwar et al., “Solid lipid based
[96] R. A. Sharma, H. R. McLelland, K. A. Hill et al., “Pharmacody- nanocarriers: an overview,” Acta Pharmaceutica, vol. 62, no. 4,
namic and pharmacokinetic study of oral Curcuma extract in pp. 433–472, 2012.
patients with colorectal cancer,” Clinical Cancer Research, vol. 7, [112] P. Gershkovich and A. Hoffman, “Effect of a high-fat meal on
no. 7, pp. 1894–1900, 2001. absorption and disposition of lipophilic compounds: the impor-
[97] G. Fricker, T. Kromp, A. Wendel et al., “Phospholipids and tance of degree of association with triglyceride-rich lipopro-
lipid-based formulations in oral drug delivery,” Pharmaceutical teins,” European Journal of Pharmaceutical Sciences, vol. 32, no.
Research, vol. 27, no. 8, pp. 1469–1486, 2010. 1, pp. 24–32, 2007.
[98] B. Gabetta, E. Bombardelli, and G. Pifferi, “Complexes of [113] R. H. Müller, M. Radtke, and S. A. Wissing, “Solid lipid
flavanolignans with phospholipids, preparation thereof and nanoparticles (SLN) and nanostructured lipid carriers (NLC)
associated pharmaceutical compositions,” 1988. in cosmetic and dermatological preparations,” Advanced Drug
[99] Y. Song, J. Zhuang, J. Guo, Y. Xiao, and Q. Ping, “Preparation Delivery Reviews, vol. 54, pp. S131–S155, 2002.
and properties of a silybin-phospholipid complex,” Die Phar- [114] A. Saupe, K. C. Gordon, and T. Rades, “Structural investigations
mazie, vol. 63, no. 1, pp. 35–42, 2008. on nanoemulsions, solid lipid nanoparticles and nanostruc-
[100] D. Singh, M. S. M. Rawat, A. Semalty, and M. Semalty, tured lipid carriers by cryo-field emission scanning electron
“Quercetin-phospholipid complex: an amorphous pharmaceu- microscopy and Raman spectroscopy,” International Journal of
tical system in herbal drug delivery,” Current Drug Discovery Pharmaceutics, vol. 314, no. 1, pp. 56–62, 2006.
Technologies, vol. 9, no. 1, pp. 17–24, 2012. [115] S. Corveleyn and J. P. Remon, “Formulation and produc-
[101] Z.-P. Chen, J. Sun, H.-X. Chen et al., “Comparative pharma- tion of rapidly disintegrating tablets by lyophilisation using
cokinetics and bioavailability studies of quercetin, kaempferol hydrochlorothiazide as a model drug,” International Journal of
and isorhamnetin after oral administration of Ginkgo biloba Pharmaceutics, vol. 152, no. 2, pp. 215–225, 1997.
[116] R. G. Strickley, “Solubilizing excipients in oral and injectable [131] Z. Zeng, G. Zhou, X. Wang et al., “Preparation, characterization
formulations,” Pharmaceutical Research, vol. 21, no. 2, pp. 201– and relative bioavailability of oral elemene o/w microemulsion,”
230, 2004. International Journal of Nanomedicine, vol. 5, no. 1, pp. 567–572,
[117] T. Tokumura, Y. Tsushima, K. Tatsuishi, M. Kayano, Y. Machida, 2010.
and T. Nagai, “Enhancement of the oral bioavailability of cin- [132] G. Chansiri, R. T. Lyons, M. V. Patel, and S. L. Hem, “Effect
narizine in oleic acid in beagle dogs,” Journal of Pharmaceutical of surface charge on the stability of oil/water emulsions during
Sciences, vol. 76, no. 4, pp. 286–288, 1987. steam sterilization,” Journal of Pharmaceutical Sciences, vol. 88,
[118] S. Doktorovova, E. B. Souto, and A. M. Silva, “Nanotoxicology no. 4, pp. 454–458, 1999.
applied to solid lipid nanoparticles and nanostructured lipid [133] Y.-N. Jiang and H.-Y. Mo, “Preparation of self-emulsifying
carriers—a systematic review of in vitro data,” European Journal soft capsule and its pharmacokinetic in rats for epimedium
of Pharmaceutics and Biopharmaceutics, vol. 87, no. 1, pp. 1–18, flavonoids,” Journal of Chinese Medicinal Materials, vol. 33, no.
2014. 5, pp. 767–771, 2010.
[119] G. Leonarduzzi, G. Testa, B. Sottero, P. Gamba, and G. Poli,
[134] X.-Q. Luo and J.-Q. Yang, “Prescription design and dissolu-
“Design and development of nanovehicle-based delivery sys-
tion evaluation of self-emulsifying drug delivery systems of
tems for preventive or therapeutic supplementation with
baicalin,” Journal of Chinese Medicinal Materials, vol. 33, no. 7,
flavonoids,” Current Medicinal Chemistry, vol. 17, no. 1, pp. 74–
pp. 1157–1159, 2010.
95, 2010.
[120] C.-F. Luo, M. Yuan, M.-S. Chen et al., “Pharmacokinetics, [135] J.-L. Tang, J. Sun, and Z.-G. He, “Self-emulsifying drug delivery
tissue distribution and relative bioavailability of puerarin solid systems: strategy for improving oral delivery of poorly soluble
lipid nanoparticles following oral administration,” International drugs,” Current Drug Therapy, vol. 2, no. 1, pp. 85–93, 2007.
Journal of Pharmaceutics, vol. 410, no. 1-2, pp. 138–144, 2011. [136] N. Chouhan, V. Mittal, D. Kaushik, A. Khatkar, and M. Raina,
[121] C.-F. Luo, N. Hou, J. Tian et al., “Metabolic profile of puerarin “Self Emulsifying Drug Delivery System (SEDDS) for phyto-
in rats after intragastric administration of puerarin solid lipid constituents: a review,” Current Drug Delivery, vol. 12, no. 2, pp.
nanoparticles,” International Journal of Nanomedicine, vol. 8, pp. 244–253, 2015.
933–940, 2013. [137] J. Yao, Y. Lu, and J. P. Zhou, “Preparation of nobiletin in self-
[122] M. Zhang, J. Truscott, and J. Davie, “Loss of MEF2D expression microemulsifying systems and its intestinal permeability in
inhibits differentiation and contributes to oncogenesis in rhab- rats,” Journal of Pharmacy and Pharmaceutical Sciences, vol. 11,
domyosarcoma cells,” Molecular Cancer, vol. 12, no. 1, article 150, no. 3, pp. 22–29, 2008.
2013. [138] M. Mosharraf and C. Nyström, “The effect of particle size and
[123] M. Shangguan, Y. Lu, J. Qi et al., “Binary lipids-based nanos- shape on the surface specific dissolution rate of microsized prac-
tructured lipid carriers for improved oral bioavailability of tically insoluble drugs,” International Journal of Pharmaceutics,
silymarin,” Journal of Biomaterials Applications, vol. 28, no. 6, vol. 122, no. 1-2, pp. 35–47, 1995.
pp. 887–896, 2014. [139] P. Zhang, Y. Liu, N. Feng, and J. Xu, “Preparation and evaluation
[124] L. Yuan, C. Y. Liu, Y. Chen, Z. H. Zhang, L. Zhou, and D. Qu, of self-microemulsifying drug delivery system of oridonin,”
“Antitumor activity of tripterine via cell-penetrating peptide- International Journal of Pharmaceutics, vol. 355, no. 1-2, pp. 269–
coated nanostructured lipid carriers in a prostate cancer model,” 276, 2008.
International Journal of Nanomedicine, vol. 8, pp. 4339–4350,
[140] L. Liu, X. Pang, W. Zhang, and S. Wang, “Formulation design
2013.
and in vitro evaluation of silymarin-loaded self-microemulsi-
[125] S. Heuschkel, A. Goebel, and R. H. H. Neubert, “Microemul- fying drug delivery systems,” Asian Journal of Pharmaceutical
sions—modern colloidal carrier for dermal and transdermal Sciences, vol. 2, pp. 150–160, 2007.
drug delivery,” Journal of Pharmaceutical Sciences, vol. 97, no.
2, pp. 603–631, 2008. [141] J. Tang, J. Sun, F. Cui, and Z. He, “Preparation of self-
emulsifying drug delivery systems of Ginkgo biloba extracts
[126] D. J. McClements, “Nanoemulsions versus microemulsions:
and in vitro dissolution studies,” Asian Journal of Traditional
terminology, differences, and similarities,” Soft Matter, vol. 8,
Medicines, vol. 1, pp. 138–141, 2006.
no. 6, pp. 1719–1729, 2012.
[127] T.-T. Tang, X.-B. Hu, D.-H. Liao, X.-Y. Liu, and D.-X. Xiang, [142] K. Kohli, S. Chopra, D. Dhar, S. Arora, and R. K. Khar, “Self-
“Mechanisms of microemulsion enhancing the oral bioavail- emulsifying drug delivery systems: an approach to enhance oral
ability of puerarin: comparison between oil-in-water and water- bioavailability,” Drug Discovery Today, vol. 15, no. 21-22, pp.
in-oil microemulsions using the single-pass intestinal perfusion 958–965, 2010.
method and a chylomicron flow blocking approach,” Interna- [143] S. Wang, M. Sun, and Q. Ping, “Enhancing effect of Labrafac
tional Journal of Nanomedicine, vol. 8, pp. 4415–4426, 2013. Lipophile WL 1349 on oral bioavailability of hydroxysafflor
[128] B.-X. Zang, M. Jin, N. Si, Y. Zhang, W. Wu, and Y.-Z. Piao, yellow A in rats,” International Journal of Pharmaceutics, vol.
“Antagonistic effect of hydroxysafflor yellow a on the platelet 358, no. 1-2, pp. 198–204, 2008.
activating factor receptor,” Yao Xue Xue Bao, vol. 37, no. 9, pp. [144] L.-Z. Lv, C.-Q. Tong, Q. Lv et al., “Enhanced absorption of
696–699, 2002. hydroxysafflor yellow A using a self-double-emulsifying drug
[129] H. Zhu, Z. Wang, C. Ma et al., “Neuroprotective effects of delivery system: in vitro and in vivo studies,” International
hydroxysafflor yellow A: in vivo and in vitro studies,” Planta Journal of Nanomedicine, vol. 7, pp. 4099–4107, 2012.
Medica, vol. 69, no. 5, pp. 429–433, 2003. [145] J. Zhang, Q. Peng, S. Shi et al., “Preparation, characterization,
[130] J. Qi, J. Zhuang, W. Wu et al., “Enhanced effect and mech- and in vivo evaluation of a self-nanoemulsifying drug delivery
anism of water-in-oil microemulsion as an oral delivery sys- system (SNEDDS) loaded with morin-phospholipid complex,”
tem of hydroxysafflor yellow A,” International Journal of International Journal of Nanomedicine, vol. 6, pp. 3405–3414,
Nanomedicine, vol. 6, pp. 985–991, 2011. 2011.
[146] J. H. Yoo, S. Shanmugam, P. Thapa et al., “Novel self-nanoe- [160] R. Yutani, T. Kikuchi, R. Teraoka, and S. Kitagawa, “Efficient
mulsifying drug delivery system for enhanced solubility and delivery and distribution in skin of chlorogenic acid and
dissolution of lutein,” Archives of Pharmacal Research, vol. 33, resveratrol induced by microemulsion using sucrose laurate,”
no. 3, pp. 417–426, 2010. Chemical and Pharmaceutical Bulletin, vol. 62, no. 3, pp. 274–
[147] V. Tsouris, M. K. Joo, S. H. Kim, I. C. Kwon, and Y.-Y. Won, 280, 2014.
“Nano carriers that enable co-delivery of chemotherapy and [161] C. Bell and S. Hawthorne, “Ellagic acid, pomegranate and
RNAi agents for treatment of drug-resistant cancers,” Biotech- prostate cancer—a mini review,” Journal of Pharmacy and Phar-
nology Advances, vol. 32, no. 5, pp. 1037–1050, 2014. macology, vol. 60, no. 2, pp. 139–144, 2008.
[148] A. F. Brito, M. Ribeiro, A. M. Abrantes et al., “Quercetin in [162] M. Zhao, S.-N. Tang, J. L. Marsh, S. Shankar, and R. K. Srivas-
cancer treatment, alone or in combination with conventional tava, “Ellagic acid inhibits human pancreatic cancer growth in
therapeutics?” Current Medicinal Chemistry, vol. 22, no. 26, pp. Balb c nude mice,” Cancer Letters, vol. 337, no. 2, pp. 210–217,
3025–3039, 2015. 2013.
[163] Z. Qiu, B. Zhou, L. Jin et al., “In vitro antioxidant and antipro-
[149] B. M. Kaminski, D. Steinhilber, J. M. Stein, and S. Ulrich, “Phy-
liferative effects of ellagic acid and its colonic metabolite,
tochemicals resveratrol and sulforaphane as potential agents
urolithins, on human bladder cancer T24 cells,” Food and
for enhancing the anti-tumor activities of conventional cancer
Chemical Toxicology, vol. 59, pp. 428–437, 2013.
therapies,” Current Pharmaceutical Biotechnology, vol. 13, no. 1,
pp. 137–146, 2012. [164] N. Wang, Z.-Y. Wang, S.-L. Mo et al., “Ellagic acid, a phenolic
compound, exerts anti-angiogenesis effects via VEGFR-2 sig-
[150] K. Park, “True combination therapy using synergistic drug naling pathway in breast cancer,” Breast Cancer Research and
combination,” Journal of Controlled Release, vol. 187, article 198, Treatment, vol. 134, no. 3, pp. 943–955, 2012.
2014.
[165] A. R. de Molina, T. Vargas, S. Molina et al., “The ellagic
[151] C. Gong, Q. Wu, Y. Wang et al., “A biodegradable hydrogel acid derivative 4,4󸀠 -Di-O-methylellagic acid efficiently inhibits
system containing curcumin encapsulated in micelles for cuta- colon cancer cell growth through a mechanism involving
neous wound healing,” Biomaterials, vol. 34, no. 27, pp. 6377– WNT16,” Journal of Pharmacology and Experimental Therapeu-
6387, 2013. tics, vol. 353, no. 2, pp. 433–444, 2015.
[152] J. Shi, Y. Wang, and G. Luo, “Ligustrazine phosphate ethosomes [166] Oslo University Hospital and University of Oslo, Dietary Inter-
for treatment of Alzheimer’s disease, in vitro and in animal vention in Follicular Lymphoma (KLYMF), NCT00455416, 2008.
model studies,” AAPS PharmSciTech, vol. 13, no. 2, pp. 485–492, [167] M. Falsaperla, G. Morgia, A. Tartarone, R. Ardito, and G.
2012. Romano, “Support ellagic acid therapy in patients with hor-
[153] J. Liu, J. Liu, H. Xu et al., “Novel tumor-targeting, self- mone refractory prostate cancer (HRPC) on standard chemo-
assembling peptide nanofiber as a carrier for effective curcumin therapy using vinorelbine and estramustine phosphate,” Euro-
delivery,” International Journal of Nanomedicine, vol. 9, no. 1, pp. pean Urology, vol. 47, no. 4, pp. 449–454, 2005.
197–207, 2013. [168] X. Wang, M.-W. Hao, K. Dong, F. Lin, J.-H. Ren, and H.-
[154] X.-X. Wang, Y.-B. Li, H.-J. Yao et al., “The use of mitochondrial Z. Zhang, “Apoptosis induction effects of EGCG in laryngeal
targeting resveratrol liposomes modified with a dequalinium squamous cell carcinoma cells through telomerase repression,”
polyethylene glycol-distearoylphosphatidyl ethanolamine con- Archives of Pharmacal Research, vol. 32, no. 9, pp. 1263–1269,
jugate to induce apoptosis in resistant lung cancer cells,” 2009.
Biomaterials, vol. 32, no. 24, pp. 5673–5687, 2011. [169] S. A. Milligan, P. Burke, D. T. Coleman et al., “The green tea
polyphenol EGCG potentiates the antiproliferative activity of c-
[155] C.-C. Chen, D.-S. Hsieh, K.-J. Huang et al., “Improving anti-
Met and epidermal growth factor receptor inhibitors in non-
cancer efficacy of (-)-epigallocatechin-3-gallate gold nanopar-
small cell lung cancer cells,” Clinical Cancer Research, vol. 15,
ticles in murine B16F10 melanoma cells,” Drug Design, Develop-
no. 15, pp. 4885–4894, 2009.
ment and Therapy, vol. 8, pp. 459–474, 2014.
[170] J.-T. Hwang, J. Ha, I.-J. Park et al., “Apoptotic effect of EGCG
[156] S. Manju and K. Sreenivasan, “Gold nanoparticles generated in HT-29 colon cancer cells via AMPK signal pathway,” Cancer
and stabilized by water soluble curcumin-polymer conjugate: Letters, vol. 247, no. 1-2, pp. 115–121, 2007.
blood compatibility evaluation and targeted drug delivery onto
[171] A. G. Paschka, R. Butler, and C. Y.-F. Young, “Induction of apop-
cancer cells,” Journal of Colloid and Interface Science, vol. 368,
tosis in prostate cancer cell lines by the green tea component,
no. 1, pp. 144–151, 2012.
(-)-epigallocatechin-3-gallate,” Cancer Letters, vol. 130, no. 1-2,
[157] C. Moorthi and K. Kathiresan, “Curcumin-piperine/curcumin- pp. 1–7, 1998.
quercetin/curcumin- silibinin dual drug-loaded nanoparticu- [172] B. Gu, Q. Ding, G. Xia, and Z. Fang, “EGCG inhibits growth
late combination therapy: a novel approach to target and treat and induces apoptosis in renal cell carcinoma through TFPI-2
multidrug-resistant cancers,” Journal of Medical Hypotheses and overexpression,” Oncology Reports, vol. 21, no. 3, pp. 635–640,
Ideas, vol. 7, no. 1, pp. 15–20, 2013. 2009.
[158] R. Censi, V. Martena, E. Hoti, L. Malaj, and P. Di Martino, “Per- [173] A. Mittal, M. S. Pate, R. C. Wylie, T. O. Tollefsbol, and S. K.
meation and skin retention of quercetin from microemulsions Katiyar, “EGCG down-regulates telomerase in human breast
containing Transcutol P,” Drug Development and Industrial carcinoma MCF-7 cells, leading to suppression of cell viability
Pharmacy, vol. 38, no. 9, pp. 1128–1133, 2012. and induction of apoptosis,” International Journal of Oncology,
[159] S. Kitagawa, K. Inoue, R. Teraoka, and S.-Y. Morita, “Enhanced vol. 24, no. 3, pp. 703–710, 2004.
skin delivery of genistein and other two isoflavones by [174] J. Hoffmann, H. Junker, A. Schmieder et al., “EGCG downreg-
microemulsion and prevention against UV irradiation-induced ulates IL-1RI expression and suppresses IL-1-induced tumori-
erythema formation,” Chemical and Pharmaceutical Bulletin, genic factors in human pancreatic adenocarcinoma cells,” Bio-
vol. 58, no. 3, pp. 398–401, 2010. chemical Pharmacology, vol. 82, no. 9, pp. 1153–1162, 2011.
[175] S. Bettuzzi, M. Brausi, F. Rizzi, G. Castagnetti, G. Peracchia, and [190] F. Yin, A. E. Giuliano, and A. J. Van Herle, “Growth inhibitory
A. Corti, “Chemoprevention of human prostate cancer by oral effects of flavonoids in human thyroid cancer cell lines,” Thyroid,
administration of green tea catechins in volunteers with high- vol. 9, no. 4, pp. 369–376, 1999.
grade prostate intraepithelial neoplasia: a preliminary report [191] S.-F. Yang, W.-E. Yang, H.-R. Chang, S.-C. Chu, and Y.-S. Hsieh,
from a one-year proof-of-principle study,” Cancer Research, vol. “Luteolin induces apoptosis in oral squamous cancer cells,”
66, no. 2, pp. 1234–1240, 2006. Journal of Dental Research, vol. 87, no. 4, pp. 401–406, 2008.
[176] W.-S. Ahn, J. Yoo, S.-W. Huh et al., “Protective effects of green [192] R.-X. Shi, C.-N. Ong, and H.-M. Shen, “Luteolin sensitizes
tea extracts (polyphenon E and EGCG) on human cervical tumor necrosis factor-𝛼-induced apoptosis in human tumor
lesions,” European Journal of Cancer Prevention, vol. 12, no. 5, cells,” Oncogene, vol. 23, no. 46, pp. 7712–7721, 2004.
pp. 383–390, 2003. [193] S.-H. Park, H. S. Park, J. H. Lee et al., “Induction of endoplas-
[177] Shandong Cancer Hospital and Institute, H. X. Zhao, and Shan- mic reticulum stress-mediated apoptosis and non-canonical
dong Cancer Hospital and Institute, Study of Epigallocatechin- autophagy by luteolin in NCI-H460 lung carcinoma cells,” Food
3-Gallate (EGCG) for Skin Prevention in Patients With Breast and Chemical Toxicology, vol. 56, pp. 100–109, 2013.
Cancer Receiving Adjuvant Radiotherapy, NCT02580279, 2015. [194] K. Ramasamy and R. Agarwal, “Multitargeted therapy of cancer
[178] Case Comprehensive Cancer Center and National Cancer by silymarin,” Cancer Letters, vol. 269, no. 2, pp. 352–362, 2008.
Institute, Defined Green Tea Catechin Extract in Treating [195] R. Agarwal, C. Agarwal, H. Ichikawa, R. P. Singh, and B. B.
Patients With Localized Prostate Cancer Undergoing Surgery, Aggarwal, “Anticancer potential of silymarin: from bench to bed
NCT01340599, 2012. side,” Anticancer Research, vol. 26, no. 6, pp. 4457–4498, 2006.
[179] P. Pugalendhi, S. Manoharan, K. Panjamurthy, S. Balakrishnan, [196] X. Zi, D. K. Feyes, and R. Agarwal, “Anticarcinogenic effect
and M. R. Nirmal, “Antigenotoxic effect of genistein against of a flavonoid antioxidant, silymarin, in human breast cancer
7,12-dimethylbenz[a]anthracene induced genotoxicity in bone cells MDA-MB 468: induction of G1 arrest through an increase
marrow cells of female Wistar rats,” Pharmacological Reports, in Cipl/p21 concomitant with a decrease in kinase activity
vol. 61, no. 2, pp. 296–303, 2009. of cyclin-dependent kinases and associated cyclins,” Clinical
Cancer Research, vol. 4, no. 4, pp. 1055–1064, 1998.
[180] H. G. Farina, M. Pomies, D. F. Alonso, and D. E. Gomez, “Anti-
[197] R. P. Singh and R. Agarwal, “Flavonoid antioxidant silymarin
tumor and antiangiogenic activity of soy isoflavone genistein
and skin cancer,” Antioxidants and Redox Signaling, vol. 4, no.
in mouse models of melanoma and breast cancer,” Oncology
4, pp. 655–663, 2002.
Reports, vol. 16, no. 4, pp. 885–891, 2006.
[198] G. Deep, R. P. Singh, C. Agarwal, D. J. Kroll, and R. Agarwal,
[181] Z.-M. Shao, J. Wu, Z.-Z. Shen, and S. H. Barsky, “Genistein “Silymarin and silibinin cause G1 and G2–M cell cycle arrest
exerts multiple suppressive effects on human breast carcinoma via distinct circuitries in human prostate cancer PC3 cells: a
cells,” Cancer Research, vol. 58, no. 21, pp. 4851–4857, 1998. comparison of flavanone silibinin with flavanolignan mixture
[182] S.-H. Kim, S.-H. Kim, S.-C. Lee, and Y.-S. Song, “Involvement silymarin,” Oncogene, vol. 25, no. 7, pp. 1053–1069, 2006.
of both extrinsic and intrinsic apoptotic pathways in apoptosis [199] Tehran University of Medical Sciences, Evaluation of Effects
induced by genistein in human cervical cancer cells,” Annals of of Silymarin on Cisplatin Induced Nephrotoxicity in Upper
the New York Academy of Sciences, vol. 1171, pp. 196–201, 2009. Gastrointestinal Adenocarcinoma, NCT01829178. 2025.
[183] Y. Nakamura, S. Yogosawa, Y. Izutani, H. Watanabe, E. Otsuji, [200] Herbert Irving Comprehensive Cancer Center and National
and T. Sakai, “A combination of indol-3-carbinol and genistein Cancer Institute, Silymarin (Milk Thistle Extract) in Treating
synergistically induces apoptosis in human colon cancer HT- Patients With Acute Lymphoblastic Leukemia Who Are Receiving
29 cells by inhibiting Akt phosphorylation and progression of Chemotherapy, NCT00055718, 2013.
autophagy,” Molecular Cancer, vol. 8, article 100, pp. 1476–4598, [201] J. Johnson and E. G. De Mejia, “Dietary factors and pancreatic
2009. cancer: the role of food bioactive compounds,” Molecular
[184] Northwestern University and National Cancer Institute, Genis- Nutrition and Food Research, vol. 55, no. 1, pp. 58–73, 2011.
tein in Treating Patients With Prostate Cancer, NCT01126879, [202] L. Gibellini, M. Pinti, M. Nasi, J. P. Montagna, S. De Biasi, and E.
2015. Roat, “Quercetin and cancer chemoprevention,” Evidence-Based
[185] Masonic Cancer Center and University of Minnesota, Genistein Complementary and Alternative Medicine, vol. 2011, Article ID
in Treating Patients Undergoing External-Beam Radiation Ther- 591356, 15 pages, 2011.
apy for Bone Metastases, NCT00769990, 2011. [203] R. Vidya Priyadarsini, R. Senthil Murugan, S. Maitreyi, K.
[186] UNC Lineberger Comprehensive Cancer Center, “National Ramalingam, D. Karunagaran, and S. Nagini, “The flavonoid
Cancer Institute (NCI) Information provided by (Responsible quercetin induces cell cycle arrest and mitochondria-mediated
Party):. genistein in preventing breast or endometrial cancer apoptosis in human cervical cancer (HeLa) cells through p53
in healthy postmenopausal women,” Tech. Rep. NCT00099008, induction and NF-𝜅B inhibition,” European Journal of Pharma-
2013. cology, vol. 649, no. 1–3, pp. 84–91, 2010.
[204] B.-E. Shan, M.-X. Wang, and R.-Q. Li, “Quercetin inhibit
[187] University of Wisconsin M and National Cancer Institute,
human SW480 colon cancer growth in association with inhi-
Genistein in Patients Who Are Undergoing Surgery for Bladder
bition of cyclin D1 and survivin expression through Wnt/𝛽-
Cancer, NCT00118040, 2010.
catenin signaling pathway,” Cancer Investigation, vol. 27, no. 6,
[188] D. R. Yoo, Y. H. Jang, Y. K. Jeon et al., “Proteomic identification pp. 604–612, 2009.
of anti-cancer proteins in luteolin-treated human hepatoma [205] F. Yang, L. Song, H. Wang, J. Wang, Z. Xu, and N. Xing,
Huh-7 cells,” Cancer Letters, vol. 282, no. 1, pp. 48–54, 2009. “Quercetin in prostate cancer: chemotherapeutic and chemo-
[189] Y. Lin, R. Shi, X. Wang, and H.-M. Shen, “Luteolin, a flavonoid preventive effects, mechanisms and clinical application poten-
with potential for cancer prevention and therapy,” Current tial (review),” Oncology Reports, vol. 33, no. 6, pp. 2659–2668,
Cancer Drug Targets, vol. 8, no. 7, pp. 634–646, 2008. 2015.
[206] S.-Y. Zheng, Y. Li, D. Jiang, J. Zhao, and J.-F. Ge, “Anticancer cancer patients,” Cancer Research, vol. 70, no. 19, pp. 7392–7399,
effect and apoptosis induction by quercetin in the human lung 2010.
cancer cell line A-549,” Molecular Medicine Reports, vol. 5, no. 3, [223] L. E. Wright, J. B. Frye, B. Gorti, B. N. Timmermann, and J.
pp. 822–826, 2012. L. Funk, “Bioactivity of turmeric-derived curcuminoids and
[207] S. C. Bischoff, University of Hohenheim, University Hospital related metabolites in breast cancer,” Current Pharmaceutical
Tuebingen, and Quercegen Pharmaceuticals, Prostate Cancer Design, vol. 19, no. 34, pp. 6218–6225, 2013.
Prevention Trial with Quercetin and Genistein (QUERGEN), [224] K.-W. Cheng, C. C. Wong, G. Mattheolabakis, G. Xie, L.
NCT01538316, 2012. Huang, and B. Rigas, “Curcumin enhances the lung cancer
[208] J. Zwicker, Dana-Farber Cancer Institute, Quercegen Pharma- chemopreventive efficacy of phospho-sulindac by improving its
ceuticals, National Heart, Lung, and Blood Institute (NHLBI), pharmacokinetics,” International Journal of Oncology, vol. 43,
Cancer Associated Thrombosis and Isoquercetin (CAT IQ), no. 3, pp. 895–902, 2013.
NCT02195232, 2015. [225] K. Madden, L. Flowers, R. Salani et al., “Proteomics-based
[209] D. R. Ferry, A. Smith, J. Malkhandi et al., “Phase I clinical trial of approach to elucidate the mechanism of antitumor effect of
the flavonoid quercetin: pharmacokinetics and evidence for in curcumin in cervical cancer,” Prostaglandins Leukotrienes and
vivo tyrosine kinase inhibition,” Clinical Cancer Research, vol. 2, Essential Fatty Acids, vol. 80, no. 1, pp. 9–18, 2009.
no. 4, pp. 659–668, 1996. [226] L.-D. Guo, X.-J. Chen, Y.-H. Hu, Z.-J. Yu, D. Wang, and J.-Z.
[210] L. G. Carter, J. A. D’Orazio, and K. J. Pearson, “Resveratrol and Liu, “Curcumin inhibits proliferation and induces apoptosis of
cancer: focus on in vivo evidence,” Endocrine-Related Cancer, human colorectal cancer cells by activating the mitochondria
vol. 21, no. 3, pp. R209–R225, 2014. apoptotic pathway,” Phytotherapy Research, vol. 27, no. 3, pp.
[211] I. Alfaras, M. Emı̀lia Juan, and J. M. Planas, “Trans-resveratrol 422–430, 2013.
reduces precancerous colonic lesions in dimethylhydrazine- [227] S. Bimonte, A. Barbieri, G. Palma, A. Luciano, D. Rea, and C.
treated rats,” Journal of Agricultural and Food Chemistry, vol. 58, Arra, “Curcumin inhibits tumor growth and angiogenesis in an
no. 13, pp. 8104–8110, 2010. orthotopic mouse model of human pancreatic cancer,” BioMed
[212] C. Salado, E. Olaso, N. Gallot et al., “Resveratrol prevents Research International, vol. 2013, Article ID 810423, 8 pages,
inflammation-dependent hepatic melanoma metastasis by 2013.
inhibiting the secretion and effects of interleukin-18,” Journal of [228] R. Wilken, M. S. Veena, M. B. Wang, and E. S. Srivatsan,
Translational Medicine, vol. 9, article 59, 2011. “Curcumin: a review of anti-cancer properties and therapeutic
[213] S. K. Roy, Q. Chen, J. Fu, S. Shankar, and R. K. Srivastava, activity in head and neck squamous cell carcinoma,” Molecular
“Resveratrol inhibits growth of orthotopic pancreatic tumors Cancer, vol. 10, article 12, 2011.
through activation of FOXO transcription factors,” PLoS ONE, [229] S.-X. Cui, X.-J. Qu, Y.-Y. Xie et al., “Curcumin inhibits telom-
vol. 6, no. 9, Article ID e25166, 2011. erase activity in human cancer cell lines,” International Journal
[214] S. Sheth, S. Jajoo, T. Kaur et al., “Resveratrol reduces prostate of Molecular Medicine, vol. 18, no. 2, pp. 227–231, 2006.
cancer growth and metastasis by inhibiting the Akt/MicroRNA- [230] H. Aoki, Y. Takada, S. Kondo, R. Sawaya, B. B. Aggarwal, and
21 pathway,” PLoS ONE, vol. 7, no. 12, Article ID e51655, 2012. Y. Kondo, “Evidence that curcumin suppresses the growth of
[215] N. Kalra, P. Roy, S. Prasad, and Y. Shukla, “Resveratrol induces malignant gliomas in vitro and in vivo through induction of
apoptosis involving mitochondrial pathways in mouse skin autophagy: role of akt and extracellular signal-regulated kinase
tumorigenesis,” Life Sciences, vol. 82, no. 7-8, pp. 348–358, 2008. signaling pathways,” Molecular Pharmacology, vol. 72, no. 1, pp.
[216] M.-L. Wu, H. Li, L.-J. Yu et al., “Short-term resveratrol exposure 29–39, 2007.
causes in vitro and in vivo growth inhibition and apoptosis of [231] M. D. Anderson Cancer Center, “Sabinsa Corporation. Trial
bladder cancer cells,” PLoS ONE, vol. 9, no. 2, Article ID e89806, of Curcumin in Advanced Pancreatic Cancer,” NCT00094445.
2014. 2014, 2016.
[217] K. S. Stakleff, T. Sloan, D. Blanco, S. Marcanthony, T. Booth, [232] N. Dhillon, B. B. Aggarwal, R. A. Newman et al., “Phase II
and A. Bishayee, “Resveratrol exerts differential effects in vitro trial of curcumin in patients with advanced pancreatic cancer,”
and in vivo against ovarian cancer cells,” Asian Pacific Journal of Clinical Cancer Research, vol. 14, no. 14, pp. 4491–4499, 2008.
Cancer Prevention, vol. 13, no. 4, pp. 1333–1340, 2012. [233] University of Rochester and J. Ryan, “Curcumin for the Pre-
[218] Chao Family Comprehensive Cancer Center, “University of vention of Radiation-induced Dermatitis in Breast Cancer
California, Irvine, University of California I, University of Patients,” NCT01042938. 2012; 2016.
California, Los Angeles,” Resveratrol for Patients with Colon [234] C. A. Nathan, Louisiana State University Health Sciences Center
Cancer. NCT00256334. 2014; 2016. Shreveport, Feist-Weiller Cancer Center, and National Cancer
[219] GlaxoSmithKline, “Sirtris. A Clinical Study to Assess the Institute (NCI), “Curcumin Biomarker Trial in Head and Neck
Safety, Pharmacokinetics, and Pharmacodynamics of SRT501 Cancer,” NCT01160302. 2014, 2016.
in Subjects with Colorectal Cancer and Hepatic Metastases,” [235] Curcumin Biomarkers, University of North Carolina, Chapel
NCT00920803. 2011, 2016. Hill, NC, USA, NCT01333917, 2013; 2016.
[220] National Cancer Institute (NCI), Resveratrol in Treating Patients [236] Tata Memorial Hospital and Pharmanza Herbals Pvt Limited
with Colorectal Cancer That Can Be Removed by Surgery, (PHPL), “Pilot Study of Curcumin Formulation and Ash-
NCT00433576, 2011/2016. wagandha Extract in Advanced Osteosarcoma (OSCAT),”
[221] University of Wisconsin, “A Biological Study of Resveratrol’s NCT00689195. 2011; 2016.
Effects on Notch-1 Signaling in Subjects with Low Grade [237] M. Cruz-Correa, D. A. Shoskes, P. Sanchez et al., “Combination
Gastrointestinal Tumors,” NCT01476592. 2015; 2016. treatment with curcumin and quercetin of adenomas in familial
[222] K. R. Patel, V. A. Brown, D. J. L. Jones et al., “Clinical adenomatous polyposis,” Clinical Gastroenterology and Hepatol-
pharmacology of resveratrol and its metabolites in colorectal ogy, vol. 4, no. 8, pp. 1035–1038, 2006.
[238] G. Garcea, D. J. L. Jones, R. Singh et al., “Detection of curcumin [253] X. Li, G. Wang, J. Zhao et al., “Antiproliferative effect of 𝛽-
and its metabolites in hepatic tissue and portal blood of patients elemene in chemoresistant ovarian carcinoma cells is mediated
following oral administration,” British Journal of Cancer, vol. 90, through arrest of the cell cycle at the G2-M phase,” Cellular and
no. 5, pp. 1011–1015, 2004. Molecular Life Sciences, vol. 62, no. 7-8, pp. 894–904, 2005.
[239] F.-Y. Tang, M.-H. Pai, Y.-H. Kuo, and X.-D. Wang, “Concomi- [254] Y.-Q. Yao, X. Ding, Y.-C. Jia, C.-X. Huang, Y.-Z. Wang, and Y.-
tant consumption of lycopene and fish oil inhibits tumor growth H. Xu, “Anti-tumor effect of 𝛽-elemene in glioblastoma cells
and progression in a mouse xenograft model of colon cancer,” depends on p38 MAPK activation,” Cancer Letters, vol. 264, no.
Molecular Nutrition and Food Research, vol. 56, no. 10, pp. 1520– 1, pp. 127–134, 2008.
1531, 2012. [255] W. Chen, Y. Lu, J. Wu, M. Gao, A. Wang, and B. Xu, “Beta-
[240] P. T. Uppala, T. Dissmore, B. H. S. Lau, T. Andacht, and S. elemene inhibits melanoma growth and metastasis via sup-
Rajaram, “Selective inhibition of cell proliferation by lycopene pressing vascular endothelial growth factor-mediated angio-
in MCF-7 breast cancer cells in vitro: a proteomic analysis,” genesis,” Cancer Chemotherapy and Pharmacology, vol. 67, no.
Phytotherapy Research, vol. 27, no. 4, pp. 595–601, 2013. 4, pp. 799–808, 2011.
[241] P. Palozza, R. E. Simone, A. Catalano, and M. C. Mele, “Tomato [256] J. Liu, Y. Zhang, J. Qu et al., “𝛽-elemene-induced autophagy
lycopene and lung cancer prevention: from experimental to protects human gastric cancer cells from undergoing apoptosis,”
human studies,” Cancers, vol. 3, no. 2, pp. 2333–2357, 2011. BMC Cancer, vol. 11, article 183, 2011.
[242] A. J. Teodoro, F. L. Oliveira, N. B. Martins, G. D. A. Maia, R. B. [257] Z. Chen and Sun Yat-sen University, “A Study on 𝛽-elemene as
Martucci, and R. Borojevic, “Effect of lycopene on cell viability Maintain Treatment for Complete Remission Patients of Newly
and cell cycle progression in human cancer cell lines,” Cancer Diagnosed Malignant Gliomas Following Standard Treatment
Cell International, vol. 12, article 36, 2012. (𝛽-elemene),” NCT02629757. 2015.
[243] P. E. Clark, M. C. Hall, L. S. Borden Jr. et al., “Phase I-II [258] A. E. Moran, A. M. Carothers, M. J. Weyant, M. Redston, and
prospective dose-escalating trial of lycopene in patients with M. M. Bertagnolli, “Carnosol inhibits 𝛽-catenin tyrosine phos-
biochemical relapse of prostate cancer after definitive local phorylation and prevents adenoma formation in the C57BL/
therapy,” Urology, vol. 67, no. 6, pp. 1257–1261, 2006. 6J/Min/+ (Min/+) mouse,” Cancer Research, vol. 65, no. 3, pp.
1097–1104, 2005.
[244] clinicaltrials.gov, “Clinical trials database,” 2015.
[259] J. J. Johnson, D. N. Syed, Y. Suh et al., “Disruption of androgen
[245] H. Kurihara, H. Koda, S. Asami, Y. Kiso, and T. Tanaka, “Con- and estrogen receptor activity in prostate cancer by a novel
tribution of the antioxidative property of astaxanthin to its dietary diterpene carnosol: implications for chemoprevention,”
protective effect on the promotion of cancer metastasis in mice Cancer Prevention Research, vol. 3, no. 9, pp. 1112–1123, 2010.
treated with restraint stress,” Life Sciences, vol. 70, no. 21, pp.
[260] M.-T. Huang, C.-T. Ho, Z. Yuan Wang et al., “Inhibition of skin
2509–2520, 2002.
tumorigenesis by rosemary and its constituents carnosol and
[246] T. Tanaka, Y. Morishita, M. Suzui, T. Kojima, A. Okumura, ursolic acid,” Cancer Research, vol. 54, no. 3, pp. 701–708, 1994.
and H. Mori, “Chemoprevention of mouse urinary bladder car- [261] R. Iratni, Y. Al Dhaheri, S. Attoub, N. Karuventevida, and K.
cinogenesis by the naturally occurring carotenoid astaxanthin,” Arafat, “P0174 Anti-metastatic and anti-tumour growth effects
Carcinogenesis, vol. 15, no. 1, pp. 15–19, 1994. of carnosol on breast cancer through autophagy and apoptosis,”
[247] T. Tanaka, H. Makita, M. Ohnishi, H. Mori, K. Satoh, and A. European Journal of Cancer, vol. 50, supplement 4, p. e59, 2014.
Hara, “Chemoprevention of rat oral carcinogenesis by naturally [262] D. Vergara, P. Simeone, S. Bettini et al., “Antitumor activity of
occurring xanthophylls, astaxanthin and canthaxanthin,” Can- the dietary diterpene carnosol against a panel of human cancer
cer Research, vol. 55, no. 18, pp. 4059–4064, 1995. cell lines,” Food and Function, vol. 5, no. 6, pp. 1261–1269, 2014.
[248] H. Jyonouchi, S. Sun, K. Iijima, and M. D. Gross, “Antitumor [263] S.-C. Huang, C.-T. Ho, S.-Y. Lin-Shiau, and J.-K. Lin, “Carnosol
activity of astaxanthin and its mode of action,” Nutrition and inhibits the invasion of B16/F10 mouse melanoma cells by sup-
Cancer, vol. 36, no. 1, pp. 59–65, 2000. pressing metalloproteinase-9 through down-regulating nuclear
[249] A. R. Rao, H. N. Sindhuja, S. M. Dharmesh, K. U. Sankar, R. factor-kappaB and c-Jun,” Biochemical Pharmacology, vol. 69,
Sarada, and G. A. Ravishankar, “Effective inhibition of skin no. 2, pp. 221–232, 2005.
cancer, tyrosinase, and antioxidative properties by astaxanthin [264] J. J. Gills, E. H. Jeffery, N. V. Matusheski, R. C. Moon, D. D.
and astaxanthin esters from the green alga haematococcus Lantvit, and J. M. Pezzuto, “Sulforaphane prevents mouse skin
pluvialis,” Journal of Agricultural and Food Chemistry, vol. 61, tumorigenesis during the stage of promotion,” Cancer Letters,
no. 16, pp. 3842–3851, 2013. vol. 236, no. 1, pp. 72–79, 2006.
[250] T. Tanaka, T. Kawamori, M. Ohnishi et al., “Suppression of [265] G. Shen, O. K. Tin, R. Hu et al., “Chemoprevention of familial
azoxymethane-induced rat colon carcinogenesis by dietary adenomatous polyposis by natural dietary compounds sul-
administration of naturally occurring xanthophylls astaxanthin foraphane and dibenzoylmethane alone and in combination in
and canthaxanthin during the postinitiation phase,” Carcino- Apc Min/+ mouse,” Cancer Research, vol. 67, no. 20, pp. 9937–
genesis, vol. 16, no. 12, pp. 2957–2963, 1995. 9944, 2007.
[251] P. Palozza, C. Torelli, A. Boninsegna et al., “Growth-inhibitory [266] S. V. Singh, R. Warin, D. Xiao et al., “Sulforaphane inhibits
effects of the astaxanthin-rich alga Haematococcus pluvialis in prostate carcinogenesis and pulmonary metastasis in TRAMP
human colon cancer cells,” Cancer Letters, vol. 283, no. 1, pp. mice in association with increased cytotoxicity of natural killer
108–117, 2009. cells,” Cancer Research, vol. 69, no. 5, pp. 2117–2125, 2009.
[252] Q. Q. Li, G. Wang, F. Huang, M. Banda, and E. Reed, “Anti- [267] B. Abbaoui, K. M. Riedl, R. A. Ralston et al., “Inhibition of blad-
neoplastic effect of 𝛽-elemene on prostate cancer cells and der cancer by broccoli isothiocyanates sulforaphane and erucin:
other types of solid tumour cells,” Journal of Pharmacy and characterization, metabolism, and interconversion,” Molecular
Pharmacology, vol. 62, no. 8, pp. 1018–1027, 2010. Nutrition and Food Research, vol. 56, no. 11, pp. 1675–1687, 2012.
[268] B. S. Cornblatt, L. Ye, A. T. Dinkova-Kostova et al., “Preclinical study with EGCG and sulindac or tamoxifen,” Mutation
and clinical evaluation of sulforaphane for chemoprevention in Research/Fundamental and Molecular Mechanisms of Mutagen-
the breast,” Carcinogenesis, vol. 28, no. 7, pp. 1485–1490, 2007. esis, vol. 523-524, pp. 119–125, 2003.
[269] J.-S. Yang, G.-W. Chen, T.-C. Hsia et al., “Diallyl disulfide [282] Y. H. Ju, D. R. Doerge, K. F. Allred, C. D. Allred, and W.
induces apoptosis in human colon cancer cell line (COLO 205) G. Helferich, “Dietary genistein negates the inhibitory effect
through the induction of reactive oxygen species, endoplasmic of tamoxifen on growth of estrogen-dependent human breast
reticulum stress, caspases casade and mitochondrial-dependent cancer (MCF-7) cells implanted in athymic mice,” Cancer
pathways,” Food and Chemical Toxicology, vol. 47, no. 1, pp. 171– Research, vol. 62, no. 9, pp. 2474–2477, 2002.
179, 2009. [283] S. Banerjee, Y. Zhang, S. Ali et al., “Molecular evidence for
[270] G. Filomeni, K. Aquilano, G. Rotilio, and M. R. Ciriolo, “Reac- increased antitumor activity of gemcitabine by genistein in vitro
tive oxygen species-dependent c-Jun NH2-terminal kinase/c- and in vivo using an orthotopic model of pancreatic cancer,”
Jun signaling cascade mediates neuroblastoma cell death Cancer Research, vol. 65, no. 19, pp. 9064–9072, 2005.
induced by diallyl disulfide,” Cancer Research, vol. 63, no. 18, pp. [284] Barbara Ann Karmanos Cancer Institute and National Cancer
5940–5949, 2003. Institute (NCI), Gemcitabine Hydrochloride and Genistein in
[271] D. Xiao, S. Choi, D. E. Johnson et al., “Diallyl trisulfide- Treating Women with Stage IV Breast Cancer, NCT00244933,
induced apoptosis in human prostate cancer cells involves c-Jun 2015.
N-terminal kinase and extracellular-signal regulated kinase- [285] B. Zhang, Z.-L. Shi, B. Liu, X.-B. Yan, J. Feng, and H.-M.
mediated phosphorylation of Bcl-2,” Oncogene, vol. 23, no. 33, Tao, “Enhanced anticancer effect of gemcitabine by genistein
pp. 5594–5606, 2004. in osteosarcoma: the role of Akt and nuclear factor-𝜅B,” Anti-
[272] J.-S. Yang, L.-F. Kok, Y.-H. Lin et al., “Diallyl disulfide inhibits Cancer Drugs, vol. 21, no. 3, pp. 288–296, 2010.
WEHI-3 leukemia cells in vivo,” Anticancer Research, vol. 26, no. [286] H. Bittencourt, “St. Justine’s Hospital. Phase I/II a study of
1, pp. 219–225, 2006. decitabine in combination with genistein in pediatric relapsed
[273] H. A. Shin, Y. Y. Cha, M. S. Park, J. M. Kim, and Y. C. or refractory malignancies,” Tech. Rep. NCT02499861, 2016.
Lim, “Diallyl sulfide induces growth inhibition and apoptosis [287] Uman Pharma, DSM Nutritional Products I, MDEIE Min-
of anaplastic thyroid cancer cells by mitochondrial signaling istry, Québec Government INRS-Institut Armand Frappier,
pathway,” Oral Oncology, vol. 46, no. 4, pp. e15–e18, 2010. and Université du Québec, “Genistein and Interleukin-2 in
[274] A. A. Baskar, S. Ignacimuthu, G. M. Paulraj, and K. S. Al Numair, Treating Patients with Metastatic Melanoma or Kidney Cancer,”
“Chemopreventive potential of 𝛽-Sitosterol in experimental NCT01628471. 2015, 2015.
colon cancer model—an in vitro and in vivo study,” BMC [288] T. Kuzel, “Northwestern University, National Cancer Insti-
Complementary and Alternative Medicine, vol. 10, article 24, tute (NCI). Genistein and Interleukin-2 in treating patients
2010. with metastatic melanoma or kidney cancer,” Tech. Rep.
[275] A. B. Awad, M. Chinnam, C. S. Fink, and P. G. Bradford, “𝛽- NCT00276835, 2015.
sitosterol activates Fas signaling in human breast cancer cells,” [289] J.-T. Hwang, J. Ha, and O. J. Park, “Combination of 5-flu-
Phytomedicine, vol. 14, no. 11, pp. 747–754, 2007. orouracil and genistein induces apoptosis synergistically in
[276] Y. Zhao, S. K. C. Chang, G. Qu, T. Li, and H. Cui, “𝛽- chemo-resistant cancer cells through the modulation of AMPK
Sitosterol inhibits cell growth and induces apoptosis in SGC- and COX-2 signaling pathways,” Biochemical and Biophysical
7901 human stomach cancer cells,” Journal of Agricultural and Research Communications, vol. 332, no. 2, pp. 433–440, 2005.
Food Chemistry, vol. 57, no. 12, pp. 5211–5218, 2009. [290] Y. Li, F. Ahmed, S. Ali, P. A. Philip, O. Kucuk, and F. H. Sarkar,
[277] R. L. Von Holtz, C. S. Fink, and A. B. Awad, “𝛽-sitosterol “Inactivation of nuclear factor 𝜅B by soy isoflavone genistein
activates the sphingomyelin cycle and induces apoptosis in contributes to increased apoptosis induced by chemotherapeu-
LNCaP human prostate cancer cells,” Nutrition and Cancer, vol. tic agents in human cancer cells,” Cancer Research, vol. 65, no.
32, no. 1, pp. 8–12, 1998. 15, pp. 6934–6942, 2005.
[278] D.-O. Moon, K.-J. Lee, Y. H. Choi, and G.-Y. Kim, “𝛽-Sitosterol- [291] L. A. Solomon, S. Ali, S. Banerjee, A. R. Munkarah, R. T. Morris,
induced-apoptosis is mediated by the activation of ERK and the and F. H. Sarkar, “Sensitization of ovarian cancer cells to cis-
downregulation of Akt in MCA-102 murine fibrosarcoma cells,” platin by genistein: the role of NF-kappaB,” Journal of Ovarian
International Immunopharmacology, vol. 7, no. 8, pp. 1044–1053, Research, vol. 1, no. 1, article 9, 2008.
2007. [292] B. F. El-Rayes, P. A. Philip, F. H. Sarkar et al., “A phase II study of
[279] A. González-Sarrı́as, J. Tomé-Carneiro, A. Bellesia, F. A. Tomás- isoflavones, erlotinib, and gemcitabine in advanced pancreatic
Barberán, and J. C. Espı́n, “The ellagic acid-derived gut micro- cancer,” Investigational New Drugs, vol. 29, no. 4, pp. 694–699,
biota metabolite, urolithin A, potentiates the anticancer effects 2011.
of 5-fluorouracil chemotherapy on human colon cancer cells,” [293] B. F. El-Rayes, S. Ali, I. F. Ali, P. A. Philip, J. Abbruzzese, and F.
Food and Function, vol. 6, no. 5, pp. 1460–1469, 2015. H. Sarkar, “Potentiation of the effect of erlotinib by genistein in
[280] C. V. Rao, K. Tokumo, J. Rigotty, E. Zang, G. Kelloff, and B. S. pancreatic cancer: the role of Akt and nuclear factor-𝜅B,” Cancer
Reddy, “Chemoprevention of colon carcinogenesis by dietary Research, vol. 66, no. 21, pp. 10553–10559, 2006.
administration of piroxicam, alpha-difluoromethylornithine, 16 [294] Barbara Ann Karmanos Cancer Institute and National Can-
alpha-fluoro-5-androsten-17-one, and ellagic acid individually cer Institute (NCI), “Genistein, gemcitabine, and erlotinib in
and in combination,” Cancer Research, vol. 51, pp. 4528–4534, treating patients with locally advanced or metastatic pancreatic
1991. cancer,” Tech. Rep. NCT00376948, 2014.
[281] H. Fujiki, M. Suganuma, M. Kurusu et al., “New TNF-𝛼 [295] Y.-W. Jeon and Y. J. Suh, “Synergistic apoptotic effect of
releasing inhibitors as cancer preventive agents from tradi- celecoxib and luteolin on breast cancer cells,” Oncology Reports,
tional herbal medicine and combination cancer prevention vol. 29, no. 2, pp. 819–825, 2013.
[296] P. Wang, S. Henning, D. Heber, and J. Vadgama, “Enhanced and Pharmacokinetics of Irinotecan in Patients with Solid
inhibition of PC-3 xenograft prostate tumor growth by com- Tumors,” NCT01859858. 2016, 2015.
bination of green tea and quercetin with docetaxel,” Cancer [310] University of Leicester, “Combining Curcumin with FOLFOX
Research, vol. 75, article 5345, 2015. Chemotherapy in Patients with Inoperable Colorectal Cancer
[297] L. Chuang-Xin, W. Wen-Yu, C. Yao, L. Xiao-Yan, and Z. Yun, (CUFOX),” NCT01490996. 2016, 2015.
“Quercetin enhances the effects of 5-fluorouracil-mediated [311] M.D. Anderson Cancer Center, “Curcumin with pre-operative
growth inhibition and apoptosis of esophageal cancer cells by capecitabine and radiation therapy followed by surgery for
inhibiting NF-𝜅B,” Oncology Letters, vol. 4, no. 4, pp. 775–778, rectal cancer,” Tech. Rep. NCT00745134, 2015.
2012. [312] M. Shakibaei, A. Mobasheri, C. Lueders, F. Busch, P. Shayan,
[298] C. P. R. Xavier, C. F. Lima, M. Rohde, and C. Pereira- and A. Goel, “Curcumin enhances the effect of chemotherapy
Wilson, “Quercetin enhances 5-fluorouracil-induced apoptosis against colorectal cancer cells by inhibition of NF-𝜅B and Src
in MSI colorectal cancer cells through p53 modulation,” Cancer protein kinase signaling pathways,” PLoS ONE, vol. 8, no. 2,
Chemotherapy and Pharmacology, vol. 68, no. 6, pp. 1449–1457, Article ID e57218, 2013.
2011. [313] J. Nautiyal, S. Banerjee, S. S. Kanwar et al., “Curcumin enhances
[299] W. Dai, Q. Gao, J. Qiu, J. Yuan, G. Wu, and G. Shen, “Quercetin dasatinib-induced inhibition of growth and transformation of
induces apoptosis and enhances 5-FU therapeutic efficacy in colon cancer cells,” International Journal of Cancer, vol. 128, no.
hepatocellular carcinoma,” Tumor Biology, vol. 37, no. 5, pp. 4, pp. 951–961, 2011.
6307–6313, 2016. [314] B. B. Aggarwal, S. Shishodia, Y. Takada et al., “Curcumin
[300] University of Medicine and Dentistry of New Jersey and suppresses the paclitaxel-induced nuclear factor-𝜅B pathway in
National Cancer Institute (NCI), “Sulindac and plant com- breast cancer cells and inhibits lung metastasis of human breast
pounds in preventing colon cancer,” Compounds in Preventing cancer in nude mice,” Clinical Cancer Research, vol. 11, no. 20,
Colon Cancer NCT00003365, 2011. pp. 7490–7498, 2005.
[301] A. K. Jain, K. Thanki, and S. Jain, “Co-encapsulation of tamox- [315] S. Lev-Ari, L. Strier, D. Kazanov et al., “Celecoxib and curcumin
ifen and quercetin in polymeric nanoparticles: implications synergistically inhibit the growth of colorectal cancer cells,”
on oral bioavailability, antitumor efficacy, and drug-induced Clinical Cancer Research, vol. 11, no. 18, pp. 6738–6744, 2005.
toxicity,” Molecular Pharmaceutics, vol. 10, no. 9, pp. 3459–3474, [316] N. Rocks, S. Bekaert, I. Coia et al., “Curcumin-cyclodextrin
2013. complexes potentiate gemcitabine effects in an orthotopic
mouse model of lung cancer,” British Journal of Cancer, vol. 107,
[302] X. Wang, Y. Chen, F. Z. Dahmani, L. Yin, J. Zhou, and J.
no. 7, pp. 1083–1092, 2012.
Yao, “Amphiphilic carboxymethyl chitosan-quercetin conjugate
with P-gp inhibitory properties for oral delivery of paclitaxel,” [317] N. P. Aditya, M. Shim, I. Lee, Y. Lee, M.-H. Im, and S. Ko,
Biomaterials, vol. 35, no. 26, pp. 7654–7665, 2014. “Curcumin and genistein coloaded nanostructured lipid carri-
ers: in vitro digestion and antiprostate cancer activity,” Journal
[303] X. He, Y. Wang, J. Zhu, M. Orloff, and C. Eng, “Resvera-
of Agricultural and Food Chemistry, vol. 61, no. 8, pp. 1878–1883,
trol enhances the anti-tumor activity of the mTOR inhibitor
2013.
rapamycin in multiple breast cancer cell lines mainly by sup-
pressing rapamycin-induced AKT signaling,” Cancer Letters, [318] Y. Tang, B. Parmakhtiar, A. R. Simoneau et al., “Lycopene
vol. 301, no. 2, pp. 168–176, 2011. enhances docetaxel’s effect in castration-resistant prostate can-
cer associated with insulin-like growth factor I receptor levels,”
[304] T. H. Kim, Y. J. Shin, A. J. Won et al., “Resveratrol enhances Neoplasia, vol. 13, no. 2, pp. 108–119, 2011.
chemosensitivity of doxorubicin in multidrug-resistant human
[319] Medical University of South Carolina and National Cancer
breast cancer cells via increased cellular influx of doxorubicin,”
Institute (NCI), Docetaxel and Lycopene in Metastatic Prostate
Biochimica et Biophysica Acta (BBA)—General Subjects, vol.
Cancer, NCT01949519, 2015.
1840, no. 1, pp. 615–625, 2014.
[320] K. S. Snima, P. Arunkumar, R. Jayakumar, and V.-K. Laksh-
[305] C.-J. Lin, C.-C. Lee, Y.-L. Shih et al., “Resveratrol enhances the manan, “Silymarin encapsulated poly (D, L-lactic-co-glycolic
therapeutic effect of temozolomide against malignant glioma in acid) nanoparticles: a prospective candidate for prostate cancer
vitro and in vivo by inhibiting autophagy,” Free Radical Biology therapy,” Journal of Biomedical Nanotechnology, vol. 10, no. 4,
and Medicine, vol. 52, no. 2, pp. 377–391, 2012. pp. 559–570, 2014.
[306] J. Y. Chan, S. P. Meng, M.-V. Clement, S. Pervaiz, and C. L. [321] D. Bielska, A. Karewicz, K. Kamiński et al., “Self-organized
Shao, “Resveratrol displays converse dose-related effects on 5- thermo-responsive hydroxypropyl cellulose nanoparticles for
fluorouracilevoked colon cancer cell apoptosis: the roles of curcumin delivery,” European Polymer Journal, vol. 49, no. 9, pp.
caspase-6 and p53,” Cancer Biology and Therapy, vol. 7, no. 8, 2485–2494, 2013.
pp. 1305–1312, 2008.
[322] A. Abderrezak, P. Bourassa, J.-S. Mandeville, R. Sedaghat-
[307] I. Ali and D. P. Braun, “Resveratrol enhances mitomycin C- Herati, and H.-A. Tajmir-Riahi, “Dendrimers bind antioxidant
mediated suppression of human colorectal cancer cell prolifer- polyphenols and cisplatin drug,” PLoS ONE, vol. 7, no. 3, Article
ation by up-regulation of p21WAF1/CIP1,” Anticancer Research, ID e33102, 2012.
vol. 34, no. 10, pp. 5439–5446, 2014. [323] L. Wang, X. Xu, Y. Zhang et al., “Encapsulation of curcumin
[308] D.-J. Zhu, X.-W. Chen, J.-Z. Wang, Y.-L. Ju, M.-Z. O. Yang, and within poly(amidoamine) dendrimers for delivery to cancer
W.-J. Zhang, “Proteomic analysis identifies proteins associated cells,” Journal of Materials Science: Materials in Medicine, vol.
with curcumin-enhancing efficacy of irinotecan-induced apop- 24, no. 9, pp. 2137–2144, 2013.
tosis of colorectal cancer LOVO cell,” International Journal of [324] S. Manju and K. Sreenivasan, “Conjugation of curcumin onto
Clinical and Experimental Pathology, vol. 7, no. 1, article 7, 2014. hyaluronic acid enhances its aqueous solubility and stability,”
[309] UNC Lineberger Comprehensive Cancer Center, “A Prospective Journal of Colloid and Interface Science, vol. 359, no. 1, pp. 318–
Evaluation of the Effect of Curcumin on Dose Limiting Toxicity 325, 2011.
[325] S. Dey and K. Sreenivasan, “Conjugation of curcumin onto [340] H. Wu, C. Lu, A. Zhou, Z. Min, and Y. Zhang, “Enhanced oral
alginate enhances aqueous solubility and stability of curcumin,” bioavailability of puerarin using microemulsion vehicle,” Drug
Carbohydrate Polymers, vol. 99, pp. 499–507, 2014. Development and Industrial Pharmacy, vol. 35, no. 2, pp. 138–
[326] K. Miyake, H. Arima, F. Hirayama et al., “Improvement of sol- 144, 2009.
ubility and oral bioavailability of rutin by complexation with 2- [341] N. Chouhan, V. Mittal, D. Kaushik, A. Khatkar, and M. Raina,
hydroxypropyl-𝛽-cyclodextrin,” Pharmaceutical Development “Self emulsifying drug delivery system (SEDDS) for phytocon-
and Technology, vol. 5, no. 3, pp. 399–407, 2000. stituents: a review,” Current Drug Delivery, vol. 12, no. 2, pp.
[327] C. Folch-Cano, J. Guerrero, H. Speisky, C. Jullian, and C. Olea- 244–253, 2015.
Azar, “NMR and molecular fluorescence spectroscopic study [342] Y. Bongkyu, Y. J. Hee, and S. Srinivasan, “Oral pharmaceutical
of the structure and thermodynamic parameters of EGCG/𝛽- composition containing lutein using self microemulsion sys-
cyclodextrin inclusion complexes with potential antioxidant tem,” 2011.
activity,” Journal of Inclusion Phenomena and Macrocyclic [343] L. Zhao, L. Zhang, L. Meng, J. Wang, and G. Zhai, “Design and
Chemistry, vol. 78, no. 1–4, pp. 287–298, 2014. evaluation of a self-microemulsifying drug delivery system for
[328] X. Cao, W.-W. Deng, M. Fu et al., “In vitro release and in vitro- apigenin,” Drug Development and Industrial Pharmacy, vol. 39,
in vivo correlation for silybin meglumine incorporated into no. 5, pp. 662–669, 2013.
Hollow-type mesoporous silica nanoparticles,” International [344] Y. Zhang, R. Wang, J. Wu, and Q. Shen, “Characterization and
Journal of Nanomedicine, vol. 7, pp. 753–762, 2012. evaluation of self-microemulsifying sustained-release pellet
[329] H. Chen, J. Wu, M. Sun et al., “N-trimethyl chitosan chloride- formulation of puerarin for oral delivery,” International Journal
coated liposomes for the oral delivery of curcumin,” Journal of of Pharmaceutics, vol. 427, no. 2, pp. 337–344, 2012.
Liposome Research, vol. 22, no. 2, pp. 100–109, 2012. [345] F. Xiaoyan, L. Jun, and W. Wen, “Study on the absorption
[330] E. Aboutaleb, F. Atyabi, M. R. Khoshayand et al., “Improved kinetics of hesperidin self-microemulsion in rat’s intestine,”
brain delivery of vincristine using dextran sulfate complex Acta Universitatis Medicinalis Anhui, vol. 8, article 010, 2011.
solid lipid nanoparticles: optimization and in vivo evaluation,” [346] J.-X. Zhu, D. Tang, L. Feng et al., “Development of self-
Journal of Biomedical Materials Research—Part A, vol. 102, no. microemulsifying drug delivery system for oral bioavailability
7, pp. 2125–2136, 2014. enhancement of berberine hydrochloride,” Drug Development
and Industrial Pharmacy, vol. 39, no. 3, pp. 499–506, 2013.
[331] Y. Wang, L. Dou, H. He, Y. Zhang, and Q. Shen, “Multi-
functional nanoparticles as nanocarrier for vincristine sulfate [347] Y. Zhao, C. Wang, A. H. L. Chow et al., “Self-nanoemulsifying
delivery to overcome tumor multidrug resistance,” Molecular drug delivery system (SNEDDS) for oral delivery of Zedoary
Pharmaceutics, vol. 11, no. 3, pp. 885–894, 2014. essential oil: formulation and bioavailability studies,” Interna-
tional Journal of Pharmaceutics, vol. 383, no. 1-2, pp. 170–177,
[332] R. Lian, Y. Lu, J. Qi et al., “Silymarin glyceryl monooleate/
2010.
poloxamer 407 liquid crystalline matrices: physical character-
ization and enhanced oral bioavailability,” AAPS PharmSciTech, [348] J. Xi, Q. Chang, C. K. Chan et al., “Formulation development
vol. 12, no. 4, pp. 1234–1240, 2011. and bioavailability evaluation of a self-nanoemulsified drug
delivery system of oleanolic acid,” AAPS PharmSciTech, vol. 10,
[333] B. Ding, P. Chen, Y. Kong et al., “Preparation and evaluation no. 1, pp. 172–182, 2009.
of folate-modified lipid nanocapsules for quercetin delivery,”
[349] S. K. Mantri, S. Pashikanti, and K. V. R. Murthy, “Development
Journal of Drug Targeting, vol. 22, no. 1, pp. 67–75, 2014.
and characterization of self-nanoemulsifying drug delivery
[334] Y.-Q. Zhao, L.-P. Wang, C. Ma, K. Zhao, Y. Liu, and N.-P. Feng, systems (SNEDDS) of atorvastatin calcium,” Current Drug
“Preparation and characterization of tetrandrine-phospholipid Delivery, vol. 9, no. 2, pp. 182–196, 2012.
complex loaded lipid nanocapsules as potential oral carriers,” [350] C. Zhang, C. Gu, F. Peng et al., “Preparation and optimization of
International Journal of Nanomedicine, vol. 8, pp. 4169–4181, triptolide-loaded solid lipid nanoparticles for oral delivery with
2013. reduced gastric irritation,” Molecules, vol. 18, no. 11, pp. 13340–
[335] Y. Yu, Y. Lu, R. Bo et al., “The preparation of gypenosides lipo- 13356, 2013.
somes and its effects on the peritoneal macrophages function in [351] Y.-J. Dang and C.-Y. Zhu, “Oral bioavailability of cantharidin-
vitro,” International Journal of Pharmaceutics, vol. 460, no. 1-2, loaded solid lipid nanoparticles,” Chinese Medicine, vol. 8,
pp. 248–254, 2014. article 1, 2013.
[336] A. Karewicz, D. Bielska, A. Loboda et al., “Curcumin-containing [352] A. R. Neves, M. Lúcio, S. Martins, J. L. C. Lima, and S.
liposomes stabilized by thin layers of chitosan derivatives,” Reis, “Novel resveratrol nanodelivery systems based on lipid
Colloids and Surfaces B: Biointerfaces, vol. 109, pp. 307–316, 2013. nanoparticles to enhance its oral bioavailability,” International
[337] X. Luo, R. Guan, X. Chen, M. Tao, J. Ma, and J. Zhao, “Opti- Journal of Nanomedicine, vol. 8, pp. 177–187, 2013.
mization on condition of epigallocatechin-3-gallate (EGCG) [353] Y. Chen, L. Pan, M. Jiang, D. Li, and L. Jin, “Nanostructured lipid
nanoliposomes by response surface methodology and cellular carriers enhance the bioavailability and brain cancer inhibitory
uptake studies in Caco-2 cells,” Nanoscale Research Letters, vol. efficacy of curcumin both in vitro and in vivo,” Drug Delivery,
9, no. 1, pp. 1–9, 2014. vol. 23, no. 4, pp. 1383–1392, 2016.
[338] J. Li, J. Chen, B.-C. Cai, and T. Yang, “Preparation, characteri- [354] M. Tsai, P. Wu, Y. Huang et al., “Baicalein loaded in tocol nanos-
zation and tissue distribution of brucine stealth liposomes with tructured lipid carriers (tocol NLCs) for enhanced stability and
different lipid composition,” Pharmaceutical Development and brain targeting,” International Journal of Pharmaceutics, vol.
Technology, vol. 18, no. 4, pp. 772–778, 2013. 423, pp. 461–470, 2012.
[339] J. Chen, G.-J. Yan, R.-R. Hu et al., “Improved pharmacokinetics [355] F. Shi, G. Yang, J. Ren, T. Guo, Y. Du, and N. Feng, “Formulation
and reduced toxicity of brucine after encapsulation into stealth design, preparation, and in vitro and in vivo characterizations of
liposomes: role of phosphatidylcholine,” International Journal of 𝛽-elemene-loaded nanostructured lipid carriers,” International
Nanomedicine, vol. 7, pp. 3567–3577, 2012. Journal of Nanomedicine, vol. 8, pp. 2533–2541, 2013.
[356] F. Li, Y. Weng, L. Wang, H. He, J. Yang, and X. Tang, “The studies for glioma,” European Journal of Pharmacology, vol. 718,
efficacy and safety of bufadienolides-loaded nanostructured no. 1–3, pp. 41–47, 2013.
lipid carriers,” International Journal of Pharmaceutics, vol. 393, [371] X. Tian, H. Yin, S. Zhang et al., “Bufalin loaded biotinylated
no. 1-2, pp. 204–212, 2010. chitosan nanoparticles: an efficient drug delivery system for
[357] M. Li, Y. Zheng, F.-Y. Shan, J. Zhou, T. Gong, and Z.-R. targeted chemotherapy against breast carcinoma,” European
Zhang, “Development of ionic-complex-based nanostructured Journal of Pharmaceutics and Biopharmaceutics, vol. 87, no. 3,
lipid carriers to improve the pharmacokinetic profiles of brevis- pp. 445–453, 2014.
capine,” Acta Pharmacologica Sinica, vol. 34, no. 8, pp. 1108–1115,
2013.
[358] X. Ma, J. Zhou, C.-X. Zhang et al., “Modulation of drug-resistant
membrane and apoptosis proteins of breast cancer stem cells by
targeting berberine liposomes,” Biomaterials, vol. 34, no. 18, pp.
4452–4465, 2013.
[359] Y.-Z. Zhao, C.-T. Lu, Y. Zhang et al., “Selection of high
efficient transdermal lipid vesicle for curcumin skin delivery,”
International Journal of Pharmaceutics, vol. 454, no. 1, pp. 302–
309, 2013.
[360] K. Hu, L. Zhu, H. Liang, F. Hu, and J. Feng, “Improved anti-
tumor efficacy and reduced toxicity of liposomes containing
bufadienolides,” Archives of Pharmacal Research, vol. 34, no. 9,
pp. 1487–1494, 2011.
[361] L.-N. Shen, Y.-T. Zhang, Q. Wang, L. Xu, and N.-P. Feng,
“Enhanced in vitro and in vivo skin deposition of apigenin
delivered using ethosomes,” International Journal of Pharma-
ceutics, vol. 460, no. 1-2, pp. 280–288, 2014.
[362] R. G. Madane and H. S. Mahajan, “Curcumin-loaded nanos-
tructured lipid carriers (NLCs) for nasal administration: design,
characterization, and in vivo study,” Drug Delivery, vol. 23, no.
4, pp. 1326–1334, 2016.
[363] J. Li, X. Guo, Z. Liu et al., “Preparation and evaluation of
charged solid lipid nanoparticles of tetrandrine for ocular drug
delivery system: pharmacokinetics, cytotoxicity and cellular
uptake studies,” Drug Development and Industrial Pharmacy,
vol. 40, no. 7, pp. 980–987, 2014.
[364] A. Anitha, V. G. Deepagan, V. V. D. Rani, D. Menon, S. V.
Nair, and R. Jayakumar, “Preparation, characterization, in vitro
drug release and biological studies of curcumin loaded dextran
sulphate-chitosan nanoparticles,” Carbohydrate Polymers, vol.
84, no. 3, pp. 1158–1164, 2011.
[365] J. Duan, Y. Zhang, S. Han et al., “Synthesis and in vitro/in vivo
anti-cancer evaluation of curcumin-loaded chitosan/poly(butyl
cyanoacrylate) nanoparticles,” International Journal of Pharma-
ceutics, vol. 400, no. 1-2, pp. 211–220, 2010.
[366] L. Bu, L.-C. Gan, X.-Q. Guo et al., “Trans-resveratrol loaded
chitosan nanoparticles modified with biotin and avidin to target
hepatic carcinoma,” International Journal of Pharmaceutics, vol.
452, no. 1-2, pp. 355–362, 2013.
[367] Q. Yao, L. Gan, S. Hou et al., “Development and biodistribution
of trans-resveratrol loaded chitosan nanoparticles with free
amino groups,” Latin American Journal of Pharmacy, vol. 31, no.
7, pp. 1038–1042, 2012.
[368] D. Zheng, C. Duan, D. Zhang et al., “Galactosylated chitosan
nanoparticles for hepatocyte-targeted delivery of oridonin,”
International Journal of Pharmaceutics, vol. 436, no. 1-2, pp. 379–
386, 2012.
[369] Z. Wang, Y. Yu, J. Ma et al., “LyP-1 modification to enhance
delivery of Artemisinin or fluorescent probe loaded polymeric
micelles to highly metastatic tumor and its lymphatics,” Molec-
ular Pharmaceutics, vol. 9, no. 9, pp. 2646–2657, 2012.
[370] W. Guo, A. Li, Z. Jia, Y. Yuan, H. Dai, and H. Li, “Transferrin
modified PEG-PLA-resveratrol conjugates: in vitro and in vivo

Improving in Vivo Efficacy of Bioactive Molecules

Uploaded by

Copyright:

Available Formats

Improving in Vivo Efficacy of Bioactive Molecules

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Improving in Vivo Efficacy of Bioactive Molecules

Uploaded by

Copyright:

Available Formats

Hindawi

Lamia Mouhid,1 Marta Corzo-Martínez,2 Carlos Torres,2 Luis Vázquez,2

Correspondence should be addressed to Ana Ramı́rez de Molina; [email protected]

Received 29 December 2016; Accepted 6 March 2017; Published 7 May 2017

Academic Editor: Akira Hara

1. Introduction However, despite their promising benefits in vitro, results

Polyphenols Phytochemical Main source Clinical trials Chemical structure

Table 2: Terpenes, organosulfur, and phytosterols commonly studied in cancer therapy.

Short systemic circulation time

Polymeric micelles (PM)

Nanostructured lipid carriers (NLCs)

Lipid and polymeric nanocapsules

(I) Gastric digestion

(II) Intestinal digestion Gastric lipase

(III) Lipid and active agent absorption

(A) (B) (C) (D) (E)

Liver Lymph node

(A) Conventional liposome (D) Theranostic liposome

higher control release and specific delivery of the loaded

Table 5: Overview of lipid-based delivery systems to administer phytochemicals by oral route.

Active ingredient Lipid-based formulation Effect of formulation Ref.

You might also like