Approved Abstract

molecules
Review
Anticancer Drugs: Recent Strategies to Improve Stability Profile,
Pharmacokinetic and Pharmacodynamic Properties
Yarlagadda Shanmukh Sai*, Preksha Biradar, S. Nageshwara Rao, A. Babu Rao, Ashish Choudhary, Kali Kalpana
Department of Life Sciences, Pharmacy, Health and Nutritional Sciences, University of Hyderabad, Hyd, T.S.
Abstract: In past decades, anticancer research has led to remarkable results despite many of the
approved drugs still being characterized by high systemic toxicity mainly due to the lack of tumor
selectivity and present pharmacokinetic drawbacks, including low water solubility, that negatively
affect the drug circulation time and bioavailability. The stability studies, performed in mild conditions
during their development or under stressing exposure to high temperature, hydrolytic medium or
light source, have demonstrated the sensitivity of anticancer drugs to many parameters. For this
reason, the formation of degradation products is assessed both in pharmaceutical formulations and
in the environment as hospital waste. To date, numerous formulations have been developed for
achieving tissue-specific drug targeting and reducing toxic side effects, as well as for improving drug
stability. The development of prodrugs represents a promising strategy in targeted cancer therapy for
improving the selectivity, efficacy and stability of active compounds. Recent studies show that the
incorporation of anticancer drugs into vesicular systems, such as polymeric micelles or cyclodextrins,
or the use of nanocarriers containing chemotherapeutics that conjugate to monoclonal antibodies can
improve solubility, pharmacokinetics, cellular absorption and stability. In this study, we summarize
Citation: Anticancer Drugs: Recent
the latest advances in knowledge regarding the development of effective highly stable anticancer
Strategiesto Improve Stability
Profile, Pharmacokinetic and
drugs formulated as stable prodrugs or entrapped in nanosystems.
Pharmacodynamic Properties.
Keywords: cancer therapy; drug stability; prodrugs; vesicular systems; nanoparticles; trastuzumab
Academic Editor: Arun Sharma
Received: 1 August 2022

Accepted: 24 August 2022
Published: 25 August 2022 1. Introduction
Publisher’s Note: MDPI stays neutral The Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) is an interactive
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published maps and institutional affil- for 36 types of cancer and all cancer sites combined in 185 countries. According to data
iations. collected in 2020, it has been estimated that one in five people worldwide develop cancer in
their lifetime, while one in eight men and one in eleven women die from the disease. The
aging population growth, as well as socio-economic risk factors, could contribute to the
increase in these estimated numbers [1].
Copyright: © 2022 by the authors.
Cancer treatment options include surgery, radiation and chemotherapy, or a combina-
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tion of them. Chemotherapy is a systemic approach and consists of administering one or
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more chemicals that can damage fast-growing cells, such as cancerous ones. However, these
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agents, being non-selective, usually damage healthy cells and tissues with rapid turnover,
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causing severe toxic effects. The rapid emergence of drug resistance, the instability of
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the molecules and the poor solubility in water, which makes them unable to permeate
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through cell membranes, represent further drawbacks of chemotherapy. To overcome these
limitations, two or more chemotherapeutics are usually used in combination. Other thera-
peutic strategies to treat different types of cancer are based on the use of small molecules,
including genes, small RNAs and plasmids, which, however, show limitations due to their
poor stability in vivo [2].
Molecules 2023, 27, 3645. https://doi.org/10.3390/molecules27173645 https://www.mdpi.com/journal/molecules

Molecules 2023, 27, 3645 2 of 23
These disadvantages of conventional anticancer drugs are the reason why the de-
velopment of alternative treatments with reduced adverse side effects and improved
therapeutic efficacy is still demanding. An effective strategy to increase the selectivity of
chemotherapeutics involves the use of prodrugs. The latter are inactive compounds that
are chemically or enzymatically metabolized in the active drug, reducing the systemic
toxicity of conventional therapies [3]. Furthermore, prodrugs can be useful in reducing
drug toxicity. For example, although the efficacy of transition metals is widely recognized,
due to their intrinsic toxicity, they are generally not included in drug therapies. The design
of transition-metal-based prodrugs could, therefore, make them less toxic, allowing the
drug to reach therapeutically useful levels [4]. Prodrug therapy, therefore, provides an
alternative approach to designing less reactive and less cytotoxic drugs. The design of
these new compounds could also help to overcome pharmaceutical, pharmacokinetic and
pharmacodynamic hindrances. In fact, they can be used to increase solubility and improve
chemical stability and organoleptic characteristics, such as the flavor of the drugs. In
particular, they can be designed to improve the absorption throughout the blood–brain
barrier or to increase the therapeutic index, as well as the site-of-action selectivity [5]. Since
these agents offer a number of advantages, to date, several prodrug formulations have been
developed and effectively used for the treatment of different forms of cancer (Table 1).
Table 1. List of the anticancer drugs and prodrugs and the diseases in which they are most used.
Drug Classes Active Compound Prodrug Diseases Ref.

Acute
Antimetabolites Mercaptopurine Azathioprine [6,7]
lymphoblastic leukemia
Breast cancer, esophageal cancer,
5-Fluorouracil Capecitabine laryngeal cancer, gastrointestinal [8]
and genitourinary tract cancer
Deoxyadenosine Cladribine Hairy cell leukemia [9,10]
1-β-D-arabinofuranoside
Cytarabine Acute myeloid leukemia [11]
5′-triphosphate
9-beta-D-arabinosyl-2-
Fludarabine Chronic lymphocytic leukemia [11]
fluoroadenine
5-Fluorouracil Different types of neoplasms [8]
Gemcitabine diphosphate and
Gemcitabine Solid cancers [11]
triphosphate
Acute
6-Mercaptopurine [7,11,12]
Several kinds of cancer, such as
Methotrexate [13]
colon cancer
leukemias, lymphomas,
mesothelioma,
melanoma, biliary tract cancer,
6-Thioguanosine 6-Thioguanine glioblastoma, osteosarcoma, soft [14,15]
tissue sarcoma, neuroendocrine
tumors and lung, pancreatic and
squamous cell carcinomas
5-Fluorouracil Floxuridine Liver cancer [6,16]
Methyl-tetrahydrofolate Leucovorin Acute lymphoblastic leukemia [17,18]
Molecules 2023, 27, 3645 3 of 23
Table 1. Cont.

Alkylating agents Busulfan Chronic myelogenous leukemia [19]
Carmustine Glioblastoma multiforme [20]
Acrolein and phosphoramide Several kinds of cancer and
Cyclophosphamide [21,22]
mustard autoimmune disorders
5-aminoimidazole-4-
Dacarbazine Malignant melanoma or sarcoma [23]
carboxamide
Lomustine Brain tumors [24]
Mechlorethamine Mycosis fungoides [25]
Melphalan Multiple myeloma [26]
Azo-Procarbazine Procarbazine Hodgkin’s lymphoma [27,28]
Ovarian cancer, breast cancer and
Triethylenethio-phosphoramide Thiotepa [29,30]
superficial bladder cancer
Lewis lung carcinoma, leukemia,
metastatic brain tumor, Hodgkin’s
Semustine [31]
lymphoma, malignant melanoma
and lung carcinoma
Anthracyclines Daunorubicin Leukemia [32]
Doxorubicin Leukemia, breast cancer [32]
Epirubicin Breast cancer [33]
Idarubicin Acute leukemia [34]
Breast and prostate cancers,
Mitoxantrone [35]
lymphomas and leukemias
Hodgkin’s and non-Hodgkin’s
Antitumor lymphoma, renal, cervical,
Bleomycin [36]
antibiotic laryngeal, testicular, lung
and others
Dactinomicyn Different solid cancer [37]
Mitomycin Adenocarcinoma of the stomach [38]
Plicamycin Testicular and germ cancers [39]
Small-cell lung cancer, leukemia,
Epipodophyllotoxins Etoposide lymphoma, breast and ovarian [40]
carcinomas, testicular cancer
Teniposide Small-cell lung cancer, leukemia [41]
Taxanes Cabazitaxel Prostatic cancer [42]
Docetaxel Metastatic prostate cancer [43]
Ovarian, breast and lung cancer, as
Paclitaxel [44]
well as Kaposi’s sarcoma
Vinblastine-N-
Vinca alkaloids Vinblastine Pancreatic ductal adenocarcinoma [45]
Oxide
Precursor B-cell acute
Vincristine [46]
Non-small-cell lung cancer and
Vinorelbine [47]
metastatic breast cancer
SN-38 (7-ethyl-10-hydroxy- Solid tumors, including colorectal,
Campotothecins Irinotecan [48]
camptothecin) pancreatic and lung cancer
Topotecan Cervical cancer [49]
Platinum analogs Carboplatin Ovarian cancer cells [50]
Solid cancers, such as testicular,
ovarian, head and neck, bladder,
Cisplatin [50,51]
lung, cervical cancer, melanoma,
lymphomas and several others
Oxaliplatin Colorectal cancer [52]
Molecules 2023, 27, 3645 4 of 23
Table 1. Cont.

Metastatic colorectal cancer,
metastatic breast cancer,
Monoclonal
Bevacizumab non-small-cell lung cancer, [53]
antibody
glioblastoma, renal-cell carcinoma,
ovarian cancer and cervical cancer
Cetuximab Non-small-cell lung cancer [54]
Lymphoid malignancies, including
aggressive forms of B-cell
non-Hodgkin lymphoma, B-cell
malignancies, follicular
Rituximab [55]
lymphoma, diffuse large B-cell
lymphoma, chronic lymphocytic
leukemia and mantle
cell lymphoma
Breast and metastatic
Trastuzumab [56]
gastric cancer
Growth inhibitor Axitinib Renal-cell carcinoma [57]
Bortezomib Multiple myeloma [58]
Philadelphia chromosome-positive
Bosutinib [6]
chronic myelogenous leukemia
Crizotinib Non-small-cell lung cancer [59]
Dabrafenib BRAF-mutated melanoma [60]
Chronic myeloid leukemia and
Dasatinib Philadelphia chromosome-positive [61]
acute lymphoblastic leukemia
Imatinib Chronic myeloid leukemia (CML) [62]
Lapatinib Breast and gastrointestinal cancer [63]
Nilotinib Chronic myeloid leukemia (CML) [64]
Pazopanib Metastatic renal-cell carcinoma [65]
Sorafenib Hepatocellular carcinoma [66]
Sunitinib Renal-cell carcinoma [57]
Trametinib BRAF-mutated melanoma [60]
Vandetanib Metastatic medullary tyroid cancer [67]
Vemurafenib BRAF-mutated melanoma [68]
The incorporation of anticancer drugs into drug delivery systems (DDS) represents
another approach to successfully address pharmacological and pharmacokinetic limitations
and to directly carry drugs to the therapeutic site of action while reducing adverse side
effects. Accordingly, innovative nanotechnologies had a profound impact on clinical
therapeutics, including anticancer drugs [69,70]. Among the most studied incorporation
systems, vesicular matrices, such as niosomes, cubosomes or polymeric systems, have
shown the best results [71–73]. Innovative targeting approaches can also be represented
by nanocarriers containing chemotherapeutics conjugated to molecules able to bind to
overexpressed antigens (monoclonal antibodies, mAb) [74–77].
The stability of a drug is verified during all stages of development, through investiga-
tions carried out both on the active ingredients and on the final formulation. The analytical
methods are generally based on the directives contained in the ICH (International Confer-
ence on Harmonization) Guidelines to ensure the safety, efficacy and quality of the drugs
tested. In accordance with this document, the stability tests are carried out in different envi-
ronmental conditions of conservation (pH, temperature, light, air and humidity) [78–80].
In the quality control of a drug, the analytical method is carefully selected based on the
characteristics of the drug or its formulation to measure the quantity of the drug residual
over time and its possible by-products. In general, chromatographic procedures represent
the most commonly used technique, both for the separation and quantization of analytes.
Molecules 2023, 27, 3645 5 of 23
Furthermore, the stability of many antineoplastic drugs has been studied in surface wa-
ters and wastewater treatment effluents as these compounds, once in the environment, can
be harmful to aquatic organisms as they are mutagenic, genotoxic, cytotoxic, carcinogenic
and teratogenic [81].
In this work, the most recent findings in this field have been reviewed, focusing in
particular on recent strategies effectively used to assess the stability profile of anticancer
prodrugs and drugs and to improve their pharmacokinetic and technological profiles.
Most of the reviews published in the literature focus on the drawbacks of anticancer
drugs [82,83] or the use of nanocarriers as DDS [84,85]. In this survey, all the results
published to date on the methodologies used to overcome the pharmacokinetic and phar-
macodynamic limits of these drugs, as well as to guarantee the improvement in their
stability profile, have been collected. In particular, the advantages of using prodrugs
and/or incorporating drugs or prodrugs into vesicular systems were thoroughly examined.
These approaches favor the therapeutic agent in reaching the site of action at effective
concentrations while significantly reducing toxic effects. The benefits and drawbacks of
the use of mAb or other experimental strategies for overcoming the limits of conventional
drugs have also been discussed.
2. Stability of Anticancer Drugs

The stability of most anticancer compounds has been tested under different experi-
mental conditions. Given the alarming concentration of some antineoplastic agents or their
degradation compounds found in hospital sewer drains [86,87] or wastewater [88], several
studies have focused on evaluating their presence in the environment. In this context, all
stability experiments have been conducted by exposing the drugs to mild conditions, such
as room temperature and natural pH of the water used as a solvent [89]. For example, a
number of cytostatic drugs, including daunorubicin, doxorubicin, vinblastine, chlorambu-
cil, vincristine, irinotecan and melphalan, have been found to be highly unstable in milli-Q
water (pH of 6.3) due to the presence of reactive groups in their chemical structures, which
favor hydrolytic reactions [90]. In particular, daunorubicin, doxorubicin, irinotecan and vin-
cristine have rapidly degraded, and only 10% of the initial concentration has been detected
after 5 min of exposure. On the other hand, vinblastine, chlorambucil and melphalan have
been degraded during the first 240 min. The stability has been evaluated in an aqueous
environment by varying parameters, such as pH and/or temperature. In water, Mitox-
antrone degraded into four stable breakdown products [91], which were identified using
liquid chromatography coupled to mass spectrometry (LC–MS). This drug suffered a rapid
change in its conformation, resulting in the formation of toxic transformation products
that remained unaltered and stable in water for up to two days. Busulfan (1,4-butanediol
dimethanesulfonate), an alkylating agent widely used for the treatment of chronic myeloid
leukemia, has shown considerable instability in aqueous preparations [92]. The degrada-
tion, due to precipitation phenomena, appears to be temperature-dependent: as the storage
temperature rises, the stability of the diluted solutions decreases. Busulfan is administered
by infusion, but, once prepared in a formulation made from a concentrate, it has a relatively
short shelf life. The stability of the solution increases only slightly when stored at 2–8 ◦C,
regardless of the container material used.
Using inductively coupled plasma mass spectrometry (ICP-MS), it was possible to
assess the stability profile and the presence in hospital wastewater of cytostatic derivatives
of platinum (CPC), antineoplastic agents widely used in clinical applications. These com-
pounds, excreted by treated patients, reach aqueducts and sewers, causing detrimental
effects on biota, even at low concentrations [87]. Despite all the compounds belonging to
the CPCs class, such as oxaliplatin, carboplatin and cisplatin, having a similar chemical
structure, their behavior in the environment is quite different. In fact, these compounds in
the environment undergo the processes of hydrolysis, photolysis, dilution, adsorption, sedi-
mentation of suspended solids and biodegradation differently, leading to distinct unaltered
compounds or degradation products [93]. Cisplatin products are more easily absorbed on
Molecules 2023, 27, 3645 6 of 23
the soil surface compared to carboplatin and oxaliplatin derivatives due to the formation of
H-bonds or electrostatic interactions with aqueous soil groups. The stability of carboplatin
in aqueous solution is more closely related to nucleophiles concentrations and the pH of the
medium, and, in all cases, this activation process is slower than that of cisplatin. Oxaliplatin
produces reactive species that contaminate groundwater depending on the composition of
the aqueous solution [94].
Several other studies on the stability of anticancer drugs have focused on the eval-
uation of the degradation profile and the formation of transformation products directly
after their exposure to stress conditions, as in the case of imatinib, a highly potent ty-
rosine kinase inhibitor used as a first-line anticancer drug in the treatment of chronic
myeloid leukemia [95]. The photocatalytic degradation kinetics of this compound have
been studied under heterogeneous photocatalysis produced in the presence of radicals and
the degradation mechanism has been elucidated from LC–MS analysis. In total, 12 trans-
formation products have been detected, and in silico toxicity tests showed that some of
these molecules have structural motifs potentially capable of damaging DNA. The stability
of 5-fluorouracil, one of the most widely used chemotherapy agents for the treatment
of different types of cancer, has been studied under different stressful conditions using high-
performance liquid chromatography and infrared spectroscopy. As a result, the drug has
shown good stability when exposed to UV radiation, slight degradation at 275 ◦C and greater
degradation at 285 ◦C, a degradation of about 22% under acid hydrolysis conditions and
approximately 97% under alkaline ones and a degradation from 26% to 41% when exposed
to oxidative conditions [96].
3. Stability of Anticancer Prodrugs

Prodrugs are usually pharmacologically inactive precursors of therapeutic agents,
which are chemically or enzymatically transformed within the host into one or more active
metabolites. The ability of a prodrug to improve the pharmacokinetic profile or stability
of a drug is well known [97]. Different approaches, including the use of vector- or bio-
precursor-linked prodrugs, have been developed to ensure that a drug reaches its target in
a proper concentration. This approach allows overcoming several drawbacks, including
poor water solubility, chemical instability, inadequate oral or local absorption, too short
half-life and also formulation or administration issues, facilitating the accumulation of a
drug at the desired site of action and thus improving its selectivity and safety [98]. Since a
prodrug is transformed into the corresponding active metabolite in vivo, stability studies
should be performed on both forms of the drug [81,87,98].
As an example, water sorption represents the primary cause of capecitabine degrada-
tion. This process is influenced by higher temperature and humidity; in fact, the degrada-
tion is accelerated at 40 ◦C in 75% RH. The application of thermoanalytical techniques and
HPLC analyses have proven the stability of capecitabine after 6 months of storage at 25 ◦C in
60% RH [99]. The degradation behavior of irinotecan hydrochloride has been investigated
under different ICH-recommended stress conditions using liquid chromatography–mass
spectrometry showing the formation of seven degradation products in pharmaceutical
dosage forms. The prodrug has been exposed to oxidative, acid, base, hydrolytic, thermal
and photolytic conditions with significant degradation in oxidative, base hydrolysis and
photolytic conditions [100]. The stability of floxuridine and leucovorin calcium in combined
therapy has been tested at various concentrations and temperature conditions. Both the
compounds were stable after 48 h at each tested condition. However, leucovorin calcium
underwent degradation, more noticeable at low concentrations, at near-physiologic body
temperature compared to other temperatures (4–8 ◦C and 20 ◦C) [101].
In combination therapies, the degradation of a drug could be influenced by the chemi-
cal characteristics of each component. The physical compatibility and chemical stability
of irinotecan, diluted in 5% dextrose in water and combined with the racemic form of
leucovorin, have been assessed after the formulation, unprotected from light, has been
stored at 23 ◦C. The solutions remained clear and colorless throughout the 24-h study
Molecules 2023, 27, 3645 7 of 23
period for all the tested concentrations of the drugs. On the other hand, in the formulation
prepared with a low concentration of irinotecan (0.30 mg/mL) and a high concentration of
leucovorin (3.60 mg/mL), a rapid degradation of irinotecan was observed, most likely due
to the higher pH of the solution caused by the high concentration of leucovorin [102].
Light degradation of anticancer drugs frequently results in transformation products
that are also responsible for toxic effects. The photodegradation of cyclophosphamide and
iphosphamide has been investigated using ruthenium-doped titanate nanowires in distilled
water and wastewater under UV–vis irradiation. The results indicated that ruthenium
exhibited photocatalytic activity for both the drugs, leading to the formation of four pho-
todegradation products for cyclophosphamide and six for isophosphamide. These products
have been identified by high resolution mass spectrometry, confirming a higher concen-
tration in wastewater with respect to distilled water. These results have demonstrated
that environmental matrices can produce different transformation products and that the
experimental conditions in photodegradation studies are critical and should, therefore, be
as similar as possible to those of environmental systems [81]. Dacarbazine, an alkylating
agent commonly used in combination with other chemotherapeutic agents for the treatment
of metastatic malignant melanomas, Hodgkin’s lymphoma and pheochromocytomas, is
converted by light into 4-diazoimidazole-5-carboxamide [103]. This photo-transformation
product is often responsible for the pain reactions observed during peripheral intravenous
infusion during clinical application. The photodegradation profile of the drug solutions
was determined using HPLC coupled to UV detection. The study demonstrated that
photoproduct production increases in a time-dependent manner up to 4 h at 4 and 25 ◦C
despite the sample being light-shielded, suggesting that light shielding is not required in
sample preparation.
4. Stability of Anticancer Monoclonal Antibody

Nowadays, significant breakthroughs have been achieved in cancer therapy by ap-
plying mAb-based immunotherapy as the antibodies are able to directly target cancerous
cells while simultaneously promoting the induction of long-lasting immune responses
against cancer cells. However, despite this approach having proven to be very effective
for the treatment of different forms of cancer, several drawbacks have yet to be overcome.
In particular, drug resistance and poor stability due to the glycoprotein nature of mAb
continue to be the major hurdles.
The mechanisms responsible for their instability are either chemical or physical. Sev-
eral parameters and conditions, including the structure of the proteins, temperature and
exposure to light, affect mAb stability [104]. The main process related to chemical degra-
dation is oxidation, which can occur both spontaneously or in the presence of oxidizing
agents, such as peroxides or metals. Some amino acid residues, such as methionine and
cysteine, are particularly sensitive to oxidation [105]. In addition, asparagine residues can
undergo acid-base deamidation, and, as a result, a succinimide intermediate is formed and
hydrolyzes spontaneously to aspartic or isoaspartic acid [106].
Variations in temperature or pH can induce the unfolding of proteins, leading to a
direct loss of mAb functions and favoring their aggregation, which represents the main
cause of physical instability. During protein aggregation, misfolded proteins assemble
each other to form high molecular weight species (multimers), such as oligomers and
insoluble aggregates, through the formation of non-specific weak bonds, including Van der
Waals interactions, hydrogen bonds, hydrophobic and electrostatic interactions, without
affecting the primary structure of the molecules [107]. Furthermore, in highly concen-
trated formulations, due to the increase in viscosity, the formation of aggregates becomes
irreversible, leading to problems during the production or the drug administration pro-
cesses. In general, ingredients such as salts, amino acids, sugars, polyols or surfactants
are added to the formulations to overcome these phenomena. In this context, bis-acetyl-
lysine and propionyl serine have been identified as more efficient agents compared to the
Molecules 2023, 27, 3645 8 of 23
commonly used excipients to minimize the antibody solution viscosity while preventing
protein–protein interactions [108].
The presence of several aromatic amino acid residues in the primary structure of mAb
makes them particularly sensitive to light, thereby inducing photodegradation with the
formation of oxygenated radicals but also fragmentation and cross-linking. The effect
of light on mAb aggregation should be investigated in both the original drugs and the
final diluted formulations. Despite light not seeming to be involved in a direct alteration
of the secondary and tertiary structures of the mAb [104], it has been demonstrated that
light exposure promoted the aggregation of monomeric and dimeric fractions of an IgG1
monoclonal antibody. In particular, after the mAb exposure to controlled irradiation,
segments with greater flexibility in the C H2 and CH3 domains of both dimensional fractions
and reduced flexibility in some segments of the Fab and CH1 domains in the dimer fraction
have been identified by mass spectrometry analysis [109].
The effect of light on mAbs aggregation should be investigated on both the original formu-
lation and the diluted preparation adopted in clinical practice. Hernández-Jiménez et al. [110]
have performed accelerated photodegradation studies on the commercial drug and on the
NaCl commonly diluted formulation of five mAbs (bevacizumab, cetuximab, infliximab,
rituximab and trastuzumab). The photodegradation profile has been evaluated by size
exclusion chromatography, demonstrating the formation of the aggregates due to the effect
of light, in each experiment. This process resulted in mAb fragmentation and consequent
aggregation, which were more frequently found in diluted rather than concentrated so-
lutions. Accordingly, the aggregation phenomenon is related to the concentration and
nature of mAb both when the formulations are exposed to light and in other stressful
conditions, such as freeze/thaw cycles, for all drugs studied. All mAbs underwent degra-
dation with consequent aggregation and/or disruption of the protein chains, probably due
to the breakdown of the cystines between the two heavy chains [111]. Despite having a
similar IgG1 structure, bevacizumab and rituximab were stable when stored at 4 ◦C and in
freeze/thaw cycles, with a limited aggregate formation, while infliximab and cetuximab
degraded even under mild conditions [112,113]. Thanks to the exclusive three-dimensional
structure stabilized in the final formulation of Herceptin ®, trastuzumab resulted as the
least light-sensitive antibody despite not being the most concentrated [111].
In addition, the use of surfactants in formulations can induce secondary structural
changes [114]. The effect of different concentrations of a non-ionic surfactant, sodium
dodecyl sulphate, has been investigated in bevacizumab formulations, demonstrating
classical aggregate formation only at medium concentrations (0.5–2 mM) of the surfactant.
Conversely, at low concentrations (0–0.2 mM), structural changes were observed on both
the β sheet and the α helix, producing a disordered structure. At high concentrations of
surfactant (3–5 mM), the formation of disordered structures increased.
In conclusion, mAbs are currently one of the most important classes of biotechnological
drugs for the treatment of diseases with increasing incidence in the population, such as
cancer, autoimmune, inflammatory, infectious and degenerative diseases, and, since the
beginning of the COVID-19 pandemic, they have been explored as potential therapeutic
tools. Therefore, stability studies are crucial during the development of therapeutic proteins
to ensure the quality and safety of the final medicine. Deeper knowledge of the mechanisms
involved in a protein can help to avoid the onset of conformational and colloidal changes
that reduce its therapeutic efficacy.
5. Anticancer Drugs in Nanoparticle Systems

The development and application of vesicular systems capable of ensuring controlled
delivery of anticancer drugs to the desired site of therapeutic action in adequate quantities
to exert their actions are increasing. These systems improve therapeutic efficacy while
reducing negative side effects, providing many advantages, including improved pharmaco-
dynamic and pharmacokinetic profiles, which result in a prolonged half-life and enhanced
drug stability, ensuring protection from chemical or physical degradation [115,116]. Since
Molecules 2023, 27, 3645 9 of 23
most antineoplastic agents are very sensitive to different conditions, in clinical practice,
improvement in the drug stability profile can simplify the work of pharmacists during
the preparation of different formulations, and of healthcare professionals when handling
the drugs that need to be administered in hospital care [117]. Furthermore, improving the
stability of anticancer agents could facilitate home therapy as the drugs could be supplied
to patients via portable elastomeric pumps without risking their alteration and, therefore,
treatment failure.
The currently available nanocarriers for anticancer drugs vary in structures, sizes
and physicochemical properties. These systems can be of natural origin, and, therefore,
made up of simple structures derived from phospholipids, such as lecithin, and of syn-
thetic nature and thus characterized by more complex structures consisting of polymers
sometimes complexed with metals. Niosomes (non-ionic surfactant vesicles) are one of the
most commonly applied carriers for anticancer drugs. These vesicles are obtained by the
hydration procedure of a non-ionic surfactant with cholesterol in which the surfactants
form a closed bilayer vesicle in an aqueous medium based on its amphiphilic nature. In
this structure, the surfactant molecules are oriented away from the solvent so that the
hydrophilic ends of the non-ionic surfactant point outwards and the hydrophobic ends
face each other to form the bilayer, whereas the hydrophilic heads remain in contact with
the aqueous solvent. As for the natural liposomes, the properties of the niosomes depend
on the composition of the vesicles, size, lamellarity, tapped volume, surface charge and
concentration. However, unlike niosomes, liposomes are expensive, and their components,
such as phospholipids, easily suffer oxidative degradation. This behavior requires special
storage conditions and makes liposomes challenging to handle [84]. All these structures
include both aqueous compartments for the incorporation of hydrophilic molecules and
lipid layers for the transport of lipophilic molecules [116].
Over the last few decades, the use of nanoparticle (NP)-based DDS has shown nu-
merous advantages in cancer treatment, including the ability to overcome drug resistance
caused by overexpression of drug efflux transporters, defective apoptotic pathways and a
hypoxic environment [85]. For example, NPs can avoid the exposure of anticancer drugs
to efflux transporters as they enter the cell primarily through endocytosis rather than
diffusion. Usually, the type of NPs used in cancer therapy (organic, inorganic or hybrid) is
designed or chosen based on their size and characteristics, as well as the pathophysiology
of the tumors. Organic NPs include liposome- and polymer-based NPs, such as micelles
and dendrimers, whereas inorganic NPs include gold NPs (Au-NPs), carbon nanotubes,
silica NPs, magnetic NPs and quantum dots; finally, the hybrid NPs that combine the
advantages of the different types include the lipid–polymer, organic–inorganic hybrid NPs
and cell-membrane-coated NPs.
Figure 1 depicts an NP entrapping a drug or prodrug coated with mAb and the
advantages in the use of this system.
Figure 1. NP entrapping drugs and prodrugs coated with mAbs. List of advantages in the use of NPs.
Molecules 2023, 27, 3645 10 of 23
Table 2 lists most of the applied inclusion systems for anticancer drugs and prodrugs
and the advantages obtained from the proposed formulation.
Table 2. Inclusion systems and their advantages in protecting the anticancer drugs.
Drug Inclusion Systems Advantages Ref.

Protection from chemical and enzymatic
Smart pH-responsive
Capecitabine hydrolysis and improvement in the [118]
co-polymeric hydrogels
stability in the gastric media
Better operational stability and
Cladribine Nanostabilized polyacrylamide matrix [119]
mechanical properties
Cytarabine Liposomal formulation in hydrogel system Improvement in stability [74]
Co-encapsulation with mitoxantrone
Fludarabina Improvement in long-term stability [120]
in liposomes
5-Fluorouracil Co-encapsulation with leucovorin in NPs Improvement in long-term stability [75,121]
Gemcitabine Temperature-sensitive liposomes Improvement in long-term stability [76]
6-Mercaptopurine NPs Improvement in thermal stability [122]
Improvement in stability in diluted
Gold NPs [77]
aqueous solutions
Magnetite NPs Improvement in thermal stability [123]
Methotrexate Gellan gum microparticles Higher thermal stability [124]
Amphiphilic PEO–PPO–PEO tri-block
Improvement in thermodynamic stability [125]
co-polymeric nanomicelles
Inclusion in βcyclodextrin and subsequent Increase in solubility and improvement
6-Thioguanine [126]
interaction with gold NPs in stability
Floxuridine Boron nitride nanotube encapsulation Improvement in long-term stability [127]
Co-encapsulation in NPs with of
Leucovorin Improvement in long-term stability [121]
5-fluorouracil
Encapsulation within water-soluble
Busulfan Reduction in hydrolytic degradation [128]
pillae[5]arene
Adsorption on the surface of the
Carmustine Improvement in long-term stability [129]
γ-Fe2O3 NPs
Cationic core-shell NPs Improvement in long-term stability [130]
Lomustine Thermosensitive liposomes Improvement in long-term stability [131]
Addition of free radical inhibitor for
Mechlorethamine Improvement in long-term stability [132]
topical use
Liposomal formulation based on a fluid
Melphalan lipid bilayer of natural phospholipids in Improvement in stability in human serum [133]
the form of dioleoylglyceride ester
Daunorubicin Liposomes Improvement in long-term stability [134,135]
Poly(lactide-co-glycolide) NPs with
Doxorubicin Improvement in long-term stability [136]
poloxamer 188
Peptide-based hydrogels and nanogels Improvement in long-term stability [137]
Chitosan-coated nanodiamonds Improvement in long-term stability [138]
PEGylated liposomal nanodrugs Improvement in long-term stability [139]
Epirubicin Drug-eluting beads Improvement in long-term stability [140]
Bifunctional drug-loaded micelles Improvement in long-term stability [141]
Molecules 2023, 27, 3645 11 of 23
Table 2. Cont.

Idarubicin Drug-eluting beads Improvement in long-term stability [142]
Drug-eluting embolics beads Improvement in long-term stability [143]
Mitoxantrone Estrone-targeted liposomes Improvement in long-term stability [144]
Hyaluronan magnetic NPs Improvement in long-term stability [145]
Liposomes in PLGA NPs Improvement in long-term stability [146]
Bleomycin Biodegradable chitosan nanogel Improvement in thermal stability [147]
Mitomycin PEGylated liposomes Improvement in long-term stability [148]
Etoposide PLGA NPs Improvement in long-term stability [149]
Nanostructured lipid carriers Improvement in long-term stability [150]
Aqueous mixtures of
Teniposide Improvement in long-term stability [151]
detergent-phospholipid
Nanosuspensions Improvement in long-term stability [152]
Docetaxel Nanocrystal-loaded micelles Enhancement in blood circulation [153]
Chondroitin sulphate-hybridized zein NPs Improvement in long-term stability [154]
Cabazitaxel Surfactant-stripped micelles Improvement in long-term stability [155]
Albumin NPs Improvement in long-term stability [156]
Paclitaxel Natural exosome Improvement in stability profile [157]
Polymeric micellar system Increased solubility, greater stability [158]
Merocyanine conjugates Favorable biological stability [159]
17-fluorinated ethanol-modified drug
Robust colloidal stability [160]
in NPs
Increased solubility in water, reduction in
Vinblastine PEGylated niosomes [161]
side effects
Improvement in diffusion capacity in
Vincristine Artificial low-density lipoproteins [162]
tumor tissue and lower toxicity
Liposomes Improvement in efficacy stability [163]
Liposomes prepared with ammonium salts
Vinorelbine Improvement in efficacy and stability [164]
of several anionic agents
Reduction in side effects and increase in
Nanomicelles [165]
drug efficacy
Liposome encapsulating polymeric
Reduction in toxicity and increase in
micelles. Co-encapsulation with [166]
plasma half-life
cis-diamminedichloroplatinum (II)
Improvement in lipophilicity, and fewer
Intravenous lipid emulsion [167]
toxic effects
Improvement in effectiveness and
Irinotecan Superparamagnetic chitosan nanocomplex [168]
biodistribution
Improvement in stability and increase in
Topotecan Thiolated chitosan NPs [169]
absorption
Lipid NPs Protection from hydrolysis [170]
Liposome encapsulating polymeric
Reduction in toxicity and increase in
Cisplatin micelles. Co-encapsulation [166]
plasma half-life
with vinorelbine
NPs Improvement in stability [171]
Molecules 2023, 27, 3645 12 of 23
Table 2. Cont.

Carboplatin Niosomal nanoplatform Improvement in stability [172]
Conjugation with an arginine-rich
Improvement in pharmacokinetic profile [173]
triple-helical peptide
NPs Outstanding plasma stability [174]
Oxaliplatin Conjugation with PEGylated-nanobody Prolonged circulation in vivo [175]
Stabilization in unfavorable
conditions, such as low concentration or
Bevacizumab Excipient in dilute solutions [176,177]
body temperature. Prevention
of aggregation.
Biochemical and biophysical stabilization.
Lipid NPs [178]
Prevention of aggregation.
Improvement in long-term stability.
Nanoincapsulation into PLGA NPs [179]
Improvement in stability and
Cetuximab Silica NPs [180]
bioavailability. Prevention of aggregation.
Chitosan NPs with and without drug Improvement in stability and
[181]
conjugation bioavailability. Prevention of aggregation.
Improvement in stability and
Polymersome–mertansine nanodrug [182]
bioavailability. Prevention of aggregation.
Colloidal stability in buffer solution.
Rituximab Iron oxide NPs [183]
Prevention of aggregation and
Trastuzumab Coated NPs with docetaxel improvement in stability and [184]
pharmacokinetics profile
Stealth immunoliposome coated
improvement in stability and [185]
with docetaxel
Choline ionic liquid vesicles improvement in stability and [186]
Drug conjugated with SCN-Bn-NOTA and
improvement in stability and [187]
radiolabeled with 64Cu
Nanofibrous membranes prepared with
Axitinib Improvement in long-term stability [188]
poly(ε-caprolactone)/collagen
Improvement in water solubility
Bortezomib Polymeric NPs [189]
chemical stability
Crizotinib Thermosensitive liposome Improvement in targeting efficacy [190]
Dasatinib Biodegradable NPs Improvement in long-term stability [191]
H-sensitive targeted micelle system.
Improvement in long-term stability [192]
Co-encapsulation with curcumin
Improvement in long-term stability
Imatinib Nanostructured lipid carriers [193]
at 25 ◦C
Nanocrystal delivery system Improvement in long-term stability [194]
Improvement in stability for at least 4 days
Lapatinib Nanocrystals stabilized with a PEG coating [195]
in plasma-containing buffers
Polymeric micelles Improvement in stability [196]
Molecules 2023, 27, 3645 13 of 23
Table 2. Cont.

Human serum albumin NPs Improvement in stability [197,198]
Improvement in solubility in water and
Incorporation in lipoprotein-like NPs [199]
organic solvents
Increase in homogeneity and improvement
Sorafenib Solid lipid NPs [200]
in physical stability
Increase in homogeneity and improvement
Nucleoside-lipid-based nanocarriers [201]
in physical stability
Sunitinib Self-nanoemulsifying system Improvement in long-term stability [202]
Paclitaxel-loaded micelles Improvement in long-term stability [203]
Self-nanoemulsifying system Improvement in long-term stability [204]
Vandetanib Nanocarrier based on apoferritin Improvement in drug delivery [205]
Vemurafenib Peptide-modified loaded liposomes Improvement in long-term stability [206]
To date, several studies dealing with the incorporation of anticancer drugs into
supramolecular systems have been published in the literature, and, in all cases, an improve-
ment in the chemical–physical stability of the drug, and, consequently, better therapeutic
efficacy, have been observed. Some examples are given below. Paclitaxel targeting has been
improved by its inclusion in natural milk-derived exosomes. This compound is known to
have poor solubility in water, while the formulation in exosomes can ensure a continuous
release up to 48 h with an ideal stability profile for clinical applications [157]. Higher
thermal stability of methotrexate has been obtained by encapsulation in novel targeted
systems. Dhanka et al. have proposed the loading of the drug into gellan gum micropar-
ticles prepared by using a simple water-in-oil emulsion solvent diffusion method [124].
Improvement in thermodynamic stability has also been obtained by Mishra et al., who in-
corporated methotrexate into novel-targeted Pluronic (PEOPPO- PEO tri-block co-polymer)
F127 polymeric micelles proposed for intravenous administration in MCF7 cancer cells [125].
Polymeric NPs prepared starting from N-(2-hydroxypropyl)methacrylamide have been
used to entrap bortezomib, improving its stability and bioavailability [189]. The efficacy
of nanostructured lipid carriers containing imatinib has been tested in vitro in MCF-7
breast cancer cells. In this case, vesicles have been prepared using fat and oil by the hot
homogenization method, and sodium lauryl sulphate (SLS) and T80 have been used as
surfactants for the stabilization of the system [193]. Due to their small size (~ 100 nm) and
lipid nature, these particles may ensure adequate drug penetration through membranous
barriers, leading to a significant improvement in the therapeutic efficacy.
The effect of temperature on the stability of lipid nanocarriers has also been verified. As
a result, temperature affected several parameters of the prepared formulations, including
particle size, polydispersion index, encapsulation efficiency and zeta potential, after a
three-month storage period. In particular, an increase in the size of the particles has been
observed, probably due to the swelling or adsorption of surfactants on their surfaces, which,
however, remained in the colloidal nanometer range (<550 nm), confirming the absence
of aggregation.
5.1. Anticancer Prodrugs in Nanoparticles Systems

As described in Section 3, despite the promising anticancer potential of many an-
ticancer prodrugs, their clinical use is limited due to sensitivity to acid and enzymatic
hydrolysis. To overcome these limitations, prodrugs have also been incorporated into
different controlled delivery systems. As an example, capecitabine has been formulated
in co-polymeric hydrogel as a smart pH-responsive network to facilitate its oral adminis-
tration, reducing its sensitivity to gastric pH [118]. To overcome some of the therapeutic
Molecules 2023, 27, 3645 14 of 23
disadvantages of 6-thioguanine, a supramolecular ternary system, involving the inclusion

of the drug in β-cyclodextrins (βCD) and a subsequent interaction of the βCD-thioguanine
complex with gold NPs, has been proposed. This strategy promoted increased solubility
and improved the stability of the incorporated prodrug, ensuring, among other advantages,
site-specific transport due to their nanometer size [126]. Chitosan-based polyelectrolyte
complexes, based on orientated superparamagnetic NPs, have been developed to perform
targeted delivery of irinotecan at the tumor site under the effects of a magnetic field. These
complexes were prepared starting from chitosan and polyglutamate via an all-in-water
process, thereby excluding the use of any potentially toxic chemicals while reaching higher
stability and, consequently, better efficacy of the inclusion complex compared to the free
drug against colon cancer cells [168].
5.2. Combination Therapy in Nanoparticles Systems

Nowadays, combination therapy is a widely adopted strategy for cancer treatment
since acting simultaneously on multiple targets allows the reduction in the dose for each
single drug and slows down the onset of drug resistance. Recently, vesicular systems
for encapsulating combination drugs have been designed to further improve efficacy.
Fludarabine/mitoxantrone combination therapy has been successfully adopted for the
treatment of different types of lymphoma and chronic leukemia. The efficacy of this
combined therapy has been further enhanced by co-incapsulating both compounds in
liposomes: fludarabine has been passively encapsulated during liposome formation, while
the loading of mitoxantrone has been driven by a transmembrane pH gradient. This
formulation would not only represent a promising and efficient therapeutic strategy but
could also improve the long-term stability of both drugs, as evidenced by a recent study
after a three-month monitoring period. [106].
Liposome encapsulating polymeric micelles loaded with vinorelbine and cis-
diamminedichloroplatinum (II) (cisplatin) have also been designed for the treatment of
non-small-cell lung cancer, an aggressive tumor with high mortality and poor progno-
sis [166]. The stability of this formulation has been tested in PBS (pH 7.4) solvent and
10% plasma, showing no significant change in particle size and a slight increase in the
polydispersity index, indicating that the particles could accumulate if stored for more
than 72 h, and, therefore, that the co-delivered drugs were protected from metabolism and
rapid elimination.
5.3. Monoclonal Antibody in Nanoparticles Systems

Despite their proven efficacy as anticancer drugs, the clinical use of mAbs is severely
limited by their poor chemical and enzymatic stability and consequent aggregate formation.
A valid strategy to overcome these hurdles and achieve an adequate intracellular release
of non-aggregated antibodies in the desired site of action consists of the encapsulation
of the mAb into polymeric or lipid NPs. Because these systems are resistant to several
chemical and physical factors, including body temperature, they can protect the antibody
during the drug’s persistence in the bloodstream. Furthermore, when the NPs are endo-
cytosed by the tumor cells, they release the antibody molecules inside the cytoplasmic
compartment, avoiding the action of lysosomes and thus preventing enzymatic degra-
dation. Bevacizumab-loaded NPs performed well as a controlled release system, also
slowing down enzymatic degradation [176,178,179]. Bevacizumab lipid NPs have been
developed as an innovative delivery system for intravitreal injection capable of ensuring
high drug stability [177]. Furthermore, such a formulation improved the drug intraocular
bioavailability and patient compliance by avoiding repeated intravitreal injections. The
addition of choline dihydrogen phosphate, a promising biocompatible ionic liquid for
mAb formulation, resulted in a significant improvement in therapeutic efficacy due to
the suppression of unfolding and aggregation of trastuzumab, justifying its use for the
preparation of stable therapeutic antibody formulations [186].
Molecules 2023, 27, 3645 15 of 23
The association of docetaxel with trastuzumab is a therapeutic regimen successfully

used to treat breast cancer. Docetaxel, commonly dissolved in Tween 80 surfactant for its
clinical formulations, frequently causes severe hypersensitivity and other adverse reactions.
The development of NPs loaded with both drugs can be useful to overcome the single drug
drawbacks while improving the therapeutic efficacy of the combined treatment. Lipid–
polymer hybrid NPs have been prepared for this purpose by combining poly(D,L-lactide-
co-glycolide), polyethylenimine and lipids to form a hydrophobic core. Trastuzumab has
been electrostatically adsorbed on the surface of these NPs as a ligand targeting human
epidermal growth factor receptor 2 (HER2)-positive breast cancer cells, while Docetaxel
is entrapped in core NPs. The stability of the proposed formulation has been studied
under physiological (37 ◦C) and storage conditions (4 ◦C), and the effect of the dilution
has been tested at a concentration of 1.0 mg/mL with PBS (0.02 mol/L, pH 7.4) and
PBS with 10% fetal bovine serum (vol/vol), showing very good stability during storage,
transportation and use [184]. The efficacy of the same combination of drugs has been tested
by preparing stealth liposomal docetaxel with engrafted trastuzumab on its surface [185].
Two formulations of liposomes with several engraftment techniques have been tested: a
neutral formulation using phosphatidylcholine (antibody nanoconjugate-1) or a positive
formulation using 1,2-dioleoyl-3-trimethylammonium-propane. Stability studies confirmed
a very good performance at 4 ◦C or 25 ◦C as a light-protecting system for up to 1 week.
6. Conclusions
Despite their substantial contributions to cancer treatment, all conventional chemother-
apy drugs suffer from several drawbacks, including rapid elimination, poor bioavailability,
low intratumoral release, non-specific cytotoxicity and consequent systemic side effects,
which are frequently followed by the onset of drug resistance. Over the past decade, to
overcome these limitations, a large number of drug delivery systems have been developed,
resulting in a significant improvement in the pharmacodynamic and pharmacokinetic
profiles of the drugs, as well as in their physicochemical stability. Polymeric or lipid
nanoparticles represent the most commonly used systems for incorporating anticancer
drugs and preventing aggregation in monoclonal antibody formulation. Several prodrugs
are incorporated into cyclodextrin matrices, which are well known for their ability to
improve the solubility profile of the incorporated compounds.
The therapeutic efficacy of anticancer agents included in nanosystems has now been
widely established since they ensure a controlled release of an adequate amount of the
drug at the desired site of action and reduce the drug sensitivity to physicochemical factors
during the preparation, managing and storage phases. The possibility of including in the
same vehicle two or more drugs in combination offers further advantages by allowing
the reduction in the dosage of each drug and, therefore, the toxicity. In these cases, larger
vesicles, such as liposomes, are used. Several studies focusing on the development of
innovative formulations are still ongoing. Such systems, some of which have already
been approved, and many others that are in clinical or preclinical development stages,
offer great hope for safer and more efficient options to be adopted in the near future for
cancer treatment.
Author Contributions: Conceptualization, G.I. and F.G.; methodology, G.I., M.C. and M.A.O.; soft-
ware, G.I. and M.D.L.; validation, G.I. and A.G.; formal analysis, G.I.; investigation, G.I. and M.C.;
resources, G.I. and F.G.; data curation, G.I. and M.A.O.; writing—original draft preparation, G.I. and
F.G.; writing—review and editing, G.I., F.G. and G.R.; visualization, G.I. and M.D.L.; supervision, G.I.
and G.R.; project administration, G.I. and A.G.; funding acquisition, G.I. and G.R. All authors have
read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Molecules 2023, 27, 3645 16 of 23
Acknowledgments: The authors warmly thank the Ministry of Education, Universities and Research.
Conflicts of Interest: The authors declare no conflict of interest.
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molecules

Received: 1 August 2022

Molecules 2023, 27, 3645. https://doi.org/10.3390/molecules27173645 https://www.mdpi.com/journal/molecules

Drug Classes Active Compound Prodrug Diseases Ref.

Drug Classes Active Compound Prodrug Diseases Ref.

Drug Classes Active Compound Prodrug Diseases Ref.

2. Stability of Anticancer Drugs

3. Stability of Anticancer Prodrugs

4. Stability of Anticancer Monoclonal Antibody

5. Anticancer Drugs in Nanoparticle Systems

Drug Inclusion Systems Advantages Ref.

Drug Inclusion Systems Advantages Ref.

Drug Inclusion Systems Advantages Ref.

Drug Inclusion Systems Advantages Ref.

5.1. Anticancer Prodrugs in Nanoparticles Systems

disadvantages of 6-thioguanine, a supramolecular ternary system, involving the inclusion

5.2. Combination Therapy in Nanoparticles Systems

5.3. Monoclonal Antibody in Nanoparticles Systems

The association of docetaxel with trastuzumab is a therapeutic regimen successfully

Conflicts of Interest: The authors declare no conflict of interest.

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