Seminars in Cancer Biology 69 (2021) 43–51

Contents lists available at ScienceDirect

Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Review

Nanomedicinal strategies as efficient therapeutic interventions for delivery

of cancer vaccines
Sarwar Beg a, *, S.M. Kawish a, Sunil K. Panda b, Mohammed Tarique c, Arshi Malik d,
Sarah Afaq d, Awad Saeed Al-Samghan e, Jawed Iqbal f, Kainat Alam g, Mahfoozur Rahman h, *
a
Department of Pharmaceutics, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard (Hamdard University), New Delhi, 110062, India
b
Menovo Pharmaceuticals Research Lab, Ningbo, 315812, People’s Republic of China
c
Center for Interdisciplinary Research in Basic Science, Jamia Millia Islamia, New Delhi, 110025, India
d
Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, 61421, Saudi Arabia
e
Department of Family and Community Medicine, College of Medicine, King Khalid University, Abha, 61421, Saudi Arabia
f
Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
g
SLES College of Nursing, Chintamani, Karnataka, 563125, India
h
Department of Pharmaceutical Sciences, SIHAS, Faculty of Health Science, Sam Higginbottom University of Agriculture, Technology and Sciences, Allahabad, 211007,
India

A R T I C L E I N F O A B S T R A C T

Keywords: The applications of gene therapy-based treatment of cancers were started almost two decades back as a boon over
Cancer the chemotherapeutic treatment strategies. Gene therapy helps in correcting the genetic sequences for treatment
Nanomedicines of cancers, thus also acts like a vaccine to induce the cellular and humoral immunity. However, the cancer
Vaccines
vaccines typically suffer from a series of biopharmaceutical challenges due to poor solubility, low systemic
Immune response
Nanoparticles
availability and lack of targeting ability. Owing to these challenges, the physicians and pharmaceutical scientists
Drug targeting have explored the applications of nanocarriers as quite promising systems for effective treatment against the
tumors. A series of nanotherapeutic systems are available to date for diverse drug therapy applications. Sys­
tematic understanding on the preparation, evaluation and application of nanomedicines as a carrier system for
delivering the cancer vaccines is highly important. The present review article provides an in-depth understanding
on the challenges associated with cancer vaccine delivery and current opportunities with diverse nanomedicinal
carriers being available for treatment of cancers.

1. Introduction out of 58 million deaths worldwide [1]. In a survey, it has been revealed
that more than 75% of moralities occurring due to cancer and related
From last couple of decades, cancer remains a major cause of human diseases are from the low and middle-income countries due to the
morbidity and mortality. Despite tremendous efforts in medical diag­ limited economy to support the resources and facilities for early stage
nosis coupled with the advancements in deep understanding of the eti­ diagnosis, prevention and treatment of cancer [1]. Looking at the rate of
ology underlying development of cancers along with the mechanism for growing incidence due to cancers, the treatment success in cancer still
metastasis of the cancer cells, the development of an effective treatment has many unmet needs. As per the current projections, the cancer sta­
strategy is considered as highly challenging [1]. As a rapidly growing tistics related death toll will be continuing to increase with an estimated
problem across the globe, cancers account for the second highest num­ 10 million people year by year, and 15.4 million by 2030. With the
ber of deaths or mortality of the human population after the cardio­ escalating number of cancer deaths, the situation is considered as highly
vascular diseases. In United States, the cancer is the considered as the alarming and has created lot of pressure on the pharmaceutical and
second leading cause of death, which is expected to be more than the biomedical scientists for the development of newer treatment opportu­
deaths due to the cardiovascular diseases in the coming years. As per the nities with high therapeutic values [2,3].
WHO statistics of 2015, cancer alone is responsible for 7.6 million deaths Multiple factors are responsible for origin of the cancers that include

* Corresponding authors.
E-mail addresses: [email protected] (S. Beg), [email protected] (M. Rahman).

https://doi.org/10.1016/j.semcancer.2019.10.005
Received 24 September 2019; Received in revised form 6 October 2019; Accepted 8 October 2019
Available online 13 October 2019
1044-579X/© 2019 Elsevier Ltd. All rights reserved.
S. Beg et al. Seminars in Cancer Biology 69 (2021) 43–51

high degree of heterogeneity in gene population which causes uncon­ patients positive with adult T-cell leukemia (ATL) viruses in some re­
trolled production of cancer cells [1]. Further, a series of complications gions of Japan, as confirmed by the Southern blot analysis [20]. Later,
arises with therapeutic alteration in the pathophysiology of organ sys­ Parkin et al. estimated that global fraction of leukemia due to HTLV-1
tems of the body. Among the diverse variants of cancers, the neoplasia is cases are attributed to only 1% [20]. However, these viruses could
considered as the highly devastating form which quickly undergoes cause human cancer, where the mechanism behind HTLV-1 leukemia is
metastasis to spread other organs and organ systems of the body. It may very rare and being partially understood. HTLV-1 viruses quickly modify
occur due to the transfer of pathogenic organisms like certain types of inside the host genome to complete a regular replication cycle to spread
human viruses [1]. Apart from these, use of immunosuppressive drugs the infections [21]. The virus particularly codes for a host cell specific
also influences the development of tumors and causes impairment to the protein called as Tax, which has multiple effects in inducing the cellular
normal immune organs systems of the body. This increases the pro­ transformation [22]. However, the role of tax genes in inducing ATL is
pensity of normal cells with increasing risk for formation of cancer cells still unconfirmed [23]. Thus, deep research investigations have been
due to weak cellular defense mechanism [2]. carried out to evaluate the role of HTLV-1 in causing ATL. In a latest
Some of the therapeutic interventions adopted for the treatment of report, it has been reported that HTLV-1 basic leucine zipper factor
cancers include surgery, radiotherapy and chemotherapy, which have (HBZ) gene is particularly responsible for causing ATL, where HBZ RNA
been very frequently used from years but have shown limited success in facilitates the promotion of T-cell proliferation in case of transgenic mice
reducing mortality rate. Surgery and radiation treatments, however, are which particularly expresses CD4+ cells related lymphomas [24].
only useful when the cancer is localized at particular site and/or organ
system(s) of the body [3]. If the disease has progressed from one part to 2.2. Hepatitis B virus (HBV)
another part(s) of the body by metastasis, these therapies are very less
useful. Besides, the chemotherapeutic treatments are also considered as In diverse literature reports, the role of HBV in causing hepatocel­
palliative for the treatment of advanced tumors, majorly in case of tu­ lular carcinoma (HCC) has been reported. A true geographical rela­
mors like lung, colorectal, breast, prostate, and pancreatic cancers [3]. tionship exist between the distributions of HBV infection and HCC [25],
However, the increasing number of cancer related deaths has essentially where antigens of the virus are not easily detectable during diagnosis of
triggered the development of cancer vaccines as a preventive measure to HCC with the help of existing diagnostic techniques during 1970s [26,
avoid multiple recurrences, thus providing ultimate therapeutic solu­ 27]. Analysis of many human samples collected during that time, a very
tions to the patients [4]. The cancer vaccines are highly effective in a low viral antigen load was observed in the tumor tissues over the normal
way that they tend to act on the immune system of the patient’s body to liver cells [273–275]. A range of epidemiological studies later planned
prevent the metastasis of the cancer cells which is quite unsuccessful in provided evidence on role of HBV in causing HCC, but detailed in­
case of chemotherapeutics-based treatment strategy. Chemotherapy vestigations of the mechanisms are missing. Typically, the causal factors
only acts as a curative therapy for cancer treatment, while the cancer like viral proteins, inflammation and genetic instability influences the
vaccines provide a preventive therapy for the treatment of cancers by mechanism and complexity of HBV in inducing the HCC symptoms.
avoiding recurrent metastasis. Some of the typical cancer causing antigens of viruses includes HBsAg
and HBx, which have been reported to develop liver cancers [28,29].
2. Cancers caused by viruses Apart from this, another mechanism that involves viral response to­
wards the chronic inflammation to produce HCCs [30,31]. Also, the
Viruses are the most influential causative factors underlying devel­ process of integration of virus into the host genome also facilitates the
opment of cancers. The first reported cases of cancers by viruses came in replication HBV in the host cell genome [32]. Upon integration, the viral
1960s with the discovery of mouse leukemia virus [5], chicken leukemia assemblies undergo fragmentation and rearrangement to produce the
virus [6] and feline lymphoma viruses [7,8], which were particularly infected viral particles [33]. These infected viral particles can prefer­
responsible for inducing leukemia in respective animals [9]. Apart from entially causes instability of the host cell chromosomes to spread the
these, a series of discoveries were observed in identifying a number of infection [34].
viruses responsible for causing human cancers [10]. In 1968,US
congress showed evidence of viruses in inducing the cancers in animals 2.3. Human papilloma virus (HPV)
and the viruses are responsible for high incidence of human cancers by
the National Cancer Institute [11,12]. Later, human oncogenic retrovi­ HPV was discovered in 1970 by recombinant DNA technology from
ruses were discovered for causing cancers in animals and humans [6,8,9, the samples collected after sequencing viral genes which exist in
13,14]. The cancer-causing viruses were thus regarded as the “tumor different cellular prototypes [35,36]. The virus was identified as the
viruses”. Of late by 1990, it was further cleared that human cancers were HPV-16 and HPV-18 in cervical cancer biopsies [37,38]. Later, many
not caused by viruses [15]. Further, advancements in the discovery of epidemiological studies have been conducted in identifying HPV DNA
viruses causing risk to the development of cancers were occurred during prototypes in patients diagnosed with cervical cancer positive cases [39,
this. Use of high-end laboratory techniques were made for conducting 40]. With the advancements in the diagnostic tests for the detection of
the virus related experiments. The epidemiological methods were HPV, the sensitivity has been increased several fold for detecting the
developed for conducting the virus-related studies for evaluating the cervical cancer with the help of biopsies at an accuracy of 97%–98% [41,
tobacco smoking related lung cancers for analysis of infectious agents. 42]. Some of the typical antigens of HPV-16 and HPV-18 produces
The details regarding the cancers causing viruses and their pathogenesis proteins like E5, E6 and E7 oncogenes with serious cancer causing ac­
in cancers have been provided below. tivities [43,44]. Among these oncogenes, E6 is particularly responsible
for inducing instability in the chromosomes by binding with p53-tumor
2.1. Human T-cell leukemia virus suppressor protein for interfering with the normal cellular functions
[45]. Apart from E6, E7 gene is also responsible for significantly creating
Human T-cell viruses were discovered as the retroviral assemblies instability in the chromosomes, thus leading to improper functioning of
causing leukemia and related cancers by Gallo et al. and co-researchers the biochemical pathways responsible for triggering degradation of the
[16]. The same provoked with the discovery of retrovirus which causes proteins [46,47]. Besides, HPVs replicates in the host cell genome and
leukemia in nonhuman primates [17], and also causes leukemia in cattle produces newer viral assemblies by over activation of the E6 and E7
[18]. The retroviruses tend to affect the T-cells to form cutaneous T-cell genes [48,49]. Moreover, the integrated viral assemblies are located in
lymphoma, thus were also termed as human T-cell leukemia retrovirus the form of a truncated structure, where both E6 and E7 genes are
(HTLV-1) in the year 1980 [13,19]. Hinuma et al. in 1982 reported the present in the intact form and undergoes transformation to cause protein

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S. Beg et al. Seminars in Cancer Biology 69 (2021) 43–51

instability [50]. Some of the cohort studies have demonstrated strong 3.2. Inactivated vaccines
associations of HPVs with cervical cancer due to long and persistent
infections [51]. Also, studies have shown that some of the mucosotropic These preparations are made from the killed microorganisms. Polio
HPV types also causes cancers of the vulva, vagina, penis, oropharynx, vaccine is a good example of the inactivated vaccine, as it produces
oral cavity and tonsil [52]. immune response in different ways as compared to the live attenuated
vaccines. These may also require multiple doses to trigger, build and/or
maintain the immunity.
2.4. Hepatitis C virus (HCV)

3.3. Toxoid vaccines

Unlike HBV, the infections due to the HCV are quite less in terms of
their connection with cancers of various organs of the body. Some of the
These preparations are made from the bacterial toxins produced in
literature reports have confirmed the role HCV in causing HCC of liver,
the body. During the preparation of these vaccines, the toxins are so
where the patients with blood transfusion developed chronic hepatitis
much weakened that it cannot cause harm to the person post-
that turned into liver cirrhosis [53,54]. The cases of HCV induced HCC
administration. Hence, these are also called as toxoids, which can
occurs with progression of chronic hepatitis into cirrhosis, which later
easily fight with the natural toxins. Examples of toxoid vaccines include
converted into the HCC of liver in the time span of 20–30 years. The
diphtheria and tetanus toxoids.
virus particularly affects RNA polymerase and creates miscoding during
the translation of proteins [55]. Systematic review and meta-analysis of
3.4. Subunit vaccines
data has suggested that nearly 75% of the patients affected with HCV
tends to eradicate the virus by the action of immune response clearance
These preparations include only the part of virus or bacteria or some
mechanism [56]. However, the role of HCV in causing HCC are promi­
of the subunits instead off the entire microorganism. As these vaccines
nent in the recent cases reported these days [57].
particularly contain only the essential antigens without any other sub­
stances, the side-effects are these preparations are quite less. DTaP-IPP
2.5. Epstein-Barr Virus (EBV) vaccine is the commonly used subunit vaccine against the diphtheria,
tetanus and acellular pertusis infections.
The role of EBV in inducing cancers was reported lately in 1969,
where the patients with Burkitt’s lymphoma (BL) showed higher anti­ 3.5. Conjugate vaccines
body titer to EBV viral capsid antigen. Some of the literature reports
have indicated higher antibody titer induced by EBV to develop the BL These preparations are effective against bacteria which possess
[58]. In this case, the virus is present in the episomes of the BL cells, polysaccharide coating. Conjugate vaccines are effective for these types
which causes progression of the viral infection in the form of tumor [58]. of bacteria, as the interaction of polysaccharides with the antigens works
well in inducing the immunization process. Some of the common
example of conjugate vaccines includes Haemophilus influenzae type B
2.6. Human Herpesvirus-8 (HHV-8)
(Hib) vaccine.
The influence of HHV-8 is particularly observed in case of patients
4. Cancer vaccines and their applications
infected with AIDS, where recurrent blood transfusion and associated
exposure to virus ultimately causes risk for developing the cancers
In the era of 21st century, the healthcare system is witnessing sig­
[59–62]. Some of the clinical studies have reported HHV-8 specific
nificant change in the measures used for the treatment of diseases [67].
T-cells and their role in developing immunosuppression in the patients.
Cancer as one of the deadliest diseases has very high mortality rate from
Three large studies conducted before the widespread use of HAART,
past two decades. Although use of chemotherapeutic treatment ap­
reported decreasing number of cases among HIV patients to produce the
proaches has shown reduction in the mortality due to cancer, yet the
incidence of cancers [63,64].
quest for adopting newer therapeutic measures for avoiding chemo­
therapeutic drug resistance has practiced a lot. In this regard, use of
3. Concept of cancer vaccines
vaccines as a potential tool for the treatment and management of cancer
shows quite a high degree of success [67,68].
As per the definition by WHO, vaccines are the biological prepara­
Vaccines used for inducing tumor-specific immune responses can
tion which helps in building immunity of the body through immune
essentially provide protective defense by triggering the adaptive im­
recognition mechanism by producing antibodies against a particular
mune system for progressive killing of the cancer cells. This strategy
disease-causing microorganism. Usually, vaccines improve the humoral
potentially helps in complete clearance of the cancer cells from partic­
and cell-mediated immunity, where upon exposure to the same disease-
ular organ(s) and/or organ system(s) of the body with negligible chances
causing organism, the body easily detects the antigens and initiates the
of tumor recurrence and metastasis to other parts [68]. Due to the
production of antibodies for self-defense mechanism. Vaccines typically
intrinsic ability of the body to recognize the tumor cells specifically by
contain live attenuated forms of the microbes, or microbial toxins and/
immune recognition mechanism, the B-cells get essentially triggers upon
or their surface proteins. There are five main types of vaccines that in­
contact with the tumor cell specific antigens to produce the antibodies
fants and young children commonly receive.
and completely destroy the target antigens. Despite high degree of
sensitivity of B-cells for the tumor cell specific antigens, these still
3.1. Live-attenuated vaccines require help from CD4+ cells mediated antigen-antibody interactions
with the help of MHC II molecules [65,66]. This phenomenon is termed
These preparations contain living virus or bacteria which have been as antibody-dependent cell-mediated cytotoxicity (ADCC), which pro­
weakened so that it does not cause serious disease in people with healthy vides high compliance with respect to the limited recurrence of the
immune systems. Due to the presence of live microorganism, these cancer cells in the body. Some of the cancer vaccines approved by FDA
vaccines closely resemble with the natural infections and quickly trigger include HBV vaccine in 1981 and HPV vaccine in 2006 for prophylactic
the immune response of the body. Examples of live attenuated vaccines use in cancers associated with them [67]. By the application of cancer
include measles, mumps, and rubella vaccine (MMR), and varicella vaccines, the demographic data suggests reduced incidence from
vaccine. developing cancers in certain high-risk individuals. Fig. 1 illustrates the

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S. Beg et al. Seminars in Cancer Biology 69 (2021) 43–51

Fig. 1. Mechanistic understding of application vaccines in inducing immunization against the cancer cells and creating immune recognition for avoiding recurrence
of cancers (adapted with permission from Neek et al., 2019 [69]).

mechanism of action of cancer vaccines in inducing immune response of their low immunogenicity, low toxicity and biocompatibility [76]. In
the body to fight against recurrence of cancers [68]. this context, the role of nanostructured systems in disease treatment,
A typical cancer vaccine particularly contains tumor-specific antigen specifically in cancer chemotherapy has been rigorously experimented.
(s), a carrier or delivery system and vaccine adjuvants for effective de­ Fig. 2 portrays various types of nanocarriers used in cancer vaccine
livery to the body. The tumor-specific antigens are usually originated delivery and active targeting of the tumor cells [77,78].
from the cancer cells and chemically are proteins, carbohydrates, gly­ Active role of nanoparticulate systems in site-specific drug targeting
coproteins or glycopeptides, gangliosides and/or genes (DNA or RNA), helps a lot, where chemotherapeutic drug resistance is a major under­
which typically encodes cancer cell specific antigens. Extensive research lying hiccup for failure of treatment therapy. Thus, idea of cancer vac­
efforts have been taken in the area of cancer vaccines in the past few cines described in the aforementioned sections have gained immense
decades. Some of the commonly known cancer vaccines under explo­ attention due to high therapeutic advantage of immune recognition-
ration are E7 protein for HPV 16 is under Phase I/II clinical trial, E7 based mechanism for generating antibodies against the target antigens
peptide (11–20) of HPV is under phase I trial and E7 epitope (83–95) expressed on the cancer cells [79,80]. Use of nanostructured systems
DNA vaccine is under Phase I trial [69–71]. All these vaccines are invariably provides benefit in improving deliverability of the cancer
constituted of proteins containing tumor cell specific antigens expressed vaccines to the specific immune cells [77]. Fig. 3 provides pictorial
on the tumor cell surface. Thus, proteins which highly expressed on the depiction of the mechanistic understanding of the nanocarriers in cancer
tumor cell specific antigens are provided in cancer vaccines for tumor vaccine delivery [81]. A wide range of nanosystems have been devel­
targeting applications [72]. Although some of the tumor antigens are oped in the recent past to overcome the formulation, delivery and
often essential for survival of the tumor cells, yet the action of vaccines therapeutic challenges associated with the drugs. These include a vari­
on these antigens helps in developing the immune response for sur­ ety of nanostructured systems constituted of lipids, polymers and/or
veillance of the tumor cells in future time. For example, the viral pro­ lipid-polymer hybrid materials [77]. Some of the instances of such as
teins HPV16 (E6 and E7) are very useful for targeting the therapeutics to nanosystems are liposomes, nanoparticles, nanoplexes, inorganic
the cervical cancer [73]. The viral antigens are delivered with the help of nanomaterials, etc. Delivery of antigenic materials for inducing immu­
a carrier system including oil-in-water emulsion, mineral salts, nization for recognition of human body against the cancers can be well
aluminum compound, microsphere (for example, chitosan), nano­ achieved using nanocarriers. The antigens rather act as immunomodu­
particles, attenuated viruses, cells and so on. latory agents against the cancer cells [77]. Moreover, the nanocarriers
also particularly help in addressing the biopharmaceutical challenges
5. Nanomedicines in cancer vaccines associated with the antigenic materials. Several literature reports have
demonstrated the potential applications of the nanotherapeutic systems
The applications of nanotechnology in diverse domains of drug de­ in the delivery of cancer vaccines where site-specific delivery is achieved
livery and biomedical research have been immensely explored. Verily, using the targeting ligands or antibodies. Moreover, multiple function­
nanosystems are constituted of miniaturized particles/tiny devices with alization on the nanoparticles are also considered to be very helpful in
size less than 1 μm in diameter [74]. The nano-sized objects are also further improving the site-specific delivery under in vivo conditions
considered to be nearly 100 ~10,000 times smaller than that of the size [82].
of mammalian cells [75]. Owing to their customizable material prop­
erties, high aspect ratio and surface modification abilities, nano­ 5.1. Polymeric nanoparticles
structured systems are greatly useful for exploring them in the treatment
of diseases affecting human civilization. Beyond nanosystems as carrier Polymeric nanoparticles have a long history of use in drug delivery
tool, applications of them as therapeutic as well as diagnostic aid have and biomedical applications for last two decades. These are typical
been highly beneficial for clinical and biological applications due to spherical particles (10–500 nm) with hollow cores (nanocapsules) or

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S. Beg et al. Seminars in Cancer Biology 69 (2021) 43–51

Fig. 2. Structural representation of various nanoparticle delivery vehicles for cancer vaccine (adapted with permission from He et al. 2016 [78]).

solid cores (nanospheres), which carry genetic materials as cargos Nevertheless, the effective immunization potential of these nanocargoes
loaded in it. Typically constituted of biocompatible and biodegradable depends on the amount of antigen loaded in the particles and their
materials like natural or synthetic copolymers, and can encapsulate a ability to protect the cargo without any degradation by the intracellular
variety of therapeutic agents in it for delivery of drugs to any specific site enzymes [91,92].
of the human body [83]. Several generation of polymeric nanoparticles The first dendritic cell-based cancer vaccine approved by USFDA in
exist till date on the basis of their structural and functional advantages 2010 using polymeric nanoparticles was reported to be highly effective
for the purpose of therapeutic delivery applications [84]. Literature in manipulating the immune response under ex vivo evaluation studies
reports have demonstrated applications in anticancer vaccine delivery, [93]. However, in vivo evaluation showed unsatisfactory response in
where specifically the immunotherapeutic proteins like modified cyto­ activating the production of antibodies by the dendritic cells which
kines and monoclonal antibodies can be administered to invoke strong generated high regulatory concerns. Similarly, other literature reports
antitumor immune activity [85]. have demonstrated the application of antigenic protein and peptides
Poly (D, L-lactic-co-glycolic) acid (PLGA) and Poly (lactic acid) (PLA) delivery using various types of polymeric nanocarriers such as PLGA
are some of the commonly biocompatible and biodegradable polymers, [94], polyglycolic acid [94], polystyrene [95] and gelatin [96]. In a
which have been approved by USFDA for human use. PLGA and PLA study published by Hamdy et al. demonstrated effectiveness of PLGA
nanoparticles have shown great potential for delivery of therapeutic nanoparticles in delivering TAA peptide (TRP-2180-188) and TLR-4
biomolecules over the last two decades [86]. The nanoparticles fabri­ ligand (7-acyl lipid A), which showed higher efficacy of peptides in
cated using these polymeric materials require suitable manufacturing generating the TRP-2-specific cytotoxic T-lymphocytes for controlling
techniques like emulsification and/or solvent evaporation. Several tumor growth through in mice. Additionally, these nanocarrier systems
literature reports have suggested optimization of the critical formulation also showed significant up-regulation of Th1 cytokines (IL-6, IL-12,
and process parameters for controlling the response parameters like IFN-γ, TNFα) and down-regulation of the pro-angiogenic vascular
particle size, zeta potential, entrapment/emasculation efficiency and endothelium growth factor (VEGF) [90]. In another study, Dominguez
drug release [87]. The specific advantages of using PLGA/ PLA based et al. worked on the novel strategy for tumor eradication where conju­
nanoparticles in cancer vaccines include their non-toxic and gated anti-RNEU and anti-CD40 antibodies loading into PLA nano­
non-immunogenic properties for co-delivery of vaccine antigens and particles showed effective induction of the immune response against
adjuvant. Besides, these nanoparticles have very good transfection ef­ tumor due to the antibodies generated against tumor causing rat
ficiency to undergo internalization by the APCs for triggering the im­ her2/neu oncogenes [97].
mune response in the body [88]. The particulate carrying the antigens Polybutylcyanoacrylate (PBCA) is another most widely accepted
with size ranging between 0.1–10 μm can induce the cellular response polymer with wide applications in the area of immunotherapy against
by MHC-I mediated expression of the antigens [89]. However, the exact the tumors. In a study, Schneider et al. investigated the application of
mechanism underlying the cellular fate of transfection and internaliza­ nanoparticles as an ideal carrier for the dual delivery of therapeutic
tion of the nanoparticles delivering the antigenic is still unknown [90]. agents, i.e., doxorubicin and anti-TGF-β genes for active immunization

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S. Beg et al. Seminars in Cancer Biology 69 (2021) 43–51

Fig. 3. Depiction of the complex pathway involved in cancer immunotherapy. Nanoparticle delivery vehicles can play a role at multiple points along this pathway.
Following cancer cell apoptosis, antigens are released (a) enabling antigen presentation (b). Ultimately, this allows for priming and activation of T-cells in lymph
nodes (c) that are trafficked back to the tumor (d) as cytotoxic T-cells (CTL). After tumor infiltration (e), recognition of cancer cell antigens by CTLs (f) follows with
CTL killing of specific cancer cells (g); (adapted with permission from Hartshorn et al. 2018 [79]).

against human glioblastoma cells. The evaluation of anti-TGF-β nano­ patients with advanced malignancies [101].
particles on rats showed longer time period of survival of the rats as
compared to the untreated rats due to the activated CD25+ T-cells [98]. 5.3. Liposomes
Besides the synthetic polymeric materials, natural materials like gelatin
has been employed widely in gene therapy applications. It possesses Liposomes are one of the quite oldest and most extensively explored
several functional groups, thus provides wide opportunity for chemical vesicular carriers in drug delivery applications. These exist in the form of
modification to make the nanocarriers susceptible for active tumor spherical unilamellar/multilamellar lipid vesicles, and usually contains
targeting and opsonization. Bourquin et al. investigated the applications phospholipid bilayer and an inner aqueous core [106,107]. Several
of gelatin nanoparticles surface-modified with cholamine hydrochloride applications of liposomes have been reported in the delivery of DNA
for faster immunization by producing antigen-specific CD8+ T-lym­ vaccine antigens. Liposomes can be used as carriers for vaccine delivery
phocytes and anti-tumor action [96]. where antigens can be encapsulated in the core, embedded in the bilayer
and/or adsorbed or engrafted to the outer surface. In relation to anti­
5.2. Magnetic nanoparticles genically stimulated liposomes, adjuvants may be used to boost the
innate immune response organ and improve tumor immunity because
The applications of magnetite nanoparticles in cancer therapy have standard liposomes have usually been known to have only small or no
been effectively used with the help of hyperthermia application [99, inherent immunoadjuvant characteristics [108]. A number of liposome
100]. These nanoparticles demonstrated significant induction in the differences in terms of their immunization potential have been
tumor regression, which ultimately enhanced MHC class I presentation researched. Since these vaccines are generally primarily DCs, the design
and anti-tumor action by T-lymphocyte mediated immune response of liposomes is based on their capacity to activate and/or deliver antigen
[101–103]. This effect has been studied in several animal tumor models to the cells [98,99]. Liposomes that carry immunogenic peptides can
using magnetite nanoparticles alone and in combination with additional fuse or be pinocyted in DC membranes. Some proteins are treated by
immunotherapies or chemotherapies, such as immunoliposomes [104, cytoplasmic MHC Class I pathway, whereas others are treated by
105] and intratumoral cytokine or DC injection [101]. Akira et al, endosomal/ lysosomal MHC Class II pathways. Traditional liposomes
studied the combined effects of Immunotherapy (IT) and intracellular consisting of neutral lipids and phosphatidylcholine, are rather
hyperthermia (IH) on melanoma. MCLs were injected into a B16 mela­ non-toxic but have a shortened systemic half-life since the reticular
noma nodule in C57BL/6 mice, which were subjected to AMF for 30 min. endothelial system (RES) is easily removed [99,100]. However, it does
This study supports the combined use of IT and IH using MCLs in have a therapeutic potential for macrophages of the RES in spleen and

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S. Beg et al. Seminars in Cancer Biology 69 (2021) 43–51

liver when trying to directly target the tumor with the liposomal cargo. stabilization. As this technology promises to produce consistent, secure,
Zhengrong et al [101] worked to eradicate established tumors of a and effective vaccines, the cancer vaccine formulations have lately been
mouse model in liposome-polycation-DNA (LPD) as a protein antigen evaluated. Shi et al [106] developed a vaccine for a co-delivery of
carrier and inducing strong and robust immune response adjuvants. immunostimulatory CpG and a gastric-cancer-specific antigen earlier
Given its excellent safety picture as a drug provider and adjuvant in past recognized MG7 [106]. They developed their nanoemulsion carrier for
clinical studies [102]. The antibiotic protein HPV 16 E7 was used to test the antigen and CpG, respectively, by means of a heavy vacuum-shear
LPD adjuvancy. While antibody response and Th2 cytokine discharge, ultrasonic emulsifier with a large payload of 70% and 93%. The nano­
such asIL-4, may not be necessary to kill cervical cancer cells, these emulsion was formed by a 0.8 percent surface active mixture of Span 80
aspects of immune response have still been measured to understand the and Tween 80 using of magnetic ultrasonic method with the aqueous
resulting immune answer carefully. They have been surprised that both phase, while the oil phase comprised the same surfactant ratio in soy­
powerful CTL and powerful antigen reactions have been caused. This bean oil, in conjunction with PEG2000 solubilization of antigen and
means that LPD can be used easily to plan HIV or disease drugs that CpG. The oil part was homogenized by means of an ultrasound generator
require both neutralizing antibodies and CTL reactions. Their research at the frequency 40 KHz, using a vacuum heavy shear emulsification tool
also aimed to assess the effectiveness of treating cervical cancer with at the pressures of 0.7 K Pa with an ultimate decrease in the size. Mice
HPV 16 E7 protein-incorporated LPD (LPD/E7 Protein). Treatment with immunized with such nanoemulsions containing MG7 and CpG were
LPDs incorporating either the wild-type or the mutant E7-protein in 3 found to be significantly inhibitors of cell development after competi­
distinct dosage plans [day 4 only, day 4 and 10, and day 6 only resulted tion in MG7-expressing carcinoma cells. The tumor protection was
always to a full tumor regression. Therefore, we think that a powerful directly associated with the production of MG7 specific antibodies and
vaccine for cervical cancer treatment may be the LPD particles that are IFN-γ. Not surprisingly, the co-delivery of the antigen CpG and MG7
integrated into cervical cancer particular antigens (E6 and E7 from the increased the MG7 specific response over to nanoemulsion vaccines
high-risk HPV types’ High Risk). Polyethylene glycol (PEG) can be used containing peptide antigen alone.
to perform this steric modification. and Christina et al, in their research
p [103] it was found that mouse vaccinations with DC-targeting stealth 6. Conclusion
liposomes (encapsulating OVA+/-LPS or IFN-γ) could produce a safe
anti-tumor reaction to OVA-expressing B16 melanoma cells [103] from Due to the adjuvants and targeted ability, nano carriers are better
pulmonary metastases. Such trials indicated, apart from the efficacy of able to deliver vaccines effectively which boosts the body’s immune
the use of concealed liposomes, that recruiting DC and simultaneously response. Mostly vaccine containing nanocarriers contain poor formu­
transmitting antigen-based risk messages were essential to the genera­ lation properties and offer improved immune response to pathogens. In
tion of a tumor-specific CTL response and thus tumor protection. These many clinical trial reports nanomedicine as carrier provide adjuvant like
are caused by the amalgamation of normal Sendai (UV-inactive) lipo­ action and lead to cellular and humoral immune responses. Recent
somes with a replicatory deficiency virus. These liposomes fuse with a studies have shown that several nanomedicines such as liposomes,
wide range of mammalian cell types, are using the Sendai virus-derived transferosomes, microphones have been authorized by USFDA, while
fusion (F) protein, and directly transfer their contents into cytoplasm many are under development. In the preclinical stage other prospective
[104]. Prophylaxis tests conducted using B16 cells aggressive melanoma nanomedicines such as polymer composites, dendrimers and carbon
showed that FLs encapsulated with tumor-lysate (TCL) have an nano-tubes were also used efficiently. However, clinical trials must
improved safety impact relative to conventional liposomes [105]. In demonstrate the safety and efficacy of such interventions.
short, TCL / FLs (100 μg) were injected three times intradermally (each
injection is 1 week apart), followed by a tumor challenge a week later. Declaration of Competing Interest
TCL/FLs could reduce the rate of cancer development by 2–3-fold
compared to conventional liposomes and TCL (plus CFA), which pro­ Authors declare conflict of interest.
vided only limited protection.
Acknowledgements
5.4. Nanoemulsion
The support of UGC Faculty Research Promotion Scheme provided to
Nanoemulsions are colloidal dispersions with surface-active film of author Sarwar Beg is acknowledged. The support of Ramalingaswami
the nano-sized oil and water droplets typically stabilized in the size Fellowship grant (BT/RLF/Re-entry/09/2015), Government of India,
range 20–200 nm. The range of nanometers provides greater kinetic Ministry of Science and Technology, Department of Biotechnology
stability with regard to sedimentation and creaming, which is a common (DBT) to author Jawed Iqbal is acknowledged. Also, the technical sup­
problem with the conventional emulsions [109]. Significant efforts in port provided by Almanac Life Science India Pvt. Ltd., New Delhi, India,
latest years have been made to develop nanoemulsions as vectors of for publishing this work is acknowledged.
vaccines. Some of them were defined subsequently for mucosal vacci­
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