Pharmaceutics 15 00889 v2

pharmaceutics
Review
Codelivery of Phytochemicals with Conventional Anticancer
Drugs in Form of Nanocarriers
Girish Kumar 1 , Tarun Virmani 1 , Ashwani Sharma 1 and Kamla Pathak 2, *
1 School of Pharmaceutical Sciences, MVN University, Aurangabad 121105, India

2 Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Saifai 206001, India
* Correspondence: kamlapathak5@gmail.com
Abstract: Anticancer drugs in monotherapy are ineffective to treat various kinds of cancer due to the
heterogeneous nature of cancer. Moreover, available anticancer drugs possessed various hurdles, such
as drug resistance, insensitivity of cancer cells to drugs, adverse effects and patient inconveniences.
Hence, plant-based phytochemicals could be a better substitute for conventional chemotherapy for
treatment of cancer due to various properties: lesser adverse effects, action via multiple pathways,
economical, etc. Various preclinical studies have demonstrated that a combination of phytochemicals
with conventional anticancer drugs is more efficacious than phytochemicals individually to treat
cancer because plant-derived compounds have lower anticancer efficacy than conventional anticancer
drugs. Moreover, phytochemicals suffer from poor aqueous solubility and reduced bioavailability,
which must be resolved for efficacious treatment of cancer. Therefore, nanotechnology-based novel
carriers are employed for codelivery of phytochemicals and conventional anticancer drugs for better
treatment of cancer. These novel carriers include nanoemulsion, nanosuspension, nanostructured
lipid carriers, solid lipid nanoparticles, polymeric nanoparticles, polymeric micelles, dendrimers,
metallic nanoparticles, carbon nanotubes that provide various benefits of improved solubility, re-
duced adverse effects, higher efficacy, reduced dose, improved dosing frequency, reduced drug
resistance, improved bioavailability and higher patient compliance. This review summarizes vari-
ous phytochemicals employed in treatment of cancer, combination therapy of phytochemicals with
anticancer drugs and various nanotechnology-based carriers to deliver the combination therapy in
treatment of cancer.
Citation: Kumar, G.; Virmani, T.;
Sharma, A.; Pathak, K. Codelivery of
Keywords: cancer; phytochemicals; codelivery; nanotechnology; novel approaches; anticancer drugs
Phytochemicals with Conventional
Anticancer Drugs in Form of
Nanocarriers. Pharmaceutics 2023, 15,
889. https://doi.org/10.3390/
1. Introduction
pharmaceutics15030889
Despite remarkable progress in treatment of cancer, the prevalence and fatality rates
Academic Editor: Xiaowei Zeng
are highest throughout the world [1]. According to a report generated by International
Received: 14 February 2023 Agency for Research on Cancer (IARC) in 2020, approximately 19.3 million new cases
Revised: 7 March 2023 and 10 million deaths due to cancer were reported across the world, whilst the new cases
Accepted: 8 March 2023 and deaths due to cancer in India were 1.32 million and 0.8 million, respectively [2]. This
Published: 9 March 2023 extremely endemic illness is currently thought to be the second most common cause of
mortality, having a significant impact on low- and middle-income countries both physically
and economically [3]. Minor lifestyle adjustments, reduced alcohol consumption and
cessation of tobacco chewing can cut cancer cases by roughly 30 to 50% [4]. Moreover,
Copyright: © 2023 by the authors.
various treatment strategies such as radiotherapy surgery, immunotherapy, aromatherapy
Licensee MDPI, Basel, Switzerland.
and chemotherapy using drugs are available to cure cancer, but chemotherapy is a very
This article is an open access article
distributed under the terms and
common and widely used treatment option for cancer [5].
conditions of the Creative Commons
The Food and Drug Administration (FDA) has approved more than 300 chemother-
Attribution (CC BY) license (https://
apeutic agents to treat cancer, but all these drugs have restricted efficacy in treatment of
creativecommons.org/licenses/by/ cancer due to the heterogeneous nature of cancer [6]. Moreover, these drugs also suffer
4.0/). from various hurdles, such as adverse effects, drug resistance, insensitivity of cancer cells
Pharmaceutics 2023, 15, 889. https://doi.org/10.3390/pharmaceutics15030889 https://www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2023, 15, 889 2 of 29
to drugs, lack of targeting and patient inconvenience [7,8]. Additionally, chemotherapeutic

drugs show their utility in cancer via single targeting of cell proteins, nucleic acids and
carcinogenic signalling pathways, which cause adaptation to change the environment
by cancerous cells, leading to further development of cancer [6]. Hence, it is required
to determine methods to demonstrate their action through multiple targeting of cancer
cells so the hurdles associated with conventional chemotherapy can be avoided. Recently,
phytochemicals have attracted the attention of researchers as a viable treatment option for
cancer due to various attributes: lesser adverse effects, action through multiple targeting,
economical, easily available, etc. [9].
Various conventional chemotherapeutic drugs are derived from plants, so researchers
are focusing their attention on phytochemicals to treat cancer [10]. These chemotherapeutic
agents in monotherapy suffer from various hindrances, which can be combated by em-
ploying codelivery of phytochemicals with conventional chemotherapeutics for efficacious
treatment of cancer [11,12]. Despite the benefits of combination therapy compared to
monotherapy, clinical outcomes are still subpar due to ignorance of poor aqueous solubility,
low bioavailability, duration of drugs at the targeting site and the targeting drug [13].
Nanotechnology-based novel carriers, such as nanoemulsion, nanosuspension, nanos-
tructured lipid carriers, solid lipid nanoparticles, polymeric nanoparticles, polymeric mi-
celles or dendrimers, can be employed for codelivery of phytochemicals with conventional
chemotherapeutic drugs to elicit optimal clinical outcomes in cancer [14]. These novel
carriers have a size range of 1–1000 nm and cause improvement in efficacy of treatment
and reduction in adverse effects associated with targeted drugs [6]. These carriers show
their potential due to possession of various characteristics of improved solubility, reduced
adverse effects, higher efficacy, improved dosing frequency, reduced drug resistance, drug
targeting, improved bioavailability and patient compliance [15,16].
2. Aetiology, Pathogenesis and Metastasis of Cancer

The terms “carcinogenesis,” “oncogenesis” and “tumorigenesis” refer to the process
that causes tumours to form (the “pathogenesis of cancer”), and the agents responsible for
causing cancer are carcinogens. Ever since the first carcinogen was discovered, a growing
number of substances have been linked to the genesis of cancer. Because of recent enormous
advancements in the fields of molecular biology and genetics, there is an increasingly large
collection of knowledge regarding the pathogenesis of cancer [17]. According to the
World Health Organization (WHO), it is reported that nearly 10 million deaths occurred
in 2020 and about one in six deaths were from cancer [18]. Nearly one-third of cancer
patients’ deaths occurred by consuming tobacco and alcohol, less consumption of fruits
and vegetables in their diet, obesity and lack of exercise. Human papillomavirus (HPV)
and hepatitis infections are the major cause of cancer, with approximately 30% of cancer
cases reported in lower- and lower-middle-income countries. Breast, lung, colon, rectum
and prostate cancers are the most prevalent types of cancer [19]. However, fortunately,
many types of cancer are curable with the right diagnosis, early detection and care.
The ability of cancer cells to grow more quickly than healthy cells is one of their
defining characteristics. The majority of conventional anticancer drugs are made to target
these quickly proliferating cells and stop, kill or slow down their proliferation. Never-
theless, these anticancer drugs also harm or destroy healthy, normal cells. The patient
will consequently have serious adverse effects and the effectiveness of the therapy will be
limited or diminished [20].
Development of a normal, healthy cell into a tumour cell is known as carcinogenesis,
which involves numerous genes and genetic changes. Carcinogenesis is a multiplex process
encompassing origination, promotion and progression [21]. The first step involves the
beginning of a permanently altered cell and is frequently linked to a mutation and several
start pathways. The initial altered cells grow and manifest as a visible mass of cells during
the second stage, which is most likely a benign lesion. Epigenetic elements that influence
Pharmaceutics 2023, 15, x FOR PEER REVIEW 3 of 33
Pharmaceutics 2023, 15, 889 several start pathways. The initial altered cells grow and manifest as a visible mass of3cells of 29
during the second stage, which is most likely a benign lesion. Epigenetic elements that
influence the proliferation of the started cells are undoubtedly present during the promo-
tionproliferation
the stage. It is not
of well understood
the started exactly
cells are how the second
undoubtedly present stage
during ofthe
carcinogenesis
promotion stage. works. It
Mostly benign or non-cancerous cells, or occasionally pre-cancerous
is not well understood exactly how the second stage of carcinogenesis works. cells, are the end
resultMostly
of promotion.
benign or When these benign
non-cancerous cellsor
cells, transition into neoplastic
occasionally pre-cancerous cells,cells,
they areexperi-
the
enceresult
end a few additional
of promotion. genetic
Whenchanges.
theseThe thirdcells
benign andtransition
final stages of carcinogenesis,
into neoplastic cells,which they
involve development
experience of malignant
a few additional genetictumours
changes.fromThe benign non-cancerous
third and final stages of tumours, are dis-
carcinogenesis,
tinct from
which the first
involve two steps of
development [22].
malignant tumours from benign non-cancerous tumours,
Stem cells
are distinct fromplay
the afirst
crucial
two role
stepsin[22].
the beginning of carcinogenesis owing to a variety of
physical,
Stemchemical
cells play orabiological stimuli,
crucial role in theincluding
beginning viruses. The sequential
of carcinogenesis stepstoare
owing crucial
a variety
in malignant
of transformation
physical, chemical of preneoplastic
or biological cells because
stimuli, including such initiated
viruses. cells would
The sequential stepsthen
are
crucial in malignant
be exposed transformation
to a promotional factor of
to preneoplastic
accelerate fullcells becausecell
neoplastic such initiated
creation cells
[23]. A would
multi-
then be exposed
cellular animal’s to a promotional
carcinogenesis factor results
process to accelerate full neoplastic
from numerous cellchemical,
cellular creation [23].
physi-A
multicellular
cal, biologicalanimal’s
or genetic carcinogenesis process results
alterations. Although mutationfrom numerous
is the primarycellular
cause ofchemical,
carcino-
physical, biological
genesis, several or genetic
additional alterations.
variables Althoughtomutation
also contribute its growth. is Use
the primary
of either cause
conven- of
carcinogenesis,
tional anticancerseveral
drugs additional variables
or plant-derived also contribute
compounds to its growth.
are available options Use of either
to reverse or
conventional anticancer
capture the process drugs or plant-derived
of carcinogenesis, influencing compounds are available
the carcinogenesis options
process to reverse
at each stage
or capturedevelopment
of cancer the process of carcinogenesis,
(Figure 1). influencing the carcinogenesis process at each
stage of cancer development (Figure 1).
Figure 1. Various stages

stages for
for progression
progression of
of cancer
cancer along
along with
with their
their treatment
treatmentapproaches.
approaches.
3. Progression in
3. Progression in Drug
Drug Treatment
Treatment forfor Cancer
Cancer
The
The medical history of cancer datesback
medical history of cancer dates backthousands
thousandsofofyears.
years.The
Thefirst records
first recordsofof
cancer
can-
patients come from the ancient Egyptian and Greek cultures, where the disease
cer patients come from the ancient Egyptian and Greek cultures, where the disease was was mostly
treated with radical
mostly treated with surgery and cautery,
radical surgery both of which
and cautery, both ofwere
whichfrequently futile andfutile
were frequently resulted
and
in
resulted in patient death [24]. Until the latter half of the 1800s, when the discovery ofand
patient death [24]. Until the latter half of the 1800s, when the discovery of X-rays X-
their application
rays and to treatment
their application of tumours
to treatment of provided the first modern
tumours provided the firsttherapeutic approach
modern therapeutic
in medical oncology, significant discoveries over the centuries enabled identification of
the biological and pathological features of tumours. Invention of anticancer drugs and
development of chemotherapy for treatment of numerous haematological and solid cancers
occurred after the Second World War.
The research for novel drugs to treat cancer has grown exponentially since this epochal
turning point. In 1950, the first anticancer drug, antimetabolite, was employed to induce
transient remission in children with acute leukaemia, followed by use of an alkylating
agent as an anticancer drug after two years. Thereafter, a combination of methotrexate and
6-mercaptopurine was employed for remission of acute leukaemia in children and adults in
1958. In a sequence of the progress of cancer treatment, cyclophosphamide was employed
to treat lymphoid leukaemia in 1959. Then, in 1962, vincristine provided promising results
in childhood lymphoid leukaemia. After that, a surprise was observed when a birth control
drug, tamoxifen, was successfully approved to treat breast cancer in 1978. Thereafter,
in 1996, anastrozole obtained approval for treatment of breast cancer. In 1990, the first
large molecule, namely rituximab, was introduced as an anticancer drug followed, by
introduction of trastuzumab in 1998 to treat breast cancer. Then, imatinib was employed to
treat myelogenous leukaemia in 2001, followed by introduction of ipilimumab in 2011 for
treatment of metastatic melanoma. In 2014, pembrolizumab was approved as an anticancer
moiety.
4. Hindrances in Cancer Treatment by Conventional Drugs

Various anticancer drugs are available to treat cancer, but these drugs pose restrictions
in therapeutic efficacy for treatment of cancer due to various reasons, such as non-specific
treatment, higher adverse effects, required higher doses, small half-life, wide biological
distribution, drug resistance, drug instability and lack of drug targeting [25]. These drugs
destroy non-cancerous cells along with cancerous cells at a high pace, leading to severe
adverse effects, which are a major cause of the increased death rate among cancer patients.
Progression of resistance by cancerous cells to anticancer drugs is a main hindrance in
efficient treatment of cancer, which occurs due to various mechanisms, such as drug efflux,
epigenetics, DNA mutation, cell death inhibition, drug degradation, drug inactivation and
drug target alteration [26,27]. The requirement of higher doses of anticancer drugs leads to
increased toxicities in non-cancerous cells and multiple-drug resistance [28]. Furthermore,
drug instability and low aqueous solubility of anticancer drugs also cause obstacles in
treatment of cancer [29]. Drugs approved by the FDA to treat cancer have been summarized
in Table 1, along with their adverse effects. Various hindrances in treatment of cancer
employing conventional anticancer drugs in monotherapy have depicted in Figure 2.
Table 1. List of anticancer drugs along with their adverse effects.
Drug Category Sub-Class Examples Adverse Effects References

Myelosuppression, alopecia
Alkylating agent Nitrogen mustard Cyclophosphamide hemorrhagic cystitis and [30]
gonadal damage
Cisplatin, Nephrotoxicity, neurotoxicity,
Platinum agents [31]
carboplatin, oxaplatin ototoxicity, myelosuppression
Leukopenia, pulmonary embolism,
5-Fluorouracil, floxuridine,
Pyrimidine derivatives neutropenia, pyrexia, [32]
gemcitabine, capecitabine
Antimetabolites thrombocytopenia and diarrhoea
Hepatotoxicity, nausea, vomiting,
Antifolates Methotrexate [33]
loss of appetite, mucosal disorders
Docetaxel, Febrile neutropenia, infusion
Taxanes [34]
paclitaxel, cabazitaxel reactions, fluid retention and fatigue
Neurotoxicity, chest pain, acute
Antimitotic agents
cardiac ischemia, acute pulmonary
Vinca alkaloids Vincristine, vinblastine [35]
effects, hand-foot syndrome, hepatic
and pulmonary toxicity
Topoisomerase-I inhibitors Topotecan, irinotecan Myelosuppression GI toxicity,
Topoisomerase inhibitors Topoisomerase-II cardiotoxicity, alopecia, [36]
Etoposide secondary leukaemia
inhibitors
Neurotoxicity, chest pain, acute cardiac is-
Vinca alkaloids Vincristine, vinblastine chemia, acute pulmonary effects, hand-foot[35]
Pharmaceutics 2023, 15, 889
syndrome, hepatic and pulmonary toxicity 5 of 29
Topoisomerase-
Topotecan, irinotecan
Topoisomerase I inhibitors Myelosuppression GI toxicity, cardiotoxi-
[36]
inhibitors Topoisomerase- 1. Cont.
TableEtoposide
city, alopecia, secondary leukaemia
II inhibitors
Drug Category Sub-Class Doxorubicin, daunorubicin,
Examples Adverse Effects References
Anthracyclines epirubicin, idarubicin, val-daunorubicin,
Doxorubicin, Cardiotoxicity, alopecia, tissue necrosis
Cardiotoxicity, alopecia,
[37,38]
Antitumor anti- Anthracyclines epirubicin, [37,38]
rubicin tissue necrosis
biotics
Antitumor antibiotics idarubicin, valrubicin
Alopecia, bone marrow suppression, fe-
Others Others Bleomycin, mitoxantrone
Bleomycin, mitoxantrone
Alopecia, bone marrow suppression, [39]
[39]
brile neutropenia,
febrile cardiotoxicity
neutropenia, cardiotoxicity
Selective estro- Hot flashes, vaginal dryness,
Hormonal drugs
Selective estrogen Hot flashes, vaginal
Tamoxifen, Raloxifen
dryness, depression,
depression, weight gain, [40]
Hormonal drugs gen receptor Tamoxifen, Raloxifen
receptor modifier [40]
weight gain, sleep disturbances
sleep disturbances
modifier
Figure 2. Various hindrances associated with conventional anticancer drugs.

Figure 2. Various hindrances associated with conventional anticancer drugs.
5. Herbal Treatment of Cancer (Phytochemical-Based Treatment of Cancer)
Because
5. Herbal of the limitations
Treatment of Cancerof(Phytochemical-Based
conventional chemotherapeutic
Treatmentdrugs, there is an urgent
of Cancer)
needBecause
for novel cancer
of the treatment.
limitations Recently, plant-derived
of conventional agents,
chemotherapeutic namely
drugs, therephytochemi-
is an urgent
cals, have drawn the attention of researchers as a new treatment modality for cancer
need for novel cancer treatment. Recently, plant-derived agents, namely phytochemicals,
owing to various attributes of less adverse effects, action through multiple pathways
have drawn the attention of researchers as a new treatment modality for cancer owing to
and cost-effectiveness [2,10]. From ancient times, humans have made great use of plants
various attributes of less adverse effects, action through multiple pathways and cost-ef-
for treatment of various kinds of ailments, including cancer [41]. Since most available
fectiveness [2,10]. From ancient times, humans have made great use of plants for treatment
conventional chemotherapeutic drugs, such as vincristine, vinblastine and paclitaxel, are
of various kinds of ailments, including cancer [41]. Since most available conventional
plant-derived, the attention of researchers turned towards phytochemicals for treatment of
chemotherapeutic drugs, such as vincristine, vinblastine and paclitaxel, are plant-derived,
cancer [42].
the attention of researchers turned towards phytochemicals for treatment of cancer [42].
According to studies, there are over 250,000 plant species in the plant kingdom, but
only about 10% of those have demonstrated their potential as a treatment option for various
kinds of diseases, depicting that a vast portion of plant species are yet to be explored,
which could cause a revolution in treatment of cancer [9]. Various phytochemicals and their
derivatives are present in diverse parts of plants, such as seeds, flowers, bark, fruit, leaf, em-
bryo and rhizomes [43,44]. In addition, these phytochemicals and their derivatives possess
various pharmacological properties, such as anti-inflammatory, antimicrobial, antifungal,

antihypertension, antiaging, antioxidant, immunomodulator, antimalarial, anticancer, etc.
Pharmaceutics 2023, 15, x FOR PEER REVIEWVarious plant-derived products, such as flavonoids, alkaloids, terpenes, vitamins,
7 gly-
of 33
cosides, minerals, oils, gums, biomolecules and other metabolites (primary or secondary),
have proven their anticancer potential owing to various mechanisms: inhibition of cancer-
cell-activating proteins, enzymes such as cyclooxygenase, topoisomerase, CDK2, Cdc2,
CDK4 kinase, MMP, MAPK/ERK, signalling pathways, activation of DNA repair mecha-
nism, induction of antioxidant action or stimulation of formation of protective enzymes
(Caspase-3, 7, 8, 9, 10, 12) [45,46] (Figure 3).
Figure 3. Various mechanisms for working of phytochemicals as an anticancer agent.
Figure 3. Various
Various mechanisms
preclinical for have
studies working of phytochemicals
demonstrated that aas an anticancerofagent.
combination phytochemicals
with conventional anticancer drugs is more efficacious than phytochemicals individually
to treat cancer because plant-derived compounds have lower anticancer efficacy than
conventional anticancer drugs.
Various phytochemicals with the potential to improve anticancer activity in codelivery
Pharmaceutics 2023, 15, x FOR PEER REVIEW curcumin, resveratrol, genistein, epigallocatechin gallate, allicin, quercetin,
include 8 ofthy-
33
moquinone, piperine, naringenin, naringin, emodin, luteolin, β-carotene, anthocyanins,
berberine, ursolic acid, withaferin A, sulforaphane and colchicine [13,47,48] (Figure 4).
Figure
Figure4.4.Various
Variousphytochemicals
phytochemicalsemployed
employedas
ascodelivery
codeliverywith
withanticancer
anticancerdrugs.
drugs.
6. Nanocarrier-Based Codeliveryhave
Although phytochemicals of Chemotherapeutic Agent withdrugs,
huge potential as anticancer Phytochemicals
they also suffer
fromTovarious
address the obstacles associated with administration of conventionaldose,
limitations, such as low solubility, poor bioavailability, high narrow
chemother-
therapeutic index, fast absorption by normal cells, high apparent volume
apeutic agents and phytochemicals in monotherapy, codelivery of these agents has of distribution
leading to
emerged asaccumulation
an imperativeofapproach,
drugs in normal
resultingcells, high clearance
in enhanced rate andefficacy
therapeutic short elimination
in cancer
half-life [13,49]. Phytochemicals also have the potential to improve
and reduced adverse effects [54]. Codelivery of drugs in cancer is advantageousanticancer properties
due to
of other chemotherapeutic
possession agentsincluding
of various attributes, by decreasing
reducedtheirnumber
adverseofeffects
doses[50,51].
leadingHence, these
to patient
days, plant-derived
compliance, reductiondrugs or phytochemicals
in multiple-drug are used
resistance in combination
and decreased drug with conventional
doses, leading to
chemotherapeutic agents for efficacious treatment of cancer with low adverse
reduction in adverse effects in non-cancerous cells [55]. Moreover, various research effects [52].
find-
To date, no combination of conventional anticancer drug with phytochemicals is available
ings have illustrated that codelivery of chemotherapeutic drugs with phytochemicals is
as an anticancer treatment, but curcumin in monotherapy is in clinical trials on the market
advantageous in terms of synergistic anticancer effects, reversing multiple-drug re-
as an anticancer drug. In NCT01294072, a phase I randomized clinical trial was conducted
sistance and reduction in adverse effects [6] (Figure 5). Phytochemicals diminish augmen-
to study the ability of plant exosomes to deliver curcumin to normal or colon cancer
tation and metastasis of cancerous cells along with increasing sensitivity of cancerous cells
tissues, enrolling 35 participants. The status of clinical trial was recruiting. The primary
to apoptosis and DNA destruction caused by chemotherapeutic agents [56,57].
outcome measure of the study was to compare concentrations of curcumin in normal tissues
Codelivery of phytochemicals with chemotherapeutic agents provides a reduction in
and cancerous tissues after 7 days of ingestion; the secondary outcome measures were
chemoresistance developed by the reduction in drug uptake by cancerous cells, stimula-
safety and tolerability of curcumin alone as determined by adverse events after 7 days of
tion of DNA repair mechanism, uncontrolled expression of drug-resistant proteins and
enrolment [53].
overexpression of carriers responsible for higher outflow of drug [6,58]. Moreover, chemo-
therapeutic agents in monotherapy are required in larger doses to elicit anticancer activity,
which leads to severe adverse effects [50], such as cardiotoxicity, nephrotoxicity, ototoxi-
city and hepatotoxicity [34,59,60]. Additionally, codelivery of antioxidants with chemo-
therapeutic drugs may result in notable toxicity reductions so that more patients can com-
plete prescribed chemotherapy regimens, improving the likelihood of success in terms of
Pharmaceutics 2023, 15, x FOR PEER REVIEW 10 of 33
tate cancer synergistically [75]. Codelivery of doxorubicin with curcumin improved anti-
cancer potential of doxorubicin along with reduction in adverse effects. To date, numer-
6. Nanocarrier-Based
ous Codelivery
conventional anticancer drugsofareChemotherapeutic
codelivered with Agent with Phytochemicals
plant-derived compounds to im-
prove their efficacy [76].
To address the obstacles associated with administration of conventional chemothera-
peuticVarious
agents andnanocarriers,
phytochemicals solidin lipid nanoparticles,
monotherapy, nanostructured
codelivery of these agentslipid carriers,
has emerged
nanoemulsions,
as polymericresulting
an imperative approach, nanoparticles, polymeric
in enhanced micelles,
therapeutic liposomes,
efficacy dendrimers,
in cancer car-
and reduced
bon nanotubes,
adverse metallic
effects [54]. nanoparticles
Codelivery of drugsandinnanoemulsions have beendue
cancer is advantageous utilized for codeliv-
to possession of
ery of anticancer
various attributes, drugs owing
including to their
reduced abilityofto
number entrap
doses the drugs
leading followed
to patient by release
compliance, on
reduc-
targeted
tion site [77,78] (Figure
in multiple-drug 6). Moreover,
resistance and decreased these alsodoses,
drug protect drug molecules
leading to reduction from hazard-
in adverse
ous environmental
effects factors,
in non-cancerous cellswhich can cause gastrointestinal
[55]. Moreover, various researchdegradation
findings have ofillustrated
the drugs [79].
that
codelivery
Modification of chemotherapeutic
in shape, size and drugssurfacewith phytochemicals
properties is advantageous
of nanocarriers in terms of
can be performed to
synergistic anticancer
elicit maximum effects,which
efficiency, reversing
leadsmultiple-drug
to improved resistance and reduction
drug efficiency, decreased in adverse
adverse
effects
effects,[6] (Figure 5).
avoidance of Phytochemicals diminishand
multiple-drug resistance augmentation
maximization andof metastasis of cancerous
drugs in targeted cells
cells
[80].along withnanocarriers
Various increasing sensitivity of cancerous
for codelivery cells to apoptosis
of conventional anticanceranddrugs
DNA withdestruction
phyto-
caused
chemicalsby chemotherapeutic
have been discussed agents [56,57]. section.
in preceding
Figure5.5. Advantages
Figure Advantages of
of codelivery
codeliveryof
ofanticancer
anticancerdrugs
drugswith
withphytochemicals.
phytochemicals.
Codelivery of phytochemicals with chemotherapeutic agents provides a reduction

in chemoresistance developed by the reduction in drug uptake by cancerous cells, stim-
ulation of DNA repair mechanism, uncontrolled expression of drug-resistant proteins
and overexpression of carriers responsible for higher outflow of drug [6,58]. Moreover,
chemotherapeutic agents in monotherapy are required in larger doses to elicit anticancer
activity, which leads to severe adverse effects [50], such as cardiotoxicity, nephrotoxicity,
ototoxicity and hepatotoxicity [34,59,60]. Additionally, codelivery of antioxidants with
chemotherapeutic drugs may result in notable toxicity reductions so that more patients
can complete prescribed chemotherapy regimens, improving the likelihood of success in
terms of tumour response and survival [61]. Hence, codelivery of phytochemicals with
chemotherapeutic agents is not only responsible for anticancer activity and reversal of
chemoresistance but also reduces adverse effects linked with chemotherapeutic agents. Ni
W et.al, prepared curcumin with 5-fluorouracil-loaded nanoparticles to provide synergistic
effects in hepatocellular carcinoma [62] and Elkashty, O.A. and Tran, S.D investigated the
synergistic effect of sulforaphane with 5-fluorouracil in which dose of 5-fluorouracil was
reduced with improved cytotoxic effects, leading to reduced adverse effects [63].
Despite the benefits of codelivery of phytochemicals with chemotherapeutic agents,
the results are insignificant [64] due to various reasons of low aqueous solubility, poor
bioavailability, lack of drug targeting to a cancerous cell and duration of targeting at cancer-
ous cell [65], and drug targeting to a particular cancerous cell with reduced adverse effects
is the main challenge faced during codelivery of phytochemicals with chemotherapeutic
agents. It is mainly due to the presence of highly organized physical, physiological and
enzymatic barriers, which results in limited drug partitioning and distribution to the target
site and nonselective tissue toxicity in combination therapies [66,67].
Furthermore, codelivery of phytochemicals with chemotherapeutic drugs is subop-
timal due to various physiochemical and pharmacodynamic characteristics of different
drug molecules, lack of optimistic dosing and scheduling of various drugs in codelivery,
hydrophobicity of the drug, first-pass effect, low aqueous solubility and poor bioavail-
ability [6]. Moreover, codelivery of small drug molecules shows more adverse effects
clinically. In addition, the differences in pharmacological fate and pharmacokinetic profile
of individual agents may cause serious side effects and systemic toxicity. These hindrances
associated with codelivery of chemotherapeutic drugs with phytochemicals prompted
development of novel drug carriers, which mainly include nanotechnology-based drug
carriers termed nanocarriers [68].
Nanocarriers are a potential option for codelivery of drugs in treatment of cancer due
to various attributes of drug targeting at the desired site, biodegradability, increased dosing
interval, reduction in adverse effects, reduction in dose, nanosize, improved stability and
inability to deliver hydrophilic as well as hydrophobic drugs [69]. Owing to their nanosize,
nanocarriers can cross various physiological hurdles and accumulate the drug in sufficient
amounts by the targeted cancerous cell, which leads to improvement in bioavailability
of the drugs and avoidance of adverse effects in healthy cells [66,70]. These are more
efficient to deliver two or more drugs together. A drug with anticipated pharmacokinetic
and pharmacodynamic characteristics can be administered using nanocarriers employing
modification in size and shape of the nanocarriers [71]. These enable the improvement in
therapeutic efficacy of drugs with reduction in adverse effects [72]. Codelivery in nanocarri-
ers enclosed the pharmacokinetics of the drugs, which enables unifying of pharmacokinetic
properties of the codelivered drugs, increased biodistribution time and enhanced selectivity
to the tumour. The remarkable advantage of nanocarriers is the ability to release therapeutic
agents in a controlled manner in terms of location, time, amount and sequence. Codelivery
systems can be considered potential candidates to maximize treatment efficiency, minimize
side effects and improve the pharmacokinetic profile of combined therapeutic agents [73].
Furthermore, they provide controlled, sustained and targeted release of the embedded
drugs. The half-life of encapsulated drugs can be increased in blood circulation.
Functionalization of nanocarriers employing stimuli responsiveness, such as pH,
temperature, time and decoration of nanocarrier’s surface with specific ligands, can be
provided, which elicits prolonged drug retention at targeted site as well as improved
cellular uptake of targeted drugs. Functionalization of nanocarriers leads to increase in
bioavailability of targeted drugs. The ligands employed for functionalization include
antibodies, aptamers, small molecules, peptides, etc. [74]. Codelivery of conventional
anticancer drug paclitaxel with naringin employing polymeric micelles improved in vitro
cytotoxicity against MCF-7 breast cancer cells and enhanced internalization of paclitaxel. In
this, naringin serves as chemosensitizer, improving the lethal effect of paclitaxel in prostate
cancer synergistically [75]. Codelivery of doxorubicin with curcumin improved anticancer
potential of doxorubicin along with reduction in adverse effects. To date, numerous

conventional anticancer drugs are codelivered with plant-derived compounds to improve
their efficacy [76].
Various nanocarriers, solid lipid nanoparticles, nanostructured lipid carriers, na-
noemulsions, polymeric nanoparticles, polymeric micelles, liposomes, dendrimers, carbon
nanotubes, metallic nanoparticles and nanoemulsions have been utilized for codelivery
of anticancer drugs owing to their ability to entrap the drugs followed by release on tar-
geted site [77,78] (Figure 6). Moreover, these also protect drug molecules from hazardous
environmental factors, which can cause gastrointestinal degradation of the drugs [79].
Modification in shape, size and surface properties of nanocarriers can be performed to elicit
maximum efficiency, which leads to improved drug efficiency, decreased adverse effects,
Pharmaceutics 2023, 15, x FOR PEER avoidance
REVIEW of multiple-drug resistance and maximization of drugs in targeted cells 11 [80].
of 33
Various nanocarriers for codelivery of conventional anticancer drugs with phytochemicals
have been discussed in preceding section.
Figure6.6.Mechanism
Figure Mechanismof
ofvarious
variousnanocarriers
nanocarrierstototarget
targetthe
thedrug
drugatatthe
thecancer
cancersite.
site.
6.1. Solid Lipid Nanocarriers (SLNs)
6.1. Solid Lipid Nanocarriers (SLNs)
Researchers have focused much attention on lipid nanoparticles because they are at the
Researchers
forefront have focused
of the fast-evolving much
field attention on lipid
of nanotechnology and nanoparticles because
hold great promise for they are at
achieving
the forefront of the fast-evolving field of nanotechnology and hold
the objective of controlled and targeted drug delivery in cancer treatment [81]. SLNs great promise for
achieving
provide the objective
various noteworthyof controlled
benefits ofand targeted
improved drug delivery
solubility, in cancer
low adverse treatment
effects, [81].
improved
SLNs provide various noteworthy benefits of improved solubility, low adverse
bioavailability of drugs, adaptability of encapsulation of both hydrophilic and hydrophobic effects,
improved
drugs, bioavailability
improved of drugs, adaptability
stability, specificity and probabilityof encapsulation
of large-scaleof both hydrophilic
production [82,83]. and
hydrophobic drugs, improved stability, specificity and probability
The properties of biodegradability and biocompatibility of SLNs make them of large-scale produc-
less
tion [82,83].
toxic than other nanocarriers, such as polymeric nanoparticles [84]. Nanosize (less than
Theeasy
400 nm), properties of biodegradability
functionalization, chemical andand mechanical
biocompatibility of and
stability SLNs make them
increased less
delivery
toxic
of than other
lipophilic nanocarriers,
phytochemicals are such
moreas polymeric nanoparticles
advantageous characteristics[84]. Nanosize
of SLNs (less also
[85]. SLNs than
400 nm), easy functionalization, chemical and mechanical stability and increased delivery
of lipophilic phytochemicals are more advantageous characteristics of SLNs [85]. SLNs
also enable to overcome several physiological barriers that hinder drug delivery to can-
cerous cells and are also able to escape multidrug resistance mechanisms characteristic of
cancerous cells. SLNs have the distinct inherent capacity to concentrate the drug in can-
enable to overcome several physiological barriers that hinder drug delivery to cancerous
cells and are also able to escape multidrug resistance mechanisms characteristic of cancerous
cells. SLNs have the distinct inherent capacity to concentrate the drug in cancerous cells
precisely due to their properties of increase in permeability and retention time [86]. When
SLNs are phagocytized at the cancerous site, the drug is delivered closer to the intracellular
site of action, leading to an increase in cell internalization [54]. SLNs deliver drugs to the
targeted cancerous site due to various mechanisms, such as active mechanisms and passive
mechanisms.
These are composed of solid lipids or a mixture of lipids and surfactants. Moreover,
aqueous phase, surface modifiers, cosurfactants stealthing agents and cryoprotective agents
may also be present in their structure [87]. The hydrophobic drug or combination of
hydrophobic drugs is entrapped in the solid lipid matrix of SLNs, enabling protection
of drugs from chemical degradation, which leads to physical stability. These improve
the half-life of drugs in blood circulation and modify their release pattern, which leads
to an increase in therapeutic efficiency of anticancer drugs [88]. Wang L. et al. prepared
paclitaxel- and narigenin-loaded SLNs to treat glioblastoma multiforme in which SLNs
were functionalized using cyclic RGD peptide sequence to improve drug targeting to
cancerous site. It was found that pharmacokinetic parameters, such as Cmax , Tmax and
relative bioavailability, of peptide functionalized SLNs were improved compared to plain
SLNs as well as drug suspension. Moreover, functionalized SLNs possessed improved
cytotoxicity compared to free drug suspension on U87MG glioma cells [89].
Pi C. et al. fabricated SLNs of curcumin and paclitaxel to treat lung cancer. It was
observed that SLNs of combination provided improved area under the curve (AUC), pro-
longation of drug residence time and increase in half-life of the drugs, resulting in long
circulation time in systemic circulation. Furthermore, the rate of lung tumour suppression
was 78.42% using SLNs of combination of paclitaxel and curcumin, whilst it was 40.53%
and 51.56% using paclitaxel and combination (paclitaxel and curcumin), respectively [90].
Despite various advantages of SLNs in cancer treatment, these also possessed some limita-
tions of poor drug loading capacity, expulsion of drug, increased incidence of polymorphic
transitions and unpredictable agglomeration, which must be addressed [91].
6.2. Nanostructured Lipid Carriers (NLCs)

To address various above-mentioned limitations of SLNs, NLCs have proven their
efficacy as advanced drug carriers in cancer treatment. Their broad relevance as drug carri-
ers is due to their distinctive characteristics, which include increased drug encapsulations,
long-term chemical and physical stability of the encapsulated drug, surface modifications
and site-specific targeting [92]. These possess liquid lipids along with solid lipids in their
structure, which provides imperfections in the lipid matrix. These imperfections cause
prevention of drug leakage during prolonged storage, resulting in improved drug load-
ing [93]. The presence of liquid lipids along with solid lipids in NLCs enables accumulation
of a large number of drugs compared to solid lipids and liquid lipids individually [16].
Drug bioavailability can be improved by NLCs, which results in improved drug transport
through the intestine and protection of drugs from the hazardous environment of the
gastrointestinal tract [94].
Moreover, NLCs enable drug targeting through the lymphatic system, resulting in
various advantages, such as avoidance of first-pass metabolism, decreased hepatotoxicity
and improved bioavailability [95]. Alhalmi A. et al. codelivered raloxifene and naringin,
employing NLCs for treatment of breast cancer. It was found that NLCs of dual drugs
provided 2.1 and 2.3 times improved permeability profiles of naringin and raloxifene
than their suspension. Furthermore, it was observed that codelivery of raloxifene with
naringin in NLCs reduced the acute toxicity of raloxifene, which could be attributed to
the antioxidant property of naringin [16]. Zhao X. et al. delivered doxorubicin with
curcumin in form of NLCs to treat liver cancer, and improved cytotoxicity and reduced
inhibitory concentration were observed in HepG2 and LO2 cells. Furthermore, Annexin-
V-fluorescein isothiocyanate/propidium iodide double staining demonstrated increased

apoptosis in HepG2 cells treated with doxorubicin and curcumin-loaded NLCs compared
to free doxorubicin and doxorubicin nanoparticles [76].
6.3. Liposomes
Due to possession of various characteristics, such as the capacity to encapsulate high
doses, possibility to deliver hydrophilic and hydrophobic drugs, increase in circulation
time of drug, biodegradability, biocompatibility, improved durability, low adverse effects,
controlled drug delivery, increased rate of dissolution, the capability of drug targeting
to individual cells, easy manufacturing and versatility, liposomes have emerged as a
potential carrier for codelivery of anticancer drugs [96,97]. These are spherical-shaped
vesicles composed of phospholipids and cholesterol bilayers, resulting in creation of two
microenvironments, which enable codelivery of the drugs [98]. These have a size range of
0.025 to 2.5 µm [99]. The amount of encapsulation of drugs in liposomes is governed by
size and number of bilayers along with size of vesicles [100]. Liposomal structures can be
modified to elicit desired therapeutic effects [101].
Liposomal entrapped drugs can be targeted to a desired site by active and passive
mechanisms. Passive targeting of liposomes enables accumulation of drugs preferentially
in cancerous cells through enhanced permeability and retention property (EPR). Active
targeting of liposomes to the desired site can be provided using functionalization of lipo-
somal surface to various kinds of antibodies, which leads to an increase in specificity to
cancerous site. Aside from the capability to target drugs by active and passive mechanisms,
liposomes also can facilitate release of drugs in specific tumour cells under influence of pH,
light, sound and enzymes [102]. In addition, liposomal efficiency at the cancerous site can
be improved using external stimuli, such as temperature, pH and ultrasound, triggering
release of drugs in the interstitium after concentrating in the desired site [90].
Otherwise, functionalization of the liposomal surface with PEG causes improved
efficiency of anticancer drugs at the targeted site owing to an increase in drug circulation
time [103]. Moreover, liposomes are less taken by GIT, heart and tissues, which leads to a
decrease in adverse effects [104]. Cheng Y. et al. codelivered cisplatin and curcumin in form
of nanoliposomes for efficient treatment of hepatocellular carcinoma. Codelivery of drugs
in form of nanoliposomes exhibited improved anticancer property against HepG2 tumour
cells, with IC50 value of 0.62 micro M. It also provided improved ROS levels intracellularly
during treatment of HCC cells. Furthermore, it provided prolonged retention time of
2.38 h compared to individual drug formulations and improved anticancer effect in animal
hepatoma H22 and human xenograft model along with reduced adverse effects [105].
6.4. Polymeric Nanoparticles

Possession of various important features of biocompatibility, biodegradability, smaller
size, increased surface volume ratio and easier modification of structure and surface,
polymeric nanoparticles (PNPs) have been extensively used for codelivery of anticancer
drugs with phytochemicals. Moreover, PNPs protect entrapped drug molecules and
controlled or sustained the release of entrapped drugs [106]. The potential of PNPs to
deliver anticancer drugs is continuously increasing due to the inability to target the drugs
only on cancerous cells.
PNPs are composed of natural, semisynthetic and synthetic polymers, which are either
biodegradable or non-biodegradable. The main characteristic of PNPs for drug targeting
in cancer is their size, which must be below 100 nm due to the inability to pass through
apertures in the endothelial of cancerous cells [107]. Second, the shape of PNPs also plays a
vital role in the efficient delivery of anticancer drugs to the target site. The shape of PNPs
must be spherical because spherical drug particles are effectively taken by the targeted
cancerous cells [108].
To enhance the circulation time of the drug and minimize the drug interactions with
blood proteins, coating with polyethene glycol can be employed. PEGylation of PNPs
causes an increase in the half-life of the drugs in the blood and leads to improvement in
the stability of drug molecules. Further, PEGylation increases the hydrophilicity of drug
molecules and enables the PNPs to encapsulate hydrophilic and lipophilic drugs, which
release the drugs in a controlled manner [109]. Interestingly, PNPs can be functionalized
with various molecules, such as folic acid, and antibodies to elicit more selectivity for
cancerous cells.
Various polymers used for preparation of PNPs include natural (gelatin, lysozyme,
cellulose, chitosan, dextran, albumin, collagen), semisynthetic (methylcellulose) and syn-
thetic polymers (polylactic acid (PLA), poly lactide-co-glycolide (PLGA), thiolated poly
methacrylic acid) [110]. PLGA is a biodegradable polymer which is approved by the FDA
for drug targeting in the treatment of cancer. The acceptability of PLGA-based nanoparticles
is mainly due to their hydrolysis in the body, during which it metabolizes in monomer units
glycolic acid and lactic acid, which ensures their reduced toxicity [111]. PNPs can provide
the controlled and targeted release of drugs at cancerous sites owing to response to various
stimuli (pH, temperature), which trigger the release of drugs at the desired site [112].
Amjadi S. et al. delivered doxorubicin and betanin via encapsulation in PEGylated
gelatin nanoparticles. These PNPs were made pH-responsive using methoxy polyethene
glycol-poly 2-dimethylamino ethyl methacrylate-co-itaconic acid to trigger the release
of the drug in a controlled way at the desired site. It was found that PNPs of doxoru-
bicin and betanin reduced the cell sustainability amount of MCF-7 cells in breast cancer
more than doxorubicin and betanin alone [113]. Hu H. et al. delivered paclitaxel and
curcumin using PLGA nanoparticles and was found that optimized formulation provided
improved cytotoxicity, having reduced IC50 in MCF-7 cells of breast cancer compared to
free drugs [114].
6.5. Dendrimers
A dendrimer is a nanometric, multibranched, star-shaped polymeric vesicle that looks
like a tree. It consists of branches interiorly, a central core and various functional groups
exteriorly [115]. The presence of various branches on the surface of the dendrimer enables
codelivery of various drugs [116]. Due to the possession of a low polydispersity index,
controlled molecular weight and improved biocompatibility, dendrimers have emerged as
drug carriers in cancer treatment. The functional groups present on the exterior surface
of dendrimers enable the entrapment of a combination of drugs in dendrimers. These
functional groups can be modified to provide drug targeting at the specific cancerous site.
Moreover, drug delivery using dendrimers causes improved aqueous solubility, stability,
bioavailability of drugs, reduced adverse effects, loading of higher dose, enhanced drug
efficacy and drug release in controlled as well as sustained manner.
Drug entrapment in dendrimers is possible due to mechanisms of physical interac-
tion and chemical interaction [117]. In physical interaction, the drug is entrapped into
dendrimers by non-covalent bonds, whilst in chemical interaction drug is covalently at-
tached to dendrimers [118,119]. Various anticancer drugs, such as methotrexate, cisplatin,
5-fluorouracil, paclitaxel and doxoroubicin, have been delivered successfully employing
dendrimers along with reduced adverse effects [118].
Various dendrimers employed for codelivery of anticancer drugs with phytochemicals
include polyamidoamine (PAMAM), poly-L-lysine (PPL) and polypropylene imine (PPI)
amongst PAMAM dendrimers have been extensively utilized for drug delivery of anticancer
drugs due to hydrophilic nature, biocompatibility and non-immunogenicity [120]. Despite
showing various benefits as drug carriers, dendrimers show hemolytic and cytotoxic
properties, which raises a major question about the safety of dendrimers [121]. These toxic
effects can be reduced using surface functionalization of functional groups present on the
exterior surface of dendrimers. Surface functionalization of dendrimers can be performed
using polyethene glycols, which increases drug circulation time owing to EPR besides
reduction in toxic effects [118,122].
Ghaffari M. et al. developed PAMAM dendrimers for codelivery of curcumin with Bcl-
2 siRNA against HeLa cells of cancer. These dendrimers provided improved cellular uptake
and greater inhibition of cancer cell proliferation than PAMAM curcumin nanoformulation
and plain curcumin drugs [123].
6.6. Polymeric Micelles (PMs)

PMs have appeared as versatile drug carriers in the era of nanocarriers due to pos-
session of various characteristics of increased aqueous solubility of the drug, marvellous
biocompatibility, enhanced permeability and reduced toxic effects [124,125]. In addition,
PMs cannot modify the drug release and concentrate it on targeted cancerous sites [126].
Due to their size in the nanometric range, they are prone to accumulate in the microenvi-
ronment of cancer through EPR [127,128].
Numerous combinations of anticancer drugs have been delivered employing PMs to
improve the synergistic effect of combined drugs but unfortunately, the traditional PMs
provided limited synergistic effect due to non-selectivity and incomplete release behaviour
of the drugs. These limitations have prompted the development of modified PMs, which
provide drug targeting to the cancerous site using active and passive mechanisms, trigger-
ing the microenvironment of cancer using specific stimuli, such as light, pH, ultrasound
and temperature [129].
PMs can be fabricated using amphiphilic di or triblock copolymers. The hydrophilic
portion of copolymer includes polymers such as PEG and poly N-isopropylacrylamide,
whilst the hydrophobic portion includes polypropylene glycol (PPG), poly caprolactone
(PCL) [130].
Sabra S.A. et al. codelivered rapamycin and wogonin in form of polymeric micelles
prepared by hydrophilic lactoferrin and hydrophobic zein. Codelivery of drugs provides
increased circulation time and targeting to specific cancer cells. Moreover, crosslinking by
glutaraldehyde was observed, which provided improved stability and reduced size. PMs
provided a fast release of wogonin, which enabled the inhibition of efflux pump resulting
in potentiation of targeting of rapamycin to cancerous site [131].
6.7. Nanoemulsions (NEs)

Researchers have shifted their attention towards nanoemulsions due to unique proper-
ties such as physical stability, higher surface area, prolonged circulation time, amphiphilic-
ity, specific drug targeting, tumour imaging properties, optical clarity, biodegradability,
improved aqueous solubility and bioavailability. Moreover, nanoemulsions can be surface
modified to enable passive and active targeting of the drugs [132,133].
NEs are colloidal dispersions of two immiscible liquids stabilized by amphiphilic
surfactants. These are in the nonmetric size range of 20–200 nm [134,135]. Due to nanosize
in addition to possession of active and passive mechanisms, NEs are enable to accumulate
in the cancer microenvironment and overcome various associated obstacles [136]. NEs
functionalization is possible using conjugation with various antibodies for targeting precise
sites. It has been evaluated that the conjugation of anticancer drugs with antibodies results
in the incorporation of drugs in cancerous cells for the successful delivery of the drugs
to the targeted site [137]. Furthermore, conjugation of drug with antibody can be made
responsive to stimuli to cause more specificity towards cancerous cells.
Various anticancer drugs have been codelivered employing NEs to improve the thera-
peutic efficacy and bioavailability of the drugs. Ganta S and Amiji M delivered combination
of paclitaxel and curcumin in form of nanoemulsion to SKOV3 cancer bearing mice. The
paclitaxel exhibited 4.1-fold improved AUC when administered in nanoemulsion form to
curcumin treated mice. Relative bioavailability of paclitaxel was 5.2-fold greater, which
resulted in 3.2-fold improved accumulation of paclitaxel in cancer tissues [138].
6.8. Carbon Nanotubes (CNTs)

Owing to various characteristics such as reduced size, increased surface area, high
drug loading capability, controlled and sustained release of the drugs and drug targeting
have focused the considerable attention of researchers towards CNTs as a potential drug
carrier to deliver anticancer drugs. Moreover, the presence of numerous sites at the surface
of CNTs facilitates the delivery of more than one drug at a time [139].
CNTs are mainly of two types namely single-walled carbon nanotubes (SWCNTs)
and multi-walled carbon nanotubes (MWCNTs) amongst MWCNTs are more prominent
recently as drug carriers [140]. MWCNTs possess considerable absorptive surface for an-
ticancer drugs, which can be targeted to the specific cancerous site [141]. CNTs should
be functionalized employing different polymers, chemical groups or biomolecules to en-
sure their targeting capacity and safety in cancer treatment owing to improvement in
hydrophilicity and reduction in cytotoxicity properties of CNTs [142]. Functionalization
of CNTs surface can be carried by covalent and non-covalent bonding of various types of
polymers and chemical groups at the surface of CNTs [143].
PEG, the most popular FDA-approved polymer has been extensively used for the
surface functionalization of CNTs to impart increased solubility and biocompatibility. Mon-
oclonal antibodies also can be conjugated with CNTs for efficient treatment of cancer [144].
Arginylglycylaspartic acid (RGD) can also be employed for surface functionalization of
CNTs resulting in active drug targeting to the cancerous site [145]. In addition, recently
carbohydrate-based polymers, such as lactose and mannose, also have been employed for
surface functionalization of CNTs to provide drug targeting to desired cancerous sites [146].
Raza K. et al. fabricated MWCNTs of docetaxel and piperine with a view of increased
tissue permeation, bioavailability and anticancer activity and was found that MWCNTs of
the conjugate of both drugs provided 6.4 times improved AUC than pure drugs [147].
6.9. Metallic Nanoparticles (MNPs)

Because of their rich surface functionalization, lengthy activity period, relatively
narrow size and shape distribution and the ability for optical or heat-based treatment
techniques, MNPs are particularly alluring in nanomedicine for targeting therapeutic
agents in cancer. Owing to their higher density, MNPs can be easily absorbed by cells,
which is helpful for cancer control strategies [148]. MNPs have also been claimed to enable
superior targeting, gene silencing and drug delivery, particularly when functionalized with
targeting ligands that allow regulated deposition into cancerous cells [149].
MNPs can alter the microenvironment of a tumour by transforming unfavourable
circumstances into ones that can be used therapeutically. For instance, external stimuli such
as light, heat, ultrasonic waves and magnetic fields might improve the capacity of MNPs to
target biological systems by changing their redox potential and producing reactive oxygen
species (ROS) that further sensitise target tissues [150].
Various MNPs employed to treat numerous kinds of cancers include gold nanoparti-
cles (Au NPs), silver nanoparticles (Ag NPs), iron oxide nanoparticles (IONPs) and zinc
oxide nanoparticles (Zn ONPs) [151]. Au NPs possess several desirable characteristics, in-
cluding low toxicity, immunogenicity, great stability, improved biocompatibility, increased
permeability, increased retention and easily functionalized surface [152]. Other extensively
studied nanoparticles are Ag NPs, which are alluring in cancer treatment due to posses-
sion of various attributes, such as unique physicochemical and biological characteristics,
including biocompatibility, high surface-to-volume ratio, powerful antibacterial activity,
outstanding surface plasmon resonance, ease of functionalization and cytotoxicity against
cancer cells [148,153]. Ag NPs can modify autophagy of cancer cells whether they work
as cytotoxic agents by themselves, in combination with transported compounds or in
conjunction with other therapies [154].
IONPs have attracted specific attention in emerging magnetic nanoparticles due to pos-
session of excellent targeting abilities under an external magnetic field [155]. In particular,
IONP-based delivery systems that are injected move via blood capillaries to the appropriate
spot when an external magnetic field is applied, releasing the medicine in cancerous cells
and boosting therapeutic efficacy without harming nearby normal cells [156].
Hiremath C. et al. developed oleic-acid-coated IONPs stabilized by folic-acid-modified
pluronicF127 for codelivery of curcumin and paclitaxel in breast cancer. It was found that
cytotoxic property of folic-acid-modified NPs was greater and was further improved on
application of external magnetic field [157]. Various nanoformulations for codelivery of
conventional anticancer drugs and phytochemicals have been summarized in Table 2.
Table 2. List of nanoformulations for codelivery of anticancer drugs with phytochemicals.
Type of
Anticancer Drug Phytochemical Type of Cancer Result Outcomes References
Nanoformulation
Exhibited 1.7–2.8 times improved Cmax and AUC0−t
for both paclitaxel and naringenin from the SLNs
than their drug suspension whilst no significant
Glioblastoma
SLNs Paclitaxel Naringenin change in Tmax was observed. Moreover, cyclic [89]
multiforme
RGD-modified SLNs possessed more improved
drug absorption than plain SLNs. It also exhibited
improved cytotoxicity than drug suspension.
Exhibited 1.40 and 2.28 times improved AUC for
curcumin and paclitaxel, respectively, provided 6.94
and 6.46 times extended residence time for
curcumin and paclitaxel, respectively, achieving
SLNs Paclitaxel Curcumin Lung cancer [90]
long circulation. The rate of tumour suppression of
SLNs was 78.42% higher than 40.53% and 51.56% for
paclitaxel and a combination of curcumin
with paclitaxel.
SLNs of curcumin with layered double hydroxide
5-fluorouracil provided a synergetic effect on
SMMC-7721 cells more strongly than plain drugs in
SLNs 5-fluorouracil Curcumin Liver cancer [158]
combination. FACS analysis exposed that SLNs of
combination prompted 80.1% apoptosis in
SMMC-7721 cells.
Possessed a noteworthy improvement in AUC of
594.21 ± 64.34 µg/mL h than 39.05 ± 7.41 µg/mL h
of Taxotere® and MRT of 31.14 ± 19.94 h than
SLNs Docetaxel Curcumin Breast cancer 7.24 ± 4.51 h of Taxotere® . Moreover, the [159]
accumulation of docetaxel was reduced in the heart
and kidney compared to Taxotere® . Targeting
efficiency towards MCF-7 cells was also revealed
using fluorescence microscopy.
Revealed increased % cell viability for normal WISH
cell line reaching 100% at 0.25 µg/mL. The lipid
NLCs Tamoxifen citrate Coenzyme Q10 Breast cancer nanocarrier exhibited LC 50 on the MCF-7 cell line [54]
of 1.6 µg/mL as compared to 4.8 µg/ml on the
WISH cell line.
Possessed anticipated physicochemical properties
α-Tocopherol
NLCs Paclitaxel Retinoblastoma and might lead to an efficacious therapeutic option [160]
succinate
to treat retinoblastoma.
Provided 5.2- and 4.8-fold improved oral
bioavailability of tamoxifen and sulforaphane along
NLCs Tamoxifen Sulforaphane Breast cancer [161]
with reduction in tamoxifen-associated toxicity
in vivo.
Exhibited improved retention of doxorubicin on
MCF-7 ADR cells. In vivo studies on MCF-7 ADR
NLCs Doxorubicin Lapachone Breast cancer [162]
tumour-bearing animal models exhibited
improved efficacy.
Demonstrated significantly improved cytotoxic
NLCs Docetaxel Curcumin Lung cancer [163]
activity towards NCI-H460 cells.
Demonstrated accumulation of drugs at brain and
cancer sites. The inhibitory effect is due to arresting
NLCs Temozolomide Curcumin Brain cancer of the S phase cell cycle along with induced [164]
apoptosis. Moreover, the toxic effects were absent at
normal doses.
Displayed improved cytotoxicity, synergistic
NLCs Doxorubicin B-element Lung cancer antitumor effect and insightful tumour [165]
inhibition ability.
Provided considerably improved apoptotic,
anti-proliferative, anti-angiogenic and
NLCs Docetaxel Curcumin Lung cancer anti-metastatic activities than Taxotere® . NLCs [166]
displayed considerably reduced adverse effects
of docetaxel
Table 2. Cont.
Type of
Nanoformulation
Provided significant cytotoxicity than
Lipid chitosan hybrid cisplatin-loaded nanoparticles as well as
Cisplatin Curcumin Ovarian cancer [167]
nanoparticles curcumin-loaded nanoparticles after 48 hours
of treatment.
Exhibited Induced tumour cells apoptosis, reduced
Hybrid nanoparticles Cisplatin Oleanolic acid Gastric carcinoma [168]
adverse effects and reversal of multidrug resistance
Provided the highest apoptosis index against MCF-7
cells. Moreover, methotrexate-induced renal and
Hybrid nanoparticles Methotrexate Beta-carotene Breast cancer [169]
hepatic toxicity was reduced by codelivery of
beta-carotene.
Exhibited significant synergistic potential along
Hybrid nanoparticles Docetaxel Resveratrol Lung cancer with best cancer inhibition ability and minimal [170]
systemic toxicity.
Exhibited significantly improved cytotoxic effects
Hybrid nanoparticles Cisplatin Curcumin Cervical cancer and demonstrated the highest anticancer potential [171]
compared to other formulations.
Displayed protruding cytotoxicity and the best
Hybrid nanoparticles Doxorubicin Gallic acid Leukemia synergistic effect. Nanoparticles revealed improved [172]
inhibition of tumour growth.
Calcium carbonate Hepatocellular Exhibited improved HepG2 cell apoptosis along
Cisplatin Oleanolic acid [173]
nanoparticles carcinoma with alleviation of drug-induced hepatotoxicity.
Provided alleviation of the hepatotoxicity produced
Nanosponge particles Tamoxifen Quercetin during the treatment along with improvement in the [174]
uptake of tamoxifen.
Demonstrated synergistic activity on the apoptosis,
proliferation and angiogenesis of hepatocellular
Hepatocellular
Lipid nanoparticles Doxorubicin Curcumin carcinoma. Moreover, the mRNA levels of MDR1, [175]
carcinoma
bcl-2 and HIF-1α and protein levels of P-gp, Bcl-2
and HIF-1α were reduced.
Ph-sensitive Possessed the smallest tumour volume of
Hepatocellular
galactosylated Sorafenib Curcumin 239 ± 14 mm3 along with an inhibition rate of 77.4% [176]
carcinoma
nanoparticles employing pH-sensitive lactosylated nanoparticles.
Exhibited synergistic antitumor efficiency
Dual targeting established by cytotoxicity and animal studies.
5-fluorouracil Curcumin Hepatocarcinoma [62]
nanoparticles These provided improved cellular uptake and
stronger cytotoxicity for cancer cells.
Exhibited 2.5 and 1.7 fold lower IC50 values after 24
and 48 h, respectively, than methotrexate
nanoparticles. The cytotoxic property was greater
PLGA nanoparticles Methotrexate Curcumin Breast cancer than in other formulations and tumour incidence [177]
and size were reduced in the case of PLGA
nanoparticles entrapped with both methotrexate
and curcumin than other formulations.
Provided higher efficacy of CD44 cell surface
glycoprotein-functionalized PLGA nanoparticles
PLGA nanoparticles Salinomycin Curcumin Breast cancer against breast cancer stem cells by the convincing [178]
arrest of G1 cell cycle and restraining
epithelial–mesenchymal transition.
Demonstrated the sustained release of both the
PLGA nanoparticles Topotecan Thymoquinone drugs, having a minimal burst release and a total [179]
percentage release of more than 90% in 96 h.
Exhibited improved efficiency revealed by increased
cellular uptake, nuclear co-localization and
cytotoxicity in MCF-7 cells. Provided 5- and 3-fold
PLGA nanoparticles Tamoxifen Quercetin Breast cancer improved oral bioavailability for tamoxifen and [180]
quercetin, respectively. Possessed a higher rate of
tumour suppression against a DMBA-induced
breast cancer model.
Exhibited noteworthy cytotoxicity on
MDA-MB-231/ADR cells and MCF-7/ADR cells.
PLGA nanoparticles Doxorubicin Resveratrol Breast cancer [181]
Moreover, co-encapsulated nanoparticles delivered
the drugs to cancer tissue.
Provided increased cytotoxicity than native drugs
solution. Moreover, suppression of tumour growth
PLGA-PEG
Gemcitabine Betulinic acid Solid tumor was more efficient in the solid tumour model than [182]
nanoparticles
the native gemcitabine and betulinic acid at the
same concentrations.
Provided improved anticancer effect of sorafenib on
Hepatocellular
PLA nanoparticles Sorafenib Plantamajoside hepatocellular carcinoma cells due to reversal of [183]
carcinoma
drug resistance.
Exhibited a tremendous synergistic effect leading to
PLA nanoparticles Daunorubicin Glycyrrhizic acid Leukemia ominously greater cell inhibition. Cell apoptosis was [184]
improved but did not influence MDR1 expression.
Table 2. Cont.
Type of
Nanoformulation
Exhibited significant improvement in mitochondrial
PLGA nanoparticles Doxorubicin Berberine Breast cancer membrane permeability along with the arrest of [185]
progression of the cell cycle at the sub-G1 phase.
Provided synergistic effect on inhibition of cancer
growth via cell cycle arrest and apoptosis induction.
PLGA nanoparticles Paclitaxel Curcumin Brain cancer [186]
Efficient brain deposition of the drug
was demonstrated.
Exhibited improved apoptosis in colorectal HT-29
cells. Moreover, nanoparticles displayed
PEGylated
Paclitaxel Dihydroartemisinin Colorectal cancer significantly improved accumulation in the cancer [187]
nanoparticles
site due to the increased permeability and
retention effect.
Exhibited improved intracellular delivery along
with increased cytotoxic effect, induced
Polymeric nanoparticles Doxorubicin Curcumin Lymphoma sophisticated rates of apoptosis in BJAB cells. BJAB [188]
cells provided inhibited tumour growth than
doxorubicin alone.
Provided substantial inhibition of cancer growth
Polymeric nanoparticles Paclitaxel Curcumin Breast cancer with elongated survival time along with reduced [189]
adverse effects.
Demonstrated improved anticancer effect along
Polymeric nanoparticles Paclitaxel Resveratrol with improvement in the sensitivity of [190]
multidrug-resistant cancer cells to the drug.
PLGA-PEG-PLGA Exhibited considerably improved growth inhibitory
5-Fluorouracil Chrysin Colon cancer [191]
polymeric nanoparticles activities in the HT29 cell line.
Exhibited improved cytotoxicity against HCT-116
Polymeric nanoparticles Doxorubicin Curcumin cells. Cellular uptake of drugs was improved via [192]
active targeting.
Exhibited internalization into gastric tumour cells
Epigallocatechin
Polymeric nanoparticles Doxorubicin Gastric cancer via CD44 ligand recognition and subsequent [193]
gallate
inhibition of cell proliferation.
Demonstrated effective accumulation of the drug in
tumour site and inhibition of tumour growth as well
Polymeric nanoparticles Paclitaxel Silybin Breast cancer [194]
as sensitization effect of silybin on paclitaxel
cytotoxic chemotherapy.
Self-assembled Ganoderma
Demonstrated improved cancer suppressive
Ph-sensitive Methotrexate lucidum Breast cancer [195]
activities with fewer adverse effects.
nanoparticles Polysaccharide
Provided increased cytotoxic effect against C6
glioma and MCF-7 cancer cell lines along with high
Gold nanoparticles Methotrexate Curcumin hemocompatibility. It also possessed active targeting [196]
proficiency against MCF-7 cancer cells due to the
presence of the “antifolate” drug methotrexate.
Provided strong deposition of the drug in the
Gold nanoparticles Doxorubicin Resveratrol Cervical cancer [197]
tumour cells.
Exhibited inhibition of the proliferation of PC-3
Epigallocatechin-
Gold nanoparticles Doxorubicin Prostate cancer tumour cells along with the enzyme-responsive [198]
3-gallate
intracellular release of doxorubicin.
Provided significantly improved early and late
apoptosis along with induction of a stronger G2 /M
Hybrid nanoparticles Paclitaxel Curcumin [199]
arrest and significantly increased subG1
cell population
Exhibited improved cytotoxicity against A549 cells
Hybrid nanoparticles Doxorubicin Curcumin [200]
along with increased cellular uptake.
Exhibited increased intracellular uptake along with
Mixed polymeric
Paclitaxel Naringin Breast cancer 65% in vitro cytotoxicity against breast cancer cells [75]
micelles
at its lower dose of 15 µg/Ml
Exhibited strongest cytotoxic properties as well as
Micelles Doxorubicin Curcumin improved cell apoptosis-inducing activities against [201]
doxorubicin-resistant MCF-7/Adr cells.
Provided a stronger synergistic effect, elongated
Polymeric micelles Docetaxel Resveratrol Breast cancer release profiles and improved cytotoxicity in [202]
MCF-7 cells.
Provided reduced Cancer-associated fibroblasts
activity and inhibited Cancer-associated fibroblasts,
Polymeric micelles Triptolide SN-38 Gastric cancer [203]
induced proliferation, migration and chemotherapy
resistance of gastric cells.
Polymeric micelles Doxorubicin Curcumin Exhibited induced apoptosis. [204]
Table 2. Cont.
Type of
Nanoformulation
Provided prolonged circulation time and privileged
tumour tissue buildup compared to the taxol
Polymeric micelles Paclitaxel Capsaicin Breast cancer [205]
solution. Micelles displayed greater
antitumor activity.
Exhibited reduced tumour but the loss of
PCM micelles Paclitaxel Cucurbitacin B Gastric cancer [206]
bodyweight was not significant.
Demonstrated improved cytotoxicity and increased
apoptosis-inducing actions in SKOV3/DOX cells.
Nanomicelles Dooxorubicin Rhein Ovarian cancer [207]
Micelles displayed better targeting ability towards
cancer along with reduced toxicity.
Demonstrated stronger inhibition and proapoptotic
activities on A2780 cells. Micelles provided
Nanomicelles Docetaxel Curcumin Ovarian cancer inhibition of tumour proliferation, suppression of [208]
tumour angiogenesis and promotion of
tumour apoptosis.
Provided superior accumulation of nanomicelles at
Nanomicelles Gemcitabine Camptothecin Breast cancer the cancer site, which could enhance therapeutic [209]
activity and reduce side effects.
Displayed inhibition of glioma growth more
ominously. Micelles increased the antitumor effect
Self-assembling micelles Dooxorubicin Honokiol Glioma of doxorubicin by increasing tumour cell apoptosis, [210]
suppressing tumour cell proliferation and
inhibiting angiogenesis.
Responsive micellar Demonstrated the maximum level along with
Paclitaxel Curcumin Breast cancer [211]
system achieving greater tumour inhibition effect.
Exhibited improved anticancer activity against
HepG2 cells having the IC50 of 0.62 Mm. Moreover,
Hepatocellular provided increased intracellular ROS levels during
Nano liposomes Cisplatin Curcumin [105]
carcinoma the HCC cell treatment. It also demonstrated the
prolonged retention time and increased
antitumor effect.
Provided distinct inhibition of tumour growth in
mice. Inhibition of tumour growth was 2–3 fold less
Liposomes Doxorubicin Curcumin [212]
in mice than in formulations having
drugs individually.
Exhibited significant inhibition of tumour growth in
the BXPC-3 pancreatic cancer model than Onivyde
Liposomes Irinotecan Berberine Pancreatic cancer [213]
and decreased the gastrointestinal toxicity in mice
caused by irinotecan.
Provided significant inhibition of tumour growth in
Triple-negative 4T1 murine mammary carcinoma model than Doxil
Liposomes Doxorubicin Berberine [214]
breast cancer and completely combat the myocardial rupture
toxicity caused by Doxil in mice.
Pachymic acid Exhibited significantly increased anticancer effect of
Liposomes Doxorubicin and dehydrotu- Breast cancer doxorubicin in cancer-bearing mice than other [215]
mulosic acid monotherapy groups.
Exhibited 10 times greater apoptosis than liposomes
of cisplatin only. Codelivery of cisplatin liposomes
Liposomes Cisplatin Curcumin Breast cancer [216]
with curcumin decreased the viability of breast
cancer cells by 82.5%.
Demonstrated improved cytotoxicity, improved
Liposomes Doxorubicin Schisandrin B Lung cancer cardiotoxicity and inhibition of the invasion and [217]
metastasis of tumours.
Exhibited improved cytotoxicity and increased
Combretastatin accumulation in the tumour site. Moreover,
Liposomes Curcumin Liver cancer [218]
A4 phosphate liposomes displayed stronger inhibition of
tumour proliferation.
Demonstrated effective delivery of drug
intracellularly in both SKOV3 and SKOV3(TR) cells.
Nanoemulsion Paclitaxel Curcumin Ovarian cancer Administration of curcumin inhibits NFkappaB [138]
activity and down-regulates P-glycoprotein
expression in resistant cells.
Demonstrated improved cytotoxicity against the
Double nanoemulsion 5-fluorouracil Curcumin Breast cancer [219]
MCF-7cells.
Table 2. Cont.
Type of
Nanoformulation
Demonstrated improved anticancer activity and
Multiwalled CNTs Docetaxel Piperine Breast cancer [147]
stronger cytotoxicity in MCF-7 cells
Exhibited decreased IC50 values along with
N-Desmethyl improved cellular uptake in drug-resistant
Multiwalled CNTs Quercetin Gastric cancer [220]
tamoxifen MDA-MB-231 cells. The drug availability in blood
circulation was also increased.
7. Conclusions
Cancer is a multistep and multifactorial disease whose prevalence and mortality rate
are increasing with time. That is why treatment of cancer became a major challenge. Re-
cently, surgery is mainly used as a treatment for cancer in association with chemotherapy.
However, chemotherapy has low proficiency as a treatment due to various obstacles, such
as adverse effects, drug resistance, insensitivity of cancer cells to drugs, lack of targeting
and patient inconvenience. Codelivery of anticancer drugs with phytochemicals can pro-
vide better therapeutic efficiency owing to synergism in treatment of cancer than anticancer
drugs in monotherapy. Recently, codelivery of conventional anticancer drugs with phyto-
chemicals has paid attention to treatment of cancer, but occurrence of overlapping, multiple
and occasionally unanticipated adverse effects is a great challenge in codelivery of anti-
cancer drugs. On this subject, encapsulation of drugs provides safer combination. Further,
incorporation of nanotechnology-based delivery systems, such as solid lipid nanoparti-
cles, nanostructured lipid carriers, liposomes, polymeric nanoparticles, nanoemulsions,
dendrimers, polymeric micelles, metallic nanoparticles, or carbon nanotubes, can elicit
maximal therapeutic efficiency to alleviate cancer due to possession of improved solubility,
reduced adverse effects, higher efficacy, improved dosing frequency, reduced drug resis-
tance, drug targeting, improved bioavailability and patient compliance. Deep knowledge
or understanding of mechanisms for cancer development as well as nanoformulations to
deliver anticancer drugs along with phytochemicals offer a new option for treatment of
cancer. Codelivery of anticancer drugs with phytochemicals has demonstrated outstanding
performance in experiments, but clinical efficiency is lacking owing to deficiency in opti-
mization of precise combination of drugs, such as sequence of drug exposure and ratio of
drugs. Hence, more thorough and effective pharmacodynamic evaluation techniques are
required to justify the rationality of codelivery of anticancer drugs with phytochemicals in
nanoformulations.
Author Contributions: Conceptualization, K.P. and T.V.; methodology, T.V. and K.P.; investigation,
G.K. and T.V.; resources, G.K. and A.S.; data curation, G.K. and T.V.; writing—original draft prepa-
ration, G.K., A.S. and T.V.; writing—review and editing, K.P. and T.V.; visualization, T.V. and K.P.;
supervision, K.P. and T.V.; project administration, K.P. 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.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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pharmaceutics

1 School of Pharmaceutical Sciences, MVN University, Aurangabad 121105, India

Pharmaceutics 2023, 15, 889. https://doi.org/10.3390/pharmaceutics15030889 https://www.mdpi.com/journal/pharmaceutics

to drugs, lack of targeting and patient inconvenience [7,8]. Additionally, chemotherapeutic

2. Aetiology, Pathogenesis and Metastasis of Cancer

Figure 1. Various stages

4. Hindrances in Cancer Treatment by Conventional Drugs

Table 1. List of anticancer drugs along with their adverse effects.

Drug Category Sub-Class Examples Adverse Effects References

Figure 2. Various hindrances associated with conventional anticancer drugs.

various pharmacological properties, such as anti-inflammatory, antimicrobial, antifungal,

Figure 3. Various mechanisms for working of phytochemicals as an anticancer agent.

Pharmaceutics 2023, 15, 889 8 of 29

Codelivery of phytochemicals with chemotherapeutic agents provides a reduction

potential of doxorubicin along with reduction in adverse effects. To date, numerous

6.2. Nanostructured Lipid Carriers (NLCs)

V-fluorescein isothiocyanate/propidium iodide double staining demonstrated increased

6.4. Polymeric Nanoparticles

6.6. Polymeric Micelles (PMs)

6.7. Nanoemulsions (NEs)

6.8. Carbon Nanotubes (CNTs)

6.9. Metallic Nanoparticles (MNPs)

Table 2. List of nanoformulations for codelivery of anticancer drugs with phytochemicals.

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