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Design of Multifunctional Nanocarriers for Delivery of Anti-Cancer Therapy
Neelesh Kumar Mehra*1,2
, Keerti Jain1,3
and Narendra Kumar Jain1
1
Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, ISF College of Pharmacy,
Moga (Panjab) India; 2
Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas
A & M Health Science Centre, Kingsville, Texas, USA 783 63; 3
National Institute of Pharmaceutical Education
and Research (NIPER Raebareli), Raebareli (U.P.) 229010, India
Abstract: Chemotherapy is the major and most widely used therapeutic strategy for the treatment of a wide vari-
ety of cancers. The non-specific/non-targeted drug delivery in chemotherapy leads to undesired side effects in nor-
mal and healthy tissues, and insufficient dosages to kill cancerous cells. Now-a-days, smart and intelligent multi-
functional targeted nanomedicines based on various nanocarriers (dendrimers, carbon nanotubes, graphene,
nanoparticles, quantum dots, self-emuslifying lipidic systems and carbon nanohorns etc) are being investigated
promisingly in cancer treatment. In this article, we review the role of smart and intellegent multifucntional nanocar-
riers in delivery of chemotherapeutic agents with the aim to develop promising treatment strategy to combat with
one of the killer of man kind i.e. cancer.
Keywords: Chemotherapy, Multifunctional, Dendrimers, Carbon nanotubes, Drug Delivery, Drug Targeting.
INTRODUCTION
Nanotechnology, a contemporary discipline, involves utilization
of nanosized biomaterials including liposomes, polymer-drug con-
jugates, graphenes, quantum dots, dendrimers, nanoparticles, car-
bon nanohorns, self emulsifying lipidic system and carbon nano-
tubes not only in drug delivery, but also in biomedical research
including bioimaging, biomedical-diagnosis and tissue engineering
[1-4]. Nanotechnology is an applicable aspect in a broader area of
nanoscience (nano means 10-9
m), which is one of the upcoming,
highly challenging and rewarding key research area of the modern
scientific set-up. The term nanotechnology includes the nanoscale
phenomena, process, biomaterials, nano-devices, nano-systems and
nano-manufacturing [5]. The in vivo use of nanotechnology in drug
delivery, imaging and diagnosis is one of the rapidly expanding
fields, which is necessary to meet the need of new delivery system
with advantages, such as improved solubility and bioavailability of
hydrophobic drugs, high drug payload, extended drug half-life,
improved therapeutic index, controlled release of bioactive(s) along
with reduced immunogenicity, and toxicity [6].
In the last two decades, outstanding progress has been made in
using nanobiomaterials to (a) target biological moiety to cancerous
cells through specific targeting ligands, and (b) increases localized
delivery by increasing serum residence time [7]. Targeted drug
delivery system is one of the most promising approach to expand
the therapeutic window by improving specificity and targetibility to
the target sites as well target-non-target tissue ratio, resulting mini-
mum effective dose and toxicities of drugs [6,8].
Designing of Multifunctional Nanocarriers
Multifunctional nanocarriers are smart and intelligent delivery
system, which could be designed and developed as per requirement.
These multifunctional nanocarriers basically consist of three main
design components: (i) a platform (core) material, (ii) encapsulated
payload/biologically active agents, and (iii) targeting/surface-
associated functional properties [9, 10, 11].
*Address correspondence to this author at the Department of Pharmaceuti-
cal Sciences, Irma Lerma Rangel College of Pharmacy, Texas A & M
Health Science Centre, Kingsville, Texas, USA 783 63; Tel: +1-361-720-
3044; E-mails: neelesh81mph@gmail.com; dr.jnarendr@gmail.com;
keertijain02@gmail.com
Modification of surface properties of nanocarriers by chemical
functional moieties including polymers and/or targeting ligands is
known as functionalization. Surface functionalization has been
achieved by incorporation, adsorption or covalent/non-covalent
coupling of polymers, combination of polymers, carbohydrates,
endogenous substances/ligands, peptides, proteins, nucleic acids
and polysaccharides to the nanoparticles surface. The various multi-
functional nanocarriers have been summarized in Fig. (1).
MULTIFUNCTIONAL NANOCARRIERS IN CANCER
CHEMOTHERAPY
Multifunctional nanocarriers are the delivery systems that could
deliver chemotherapeutic agent at desired/specific/target sites with
improved therapeutic outcomes. In this review, the multifunctional
nanocarriers used for chemotherapeutic delivery to cancerous cells
are emphasized briefly.
Carbon nanotubes in Delivery of Chemotherapeutic Agents
Carbon nanotubes (CNTs) were first discovered in 1991 by
Sumio Iijima (Japanese Microscopist) during his TEM observation
[12]. CNTs are among the most interesting and attractive drug de-
livery nanovectors currently under investigation. CNTs are three-
dimensional sp2
hybridized, condensed benzene rings rolled up into
seamless hollow tubular cylinder and classified into four categories
based on the presence of number of wall: single-, double-, triple-,
and multi-walled carbon nanotubes (SWCNTs, DWCNTs,
TWCNTs and MWCNTs, respectively). Functionalized CNTs (f-
CNTs) have shown great promise as drug delivery systems due to
their easy penetration and ability to cross biological barriers. How-
ever, specific translocation mechanisms (endocytosis or tiny nano-
needle like penetration) of f-CNTs are not yet fully elucidated [8,
13-16]. Functionalization is a well known approach for surface
alteration of nanomaterials [1].
f-CNTs have high surface area, which facilitates multiple at-
tachment of chemical functional moieties as well high payload of
drug molecules on to the surface or inside the nanotubes via various
interaction mechanisms (hydrophobic, electrostatic, - stacking
interactions). The degree and type of functionalization of CNTs
also plays a pivotal role in delivery of chemotherapeutic agents [3,
13, 16]. CNTs have been functionalized using two main approaches
based on (i) covalent, and (ii) non-covalent linkages between
Neelesh Kumar Mehra

2. 2 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Mehra et al.
chemical functional moieties and surface of nanotubes [17-18]. f-
CNTs have the ability to deliver water-insoluble (hydrophobic)
drugs (taxol derivatives; paclitaxel and docetaxel) by conjugation
onto the surface of the nanotubes [19]. The various transcellualr
trafficking pathways known to be involved in transport of f-CNTs
include endocytosis, pinocytosis, fluid-phase diffusion, carrier and
receptor-mediated and facilitated transport mechanism. Interest-
ingly, CNTs have the capacity to form supramolecular complexes
with polycyclic aromatic molecules through - stacking interac-
tions [20]. In this context, an anthracycline antibiotic (Doxorubicin
hydrochloride; DOX) is most investigated chemotherapeutic agent
till today. The significant contributions of f-CNTs in delivery of
DOX for cancer treatment have been revealed in last one decade.
High payload with controlled release was observed with f-CNTs for
targeted delivery of Dox devoid any significant toxicity [20-21].
Block copolymers based MWCNTs aqueous dispersions are able to
form supramolecular complexes with the aromatic chromophore
and DOX via - stacking and enhance the cytotoxic activity [22].
Till date huge reports have been available on DOX delivery
using multifunctional CNTs after decoration of targeting ligands
like hyaluronic acid (HA) [23], hydroxybenzoic acid (HBA) [24],
vitamin E (TPGS) [25], estrone (ES) [13], folic acid (FA) and chi-
tosan (CHI) etc [26-27] for drug delivery and targeting purpose.
Our laboratory has explored the multifunctional CNTs as
nanovectors for delivery of chemotherapeutics in cancer therapy
employing dexamethasone [28], folate [21], vitamin E [25] and
estrone [13, 29] as targeting moiety. We have also reported that the
multifunctional CNTs showed the controlled and sustained release
of DOX [21, 25] and gemcitabine [30].
Very recently, we have compared the targeting potential of ES
and FA appended PEGylated MWCNTs [13] and TPGS appended
PEGylated MWCNTs [25] on MCF-7 tumor bearing Balb/c mice
for targeted delivery of DOX and shown in Fig. (2).
Collagen is the most abundant protein in mammals and has
wide variety of application in regenerative medicine and tissue
engineering owing to their regular helical structure, excellent bio-
compatibility and immunogenicity. The uptake and intracellular
distributions of well-dispersed, collagen-SWCNTs suspension was
investigated [31] in bovine articular chondrocytes (BACs). The
collagen-SWCNTs suspension showed no obvious negative cellular
effects on BACs and upto ten million SWCNTs were internalized
and found most prevalent in the region of perinuclear. The cellular
uptake and intracellular distribution of collagen functionalized
SWCNTs are more suitable in bio-nanomedicine and cancer che-
motherapy.
Various multifunctional CNTs have been designed, developed
and evaluated for the nucleic acid delivery such as siRNA and dual
delivery of anticancer agent and siRNA in cancer therapy [32-35].
Phospholipid-coated CNTs functionalized with amine-terminated
polyethylene glycol (PL-PEG2000-NH2) were shown to be efficient
in siRNA and DNA delivery in human T cells and primary cells
[33].
Liposomes in Delivery of Chemotherapeutic Agents
Liposomes are the nano-particulate or colloidal carriers with
nanometric size range. Liposomes are made up of aqueous core
encapsulated within phospholipid bilayers which are formed spon-
taneously. Surface functionalized liposomes are undergoing exten-
sive investigation for targeted delivery of anticancer drugs in order
to improve solubility and pharmacokinetic profile, increase thera-
peutic index with increase in therapeutic efficacy and simultaneous
reduction in side effects. They have been successfully exploited in
cancer therapy, carrier for antigens, pulmonary delivery, leishmani-
asis, ophthalmic drug delivery etc. Advanced variants of liposomes
including multifunctional liposomes and modified liposomes i.e.
ethosomes, transfersomes are also being explored for drug delivery
applications. Various surface functionalization strategies to facili-
tate recognition by cell surface receptors are used to design multi-
functional liposomes. They could work in a very smart and intelli-
gent way, and selectively act to target sites. Functionalized
liposomes have shown good results ex vivo but in vivo efficacy and
stability have shown some vague and controversial results. Multi-
functional liposomes have shown promising propensity in therapeu-
tic delivery including aptamers and small-interfering ribonucleic
acid (siRNA) [1, 36-41]. Liposome was first discovered in 1965 by
Bangham [42]. The DOXIL (Ben Venue Laboratories, Inc Bedford,
OH) was the first United States of Food and Drug Administration
(USFDA) approved liposomal pharmaceutical drug product for the
treatment of chemotherapy refractory acquired immune deficiency
syndrome (AIDS)-related Kaposi’s sarcoma. Currently there are
about dozen liposomal based formulations that have been approved
Fig. (1). Various multifunctional nanocarriers for delivery of chemotherapeutic agents.

3. Design of Multifunctional Nanocarriers for Delivery of Anti-Cancer Therapy Current Pharmaceutical Design, 2015, Vol. 21, No. 00 3
for clinical use and more are in stages of clinical trials. Lipo-
dox®
(TTY Biopharm Company Ltd, Taipei, Taiwan) is a second
generation of PEGylated liposomal doxorubicin formulation. Ther-
moDox®
(Celsion Corporation, Lawrenceville, New Jersey), a pro-
prietary thermo-sensitive liposomes (TSL) encapsulated DOX, has
recently entered in Phase III clinical trials for the treatment of hepa-
tocellular carcinoma [28, 43-47].
Nanoparticles in Delivery of Chemotherapeutic Agents
Nanoparticles based chemotherapeutic drug delivery systems
have created tremendous impact and enthusiasm in practically
every branch of biomedicines (ophthalmology, cardiology, endocri-
nology, pulmonology, immunology, and oncology). These nanopar-
ticulate delivery systems have wide impact on highly specialized
area, especially drug targeting to tumor. Nanoparticles have gained
more attention and importance in pharmaceutical and biomedical
applications because they are made of biocompatible and biode-
gradable polymers and serve as good nano-candidate in drug deliv-
ery and targeting [47-48]. Importantly, very small particles (<200
nm) are not easily cleared out by mechanical clearance mechanism of
reticulo endothelial system (RES), while larger particles (>200 nm) can
be filtered and removed from the body [39, 48]. Nanoparticles could
deliver chemotherapeutic agent to specific sites by size-dependent
passive targeting approach. Nanoparticles have generally taken up
by the liver within a few minutes after intravenous (i.v.) injection
after proper optimization process [49]. Currently various modified
forms of nanoparticles have been available like core shell-
nanoparticles, self-assembled nanoparticles, super-paramagnetic
iron oxide nanoparticles (SPIONs), gold nanoparticles (GNPs),
Fig. (2). DNA content and cell cycle analysis of the DOX and developed MWCNTs formulations on MCF-7 cell lines using flow cytometry. Cells were incu-
bated with the formulation and analyzed by flow cytometry. Cell cycle results displayed as a histogram. Dip G1: proportion of cells in G0/G1 phase; Dip G2:
proportion of cells in G2 phase; Dip S: proportion of cells in S phase. Peaks corresponding to G1/G0, G2/M, and S phases of the cell cycle were indicated
(Above). Qualitative and Quantitative cellular uptake of the DOX in MCF-7 cell: (FA & A) Control, (FB & B) Free DOX solution, (FC & C)
DOX/MWCNTs, and (FD & D) DOX/TPGS-MWCNTs formulations (Below).
(Reproduced with copyright permission from Mehra et al., 2014 [25]. Elsevier Pvt. Ltd).

4. 4 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Mehra et al.
magnetic nanoparticles (MNPs), solid lipid nanoparticles (SLNs)
etc and are used in drug delivery and targeting.
Dendrimers in Delivery of Chemotherapeutic Agents
Dendrimer is derived from a Greek word dendron that means
“tree”, with a number of branching units and defined as synthetic,
monodisperse, uniform with well defined size and shape, globular,
nano-sized (1-100 nm) biomacromolecules. The size of dendrimers
increases systematically, as does the generation numbers, ranging
from several to tens of nanometric in diameter. The hyperbranched
dendrimers generated great deal of interest in delivery of che-
motherapeutics owing to their mono-dispersity, high-density of
peripheral functional group, well-defined as well as precise shape
and size, surface chemistries, host-guest interaction chemistry, inte-
rior cavities for higher entrapment of biomolecules and multi-
valency [50-54]. In last few decades hyperbranched dendrimers has
attained recognition among the few leading nanovectors in solubil-
ity enhancement, gene therapy, malaria, cancer, acquired immu-
nodeficiency syndrome (AIDS), microbial infections, tissue regen-
eration and remodulation and imaging and diagnostic application
[50, 51, 54]. SPL7013 Gel (VivaGel®
) is a vaginal microbicide for
prevention of HIV and HSV infection developed by Starpharma Pvt
Ltd (Melbourne, Australia). Currently, VivaGel® is under Phase II
clinical trials for its efficacy against vaginal infection [51].
Dendrimers have been used immensely in chemotherapeutic
delivery through passive as well as active targeting approaches,
which is achieved by chemical modifications of branching units and
end-surface functional groups of dendrimers. Dendrimers is being
used in the targeting of cancer employing of various imaging and
targeting moieties as shown in Fig. (3) [1, 50, 51, 54]. Dendrimers-
doxorubicin conjugate as enzyme-sensitive, mPEGylated peptide
dendrimers- tetra-peptide sequence Gly-Phe-Leu-Gl (GFLG)-
doxorubicin conjugates (dendrimers-GFLG-DOX) was developed
and extensively characterized as chemotherapeutic drug delivery
nano-carriers via two-step highly efficient copper-catalyzed alkyne-
azide click cycloaddition (CuAAC) reaction. The mPEGylated
peptide dendrimers-DOX conjugate showed significant potentials
as candidate for enzyme-sensitive drug delivery in cancer therapy
[55]. PEGylated poly (amido)amine (PAMAM) dendrimers-DOX
conjugate-hybridized gold nanorod (PEG-DOX-PAMAM-AuNR)
for combined cancer photothermal-chemotherapy was developed
and evaluated. The PEG-DOX-PAMAM-AuNR exhibited higher
therapeutic efficacy based on in vitro and in vivo studies [56].
Graphenes in Delivery of Chemotherapeutic Agents
Graphene, a thinnest material in the universe is flexible, two-
dimensional, single layer of carbon atoms arranged densely in a
honeycomb crystal lattice, in which carbon-carbon (C-C) bond (sp2
)
length is approximately 0.142 nm [57-60]. Graphenes have at-
tracted much more attention in modern nanoscience and nanotech-
nology due to their unique extraordinary structure and physico-
chemical properties including light weight, low cost and availability
as high performance composite materials in a diverse range [61-62].
The pristine graphenes are unsuitable in biomedical applications
owing to their agglomeration tendency. Recent advances in the
development of reliable techniques for the chemical modifications
of the graphene provide an additional impetus toward exploring the
scope of their applications [59, 63].
Glycyrrhizin (GL) has anti-inflammatory, anti-allergenic, anti-
hepatotoxic, anti-ulcer and anti-viral properties [64-65]. Wang &
co-workers reported the hepatocyte-targeted delivery using gra-
phene oxide (GO) decorated with glycyrrhizin (GL) through strong
hydrogen-bonding interaction. A high loading of GL on GO and
pH-dependent release behaviour was obtained and attributed to the
hydrogen-bonding interaction between GO and GL [64].
Combination therapy resolved the major hurdles of conven-
tional delivery system and chemotherapy and most widely used by
researchers. The DOX loaded PEGylated nanographene oxide
(NGO-PEG-DOX) was developed, which facilitated combined
chemotherapy and photothermal therapy in a single system. The
combined treatment strategy demonstrated a synergistic effect,
resulting in higher therapeutic efficacy, as compared to chemother-
apy or photothermal therapy alone and completely destructed tumor
[66].
Carbon nanohorns in Delivery of Chemotherapeutic Agents
Carbon nanohons (CNHs) represent a new, alternative type of
carbon based nanomaterials. CNHs comprise of single graphence
Fig. (3). Multifunctional dendrimers-CNTs hybrids based nanoconjuagtes in cancer chemotherapy.

5. Design of Multifunctional Nanocarriers for Delivery of Anti-Cancer Therapy Current Pharmaceutical Design, 2015, Vol. 21, No. 00 5
tubes with 205 nm in diameter and 40-50 nm in lengths. CNHs have
an irregular, horn-like shape (conically-closed tip) [67-69] but are
usually aggregate in assemblies that are reminiscent of dahlia flow-
ers with a diameter that goes from 80 to 100 nm, although they can
also form buds and seeds [69-70]. Single-walled carbon nanohorns
(SWCNHs) are horn-shaped single-walled tubules with conical
shape that have been widely studied for diverse applications includ-
ing drug delivery, targeting and tissue engineering. SWCNHs do
not exhibit cytotoxicity and hence may have potential application as
drug carrier in delivery of chemotherapeutics [71]. CNHs are al-
ready being used as delivery systems in nanomedicines. Sevral
research reports demonstrated that the CNHs could easily deliver
Cis-platin [72], Vincristine [73], and Doxorubicin [74] etc.
A recent report suggests that the targeted drug delivery system
based on oxidized SWCNHs (ox-SWCNHs) were first modified
non-covalently with sodium alginate (SA; natural polysaccharide)
and then loaded with DOX, followed by binding with humanized
anti-vascular endothelial growth factor (anti-VEGF) monoclonal
antibody as targeting group (DOX@ox-SWCNHs/SA-mAb). The
(DOX@ox-SWCNHs/SA-mAb) showed better anti-tumor activity
on human breast adenocarcinoma (MCF-7) and human embryonic
kidney 293 (HEK 293) cells devoid of any hepatotoxicity, car-
diotoxicity and nephrotoxicity [75].
Very recently targeted killing of cancer cells using IGF-IR anti-
body-directed oxidized carbon nanhorns based vincristine (VCR)
delivery (VCR@ox-SWCNHs-PEG-mAb) was reported. The
VCR@ox-SWCNHs-PEG-mAb showed higher antitumour efficacy
with minimal side effecte to normal organs in in vivo tumor model
in mice [72].
Quantum Dots (QDs) in Delivery of Chemotherapeutic Agents
QDs are also being explored as multifunctional nanomedicines
for delivery of anticancer chemotherapeutic agents. In the last few
decades, QDs have received considerable interest in the diagnosis,
imaging and treatment of cancer and other diseases. QDs are the
optical semiconducting in-organic nanomaterial comprising of ele-
ments from periodic group (II-VI) [76-78]. Their properties are
ascribed due to their physical size, ranging from 10-100 Å in radius.
QDs are 1-10 nm in size are credential to fluorescence under ligh
source such as laser. QDs inherently possess numerous advantages
over traditional fluorescent dyes such as increased photostability,
higher brightness, and narrow fluorescence spectra [77, 79]. Till
date various researchers and scientists have developed fluorescent
nanoprobes and evaluated them on various animal models and rep-
resent one of the fastest moving and exciting interfaces of nano-
technology. QDs have unique optical properties, such as a broad
absorption spectrum, narrow, size-tunable emission spectrum, high
photostability, quantum efficiency, and strong non-linear response,
from quantum confinement effects. The toxicity of QDs could be
easily minimized by coating of PEG, polymers and other
biomaterials, which make them more biocompatible and better
candidate in cancer theragnostics [77, 79].
Ovarian cancer is one of the most common gynecological ma-
lignancies in industrialized nations. Savla and co-workers [79] de-
signed tumor-targeted pH-responsive QDs-mucin 1 aptamer-DOX
(QD-MUC1-DOX) conjugate for chemotherapy of ovarian cancer,
wherein DOX was attached to QDs via pH-sensitive hydrazone
bond to provide greater stability in systemic circulation. The QDs-
MUC1-DOX conjugate shows high potential in treatment of
multidrug resistant ovarian cancer.
Hybrid nanomaterials made by conjugating silicon dioxide
coated QDs with graphene sheets for theranostic application in
cancer treatment via fluorescence imaging as well as localized de-
livery of anticancer drug, DOX. These hybrid QDs conjugated gra-
phene sheets (HQDs) showed efficient monitoring of intracellular
delivery of DOX with preferential deposition into cancer cells (Fig.
4 & 5) [80].
Self Emulsifying Drug Delivery systems (SEDDS)
Oral route is most prefereed route of administration, however
approximately 40% of new drug moieties have poor-aqeuous solu-
bility and the oral delivery of such drugs is constrained due to the
Fig. (4). Preparation of Water Dispersible DOX-Graphene-HQDs-Tr. Where. A: GO. B: PSS coated graphene. C: graphene-HQDs. D: graphene-HQDs-Trf. E:
DOX-graphene-HQDs-Trf. (Reproduced with copyright permission from Chen et al., 2013 [80]. American Chemical Society).

6. 6 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Mehra et al.
low bioavailability, high inter- and intra-subject variability, and a
lack of dose proportionality. To overcome these associated prob-
lems, various strategies have been exploited including the use of
lipids, surfactants, permeation enhancers, micronization, salt forma-
tion, cyclodextrins, dendrimers, nanoparticles and solid dispersions
etc [81-82]. Self-emulsifying drug delivery systems (SEDDS) have
attracted considerable interest after commercial success of immuno-
suppresive agent cyclosporine A (Neoral®
) and saquinavir (For-
tovase®
). Self-emulsifiying formulations are isotropic mixtures of
oils (natural and synthetic) with surfactants (lipophilic or hydro-
philic) and co-solvents, which spontaneously emulsify when ex-
posed to the gastrointestinal fluids to form emulsion or micro-
emulsions [83-84]. Solid-self-nanoemulsifying drug delivery sys-
tem (s-SNEDDS) also provides another nanotool for drug delivery
ascribed to their ability to increases oral bioavailability of lipophilic
drugs [85- 86]. Tamoxifen (Tmx) is a non-steroidal anti-estrogen
and widely used hormonal drug in treatment of estrogen positive
breast cancer at multiples stages. Jain & co-workers reported the
oral delivery of Tmx and quercetin combination loaded into solidi-
fied self-nanoemulsifying drug delivery systems (s-Tmx-QT-
SNEDDS). This SNEDDS based nanosystem of Tmx showed sig-
nificant increase in cytotoxicity with approximately 32- and 22-fold
decrease in the inhibitory dose for tamoxifen and quercetin, respec-
tively. These results support the possible clinical application of
SNEDDS in oral delivery of drug [87-88].
CONCLUSION AND FUTURE PERSPECTIVES
The various nanocarriers (liposomes, nanoparticles, polymeric
nanoparticles, dendrimers, carbon nanohorns, graphenes and carbon
nanotubes) are currently being emerged in drug delivery and target-
ing with diverse pharmaceutical, medical and biotechnological
applications. Attachment of numerous chemical functional moieties
such as imaging, peptides, antibody, targeting ligands, siRNA and
drugs make them more smart and intelligent. Success of these mul-
tifunctional nanocarriers is further supported by availability of mar-
keted products. Also, various nanotechnology products are under
extensive clinical trials and preclinical development phases. These
multifunctional nanocarriers provide targetability, longevity, intra-
cellular penentration and high payload as well as minimal toxicity
of the bioactives. Multifunctional hybrid nanomaterials also seems
to be worth exploring because of enormous possibilities of individ-
ual nanomaterials vis a vis their hybrids, while encashing upon well
established advantages of functionalization. We believe that in fu-
ture these multifunctional nanocarriers will spark research in bio-
medical and pharmaceutical arena and can provide complete cure
from deadly diseases including cancer, HIV/AIDS, malaria and
tuberculosis and so on.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Jain K, Mehra NK, Jain NK. Potential and emerging trends in
nanopharmacology. Curr Opin Pharmacol 2014; 15: 97-106.
[2] Koo OM, Rubinstein I, Onyukel H. Role of nanotechnology in
targeted drug delivery and imaging: a concise review. Nanomed:
Nanotechnol. Biol Med 2005; 1: 193-212.
[3] Mehra NK, Mishra V, Jain NK. Receptor based targeting of thera-
peutics. Ther Del 2013; 4(3): 369-94.
Fig. (5). Fluorescent microscopic images of HEK293 cells directly labeled by graphene-HQDs-Trf-3 for 4 hr (a); HeLa cells incubated with (b) graphene-
HQDs-3 for 4 hr, (c) Trf for 2 hr followed by graphene-HQDs-Trf-3 for 4 hr, graphene-HQDs-Trf-3 for 1 hr (d) and 4 hr (e). Left: the bright-field images.
Middle: the fluorescent images. Right: the merged images of the left and middle ones. (Reproduced with copyright permission from Chen et al., 2013 [80],
American Chemical Society).

7. Design of Multifunctional Nanocarriers for Delivery of Anti-Cancer Therapy Current Pharmaceutical Design, 2015, Vol. 21, No. 00 7
[4] Mehra N K, Jain AK, Lodhi N, Dubey V, Mishra D, Jain NK.
Challenges in the use of carbon nanotubes for biomedical
application. Crit Rev Ther Drug Carr Sys 2008; 25(2): 169-206.
[5] Jain AK, Mehra NK, Lodhi N, et al. Carbon nanotubes and their
toxicity. Nanotoxicology 2007; 1(3): 167-97.
[6] Jain NK, Mishra V, Mehra NK. Targeted drug delivery to macro-
phages. Exp Opin Drug Deliv 2013; 10(3): 353-67.
[7] Steichen SD, Caldorera-Moore M, Peppas NA. A review of current
nanoparticles and targeting moieties for the delivery of cancer
therapeutics. Euro J Pharm Sci 2013; 48: 416-27.
[8] Mehra NK, Jain K, Jain NK. Pharmaceutical and biomedical appli-
cation of surface engineered carbon nanotubes. Drug Discov Today
2015; 20(6): 750-9.
[9] Taratula O, Garbuzenko O, Savla R, Wang YA, He H, Minko T.
Multifunctional nanomedicines platform for cancer specific deliv-
ery of siRNA by superparamagnetic iron oxide nanoparticles-
dendrimer complexes. Curr Drug Deliv 2011; 8(1): 59-69.
[10] Singh RK, Patel KD, Kim JJ, et al. Multifunctional hybrid nanocar-
rier: magnetic CNTs ensheathed with mesoporous silica for drug
delivery and imaging system. ACS Appl Mater Interfaces 2014;
6(4): 2201-8.
[11] Wen Y, Meng WS. Recent in vivo evidences of particle based
delivery of small-interfering RNA (siRNA) into solid tumors. J
Pharm Innov 2014; 9(2): 158-73.
[12] Iijima S. Helical microtubules of graphitic carbon. Nature 1991;
354: 56-8.
[13] Mehra NK, Jain NK. One platform comparison of estrone and folic
acid anchored surface engineered MWCNTs for doxorubicin deliv-
ery. Mol Pharm 2015 12(2): 630-43.
[14] Mehra NK, Mishra V, Jain NK. A review of ligand tethered surface
engineered carbon nanotubes. Biomaterials 2014; 35(4): 1267-83.
[15] Lacerda L, Russier J, Pastorin G, et al. Translocation mechanisms
of chemically functionalized carbon nanotubes across plasma
membranes. Biomaterials 2012; 33: 3334-43.
[16] Fabbro C, Ali-Boucetta H, Da Ros T, Kostarelos K, Bianco A,
Prato M. Targeting carbon nanotubes against cancer. Chem Comm
2012; 48: 3911-26.
[17] Mehra NK, Jain NK. Multifunctional hybrid-carbon nanotubes:
new horizon in drug delivery and targeting. J Drug Target. 2015.
(Epub ahead of print; doi: 10.3109/1061186X.2015.1055571).
[18] Mehra NK, Jain NK. Cancer targeting propensity of folate
conjugated surface engineered multi-walled carbon nanotubes.
Colloids and Surface B: Biointerfaces. 2015; 132: 17-26.
[19] Sobhani Z, Dinarvand R, Atyabi F, Ghahremani M, Adeli M. In-
creased paclitaxel cytotoxicity against cancer cell lines using a
novel functionalized carbon nanotubes. Int J Nanomed 2011; 6:
705-19.
[20] Liu Z, Sun X, Nakayama-Ratchford N, Dai H. Supramolecular
chemistry on water-soluble carbon nanotubes for drug loading and
delivery. ACS Nano 2007; 1(1): 50-6.
[21] Mehra NK, Jain NK. Development, characterization and cancer
targeting potential of surface engineered carbon nanotubes. J Drug
Target 2013; 21(8): 745-58.
[22] Al-Boucetta H, Al-Jamal KT, McCarthy D, Prato M, Bianco A,
Kostarelos K. Multiwalled carbon nanotubes-doxorubicin su-
pramolecular complexes for cancer therapeutics. Chem Commun
2008; 459-61.
[23] Datir SR, Das M, Singh RP, Jain S. Hyaluronate tethered smart
multi walled carbon nanotubes for tumor-targeted delivery of
doxorubicin. Bioconj Chem 2011; 23(11): 2201-13.
[24] Gu YJ, Cheng J, Jin J, Cheng SH, Wong WT. Development and
evaluation of pH-responsive single-walled carbon nanotube-
doxorubicin complexes in cancer cells. Int J Nanomed 2011; 6:
2889-98.
[25] Mehra NK, Verma AK, Mishra PR, Jain NK. The cancer targeting
potential of D- -tocopheryl polyethylene glycol 1000 succinate
tethered multi walled carbon nanotubes. Biomaterials 2014; 35:
4573-88.
[26] Huang H, Yuan Q, Shah JS, Misra RDK. A new family of folate-
decorated and carbon nanotubes-mediated drug delivery system:
synthesis and drug delivery response. Adv Drug Deliv Rev 2011;
63: 1332-9.
[27] Ji Z, Lin G, Lu Q, et al. Targeted therapy of SMMC-7721 liver
cancer in vitro and in vivo with carbon nanotubes based drug deliv-
ery systems. J Colloid and Interface Sci 2012; 365: 143-9.
[28] Lodhi N, Mehra NK, Jain NK. Development and characterization
of dexamethasone mesylate anchored on multi walled carbon nano-
tubes. J Drug Target 2013; 21(1): 67-76.
[29] Das M, Singh R P, Datir SR, Jain S. Intracellular drug delivery and
effective in vivo cancer therapy via estradiol-PEGappended multi
walled carbon nanotubes. Mol Pharm 2013; 10(9): 3404-16.
[30] Singh R, Mehra NK, Jain V, Jain NK. Folic acid conjugated carbon
nanotubes for gemcitabine HCL delivery. J Drug Target 2013;
21(6): 581-92.
[31] Mao H, Kawazoe N, Chen G. Uptake and intracellular distribution
of collagen-functionalized single-walled carbon nanotubes. Bioma-
terials 2013; 34: 2472-9.
[32] Varkouhi AK, Foillard S, Lammers T, et al. siRNA delivery with
functionalized carbon nanotubes. Int J Pharm 2011; 416: 419-25.
[33] Liu Z, Winters M, Holodniy M, Dai H. SiRNA delivery into human
T cells and primary cells with carbon-nanotube transporters.
Angew Chem Int Ed Engl 2007; 46: 2023-7.
[34] Al-Jamal KT, Toma FM, Yilmazer A, et al. Enhanced cellular
internalization and gene silencing with a series of cationic Den-
dron-multiwalled carbon nanotubes: siRNA complexes. FASEB J
2010; 24(11): 4354-65.
[35] Cheung W, Pntoriero F, Taratula O, Chen AM, He H. DNA and
Carbon nanotubes as medicine. Adv Drug Deliv Rev 2010; 62(6):
633-49.
[36] Sousa S, Auriola S, Monkkonen J, Maatta J. Liposomes encapsu-
lated zoledronate faours M1-like behaviour in murine macrophages
cultured with soluble factors from breast cancer cells. BMC Cancer
2015; 15: 4
[37] Yuan A, Tang X, Qiu X, Jiang K, Wu J, Hu Y. Activatable pho-
todynamic destruction of cancer cells by NIR dye/photosensitizer
loaded liposomes. Chem Comm 2015; 51: 3340-2.
[38] Muthu MS, Kulkarni SA, Xiong J, Feng SS. Vitamin E TPGS
coated liposomes enhanced cellular uptake and cytotoxicity of do-
cetaxel in brain cancer cells. Int J Pharm 2011; 421: 332-40.
[39] Nahar M, Dutta T, Murugesan S, et al. Functional polymeric
nanoparticles: an efficient and promising tool for active delivery of
bioactives. Crit Rev Ther Drug Carr Sys 2008; 23(4): 259-318.
[40] Kaasgaard T, Andresen TL. Liposomal cancer therapy: exploiting
tumor characeteristics. Exp Opin Drug Delivery 2010; 7(2): 225-
43.
[41] Zhao L, Wei Y, Zhong X, et al. PK and tissue distribution of do-
cetaxel in rabbits after i.v. administration of liposomal and in-
jectable formulations. J Pharm Biomed Anal 2009; 49: 989-96.
[42] Bangham AD. Diffusion of univalent ions across unilamellar of
swollen phospholipids. J Mol Biol 1965; 13: 238-52.
[43] Toh MR, Chiu GNC. Liposomes as sterile preparations and limita-
tions of sterilization techniques in liposomal manufacturing. Asian
J Pharm Sci 2013; 8(2): 88-95.
[44] Fan Y, Zhang Q. Development of liposomal formulations: from
concept to clinical investigations. Asian J Pharm Sci 2013; 8(2):
81-7.
[45] Kaminskas LM, McLeoad VM, Kelly BD, et al. A comparison of
changes to doxorubicin pharmacokinetics, antitumor activity, and
toxicity mediated by PEGylated dendrimers and PEGylated
liposomes drug delivery systems. Nanomed: Nanotechnol Biol Med
2012; 8(1): 103-11.
[46] Chang HI, Yeh MK. Clinical development of liposomes-based
drugs: formulation, characterization, and therapeutic efficacy. Int J
Nanomed 2012; 7: 49-60.
[47] Gao H, Zhang Q, Yu Z, He Q. Cell-penetrating peptide-based intelli-
gent liposomal systems for enhanced drug delivery. Curr Pharm
Biotechnol. 2014; 15: 210-9.
[48] Liu Y, Li K, Pan J, Liu B, Feng SS. Folic acid conjugated nanopar-
ticles of mixed lipid monolayer shell and biodegradable polymer
core for targeted delivery of docetaxel. Biomaterials 2010; 31: 330-
8.
[49] Xu Z, Chen L, Gu W, et al. The performance of docetaxel-loaded
solid lipid nanoparticles targeted to hepatocellualr carcinoma. Bio-
materials 2009; 30: 226-32.
[50] Agrawal U, Mehra NK, Gupta U, Jain NK. Hyperbranched den-
dritic nano-carriers for topical delivery of dithranol. J Drug Target
2013; 21(5): 497-506.
[51] Kesharwani P, Jain K, Jain NK. Dendrimer as nanocarrier for drug
delivery. Prog Polym Sci 2014; 39: 268-307.

8. 8 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Mehra et al.
[52] Kesharwani P, Tekade RK, Jain NK. Dendrimer generational no-
menclature: the need to harmonize. Drug Discov Today 2015;
20(5): 497-9.
[53] Wu LP, Ficker M, Christensen JB, Trohopoulos PN, Moghimi SM.
Dendrimers in medicine: Therapeutic concepts and pharmaceutical
challenges. Biconj Chem 2015; 26(7): 1198-211.
[54] Jain K, Verma A, Mishra PR, Jain NK. Characterization and
evaluation of amphotericin B loaded MDP conjugated
poly(propylene imine) dendrimers. Nanomed: Nanotechnol Biol
Med 2015; 11(3): 705-13.
[55] Zhang C, Pan D, Luo K, et al. Dendrimer-doxorubicin conjugate as
enzyme-sensitive and polymeric nanoscale drug delivery vehicle of
ovarian cancer therapy. Polym Chem 2014; 5: 5227-35.
[56] Li X, Takashima M, Yuba E, Harada A, Kono K. PEGylated
PAMAM dendrimers-doxorubicin conjugate-hybridized gold nano-
rod for combined photothermal-chemotherapy. Biomaterials 2014;
35(24): 6576-84.
[57] Ku SH, Park CB. Myoblast differentiation on graphene oxide.
Biomaterials 2013; 34: 2017-23.
[58] Chowdhury SM, Lalwani G, Zhang K, Yang JY, Neville K,
Sitharaman B. Cell specific cytotoxicity and uptake of graphene
nanoribbons. Biomaterials 2013; 34: 283-93.
[59] Shen H, Zhang L, Liu M, Zhang Z. Biomedical applications of
graphene. Theranostics 2012; 2(3): 283-94.
[60] Batzil M. The surface science of graphene: metal interfaces, CVD
synthesis, nanoribbons, chemical modifications and defects. Surf
Sci Reports 2012; 67: 83-115.
[61] Depan D, Shah J, Misra RDK. Controlled release of drug from
folate-decorated and graphene mediated drug delivery system: syn-
thesis, loading efficiency and drug release response. Mat Sci Eng C
2011; 31: 1305-12.
[62] Liu J, Guo S, Han L, Ren W, Liu Y, Wang E. Multiple pH-
responsive graphene composites by non-covalent modification with
chitosan. Talanta 2012; 101: 151-6.
[63] Tinchev SS, Surface modification of diamond-like carbon films to
graphene under low energy ion beam irradiation. App Surf Sci
2012; 258: 2931-4.
[64] Wang Z, Gao Y, Xia J, Zhang F, Xia Y, Li Y. Synthesis and char-
acterization of glycyrrhizin-decorated graphene oxide for hepato-
cyte-targeted delivery. C R Chimie 2012; 15: 708-13.
[65] Chopdey PK, Tekade RK, Mehra NK, Mody N, Jain NK.
Glycyrrhizin conjugated dendrimer and multi-walled carbon
nanotubes for liver specific delivery of doxorubicin. J Nanosci
Nanotechnol 2015; 15(2): 1088-100.
[66] Zhang W, Guo Z, Huang D, Liu Z, Guo X, Zhong H. Synergistic
effect of chemo-photothermal therapy using PEGylated graphene
oxide. Biomaterials 2011; 32: 8555-61.
[67] Zhang M, Yang M, Bussy C, Iijima S, Kostarelos K, Yudasaka M.
Biodegradation of carbon nanohorns in macrophage cells.
Nanoscale 2015; 7(7): 2834-40.
[68] Ajima K, Yudasaka M, Murakami T, Maigne A, Shiba K, Iijima S.
Carbon nanohorns as anticancer drugs carriers. Mol Pharm 2005;
2(6): 475-80.
[69] Guerra J, Herrero MA, Carrion B, et al. Carbon nanohorns func-
tionalized with polyamidoamine dendrimers as efficient biocarrier
materials for gene therapy. Carbon 2012; 50: 2832-44.
[70] Whitney JR, Sarkar S, Zhang J, et al. Single walled carbon nano-
horns as photothermal cancer agents. Lasers Surg Med 2011; 43(1):
43-51.
[71] Zhu S, Xu G. Single-walled carbon nanohorns and their applica-
tions. Nanoscale 2010; 2: 2538-49.
[72] Dewitt MR, Pekkanen AM, Robertson J, RYlander CG, Nichole
Rylander M. Influence of hyperthermia on efficacy and uptake of
carbon nanohorns-cisplain conjugates. J Biomech Eng 2014;
136(2): 021003.
[73] Li N, Zhao Q, Shu C, et al. Targeted killing of cancer cells in vivo
and in vitro with IGF-IR antibody-directed carbon nanohorns based
drug delivery. Int J Pharm 2015; 478(2): 644-54.
[74] Murakami T, Fan J, Yudasaka M, Iijima S, Shiba K. Solubilization
of single-wall carbon nanohorns using a PEG-doxorubicin conju-
gates. Mol Pharm 2006; 3(4): 407-14.
[75] Ma X, Shu C, Guo J, et al. Targeted cancer therapy based on sin-
gle-wall carbon nanohorns with doxorubicin in vitro and in vivo. J
Nanopart Res 2014; 16: 2497.
[76] Mishra RDK. Quantum dots for tumor-targeted drug delivery and
cell imaging. Nanomed 2008; 3(3): 271-4.
[77] Chakravarthy KV, Davidson BA, Helinski JD, D et al. Doxorub-
cin-conjugated quantum dots to target alveolar macrophages and
inflammation. Nanomed: nanotechnol. Biol Med 2011; 7: 88-96.
[78] Qi L, Gao X. Emerging application of quantum dots for drug deliv-
ery and therapy. Exp Opin Drug Deliv 2008; 5(3): 263-7.
[79] Savla R, Taratula O, Garbuzenko O, Minko T. Tumor targeted
quantum dot-mucin 1 aptamer-doxorubicin conjugate for imaging
and treatment of cancer. J Control Rel 2011; 153: 16-22.
[80] Chen ML, He YJ, Chen XW, Wang JH. Quantum-Dot-conjugated
graphene as a probe for simultaneous cancer-targeted fluorescent
imaging, tracking and monitoring drug delivery. Bioconj Chem
2013; 24: 387-97.
[81] Zhang L, Zhu W, Yang C, et al. A novel folate-modified self-
microemulsifying drug delivery system of curcumin for colon tar-
geting. Int J Nanomed 2012; 7: 151-62.
[82] Nipun TS, Islam SMA. SEDDS of gliclazide: preparation and
characterization by in vitro, ex-vivo and in-vivo techniques. Saudi
Pharm J 2014; 22(4): 343-8.
[83] Kohli K, Chopra S, Dhar D, Arora S, Khar RK. Self-emulsifying
drug delivery systems: an approach to enhance bioavailability.
Drug Discovery Today 2010; 15(21-22): 958-65.
[84] Wei Y, Ye X, Shang X, et al. Enhanced oral bioavailability of
silybin by a supersaturable self-emulsifying drug delivery system
(s-SEDDS). Colloids and Surface A: Physicochemical and Eng As-
pects 2012; 396: 22-8
[85] Gursoy RN, Benita S. Self-emulsifying drug delivery systes
(SEDDS) for improved oral delivery of lipophilic drugs. Biomed &
Pharmacotherpay 2004; 58(3): 173-82.
[86] Jain AK, Thanki K, Jain S. Novel self-nanoemulsifying formula-
tion of quercetin: Implications of pro-oxidant activity on the anti-
cancer efficacy. Nanomed: Nanotechnol Biol Med 2014; 10: 959-
69.
[87] Jain AK, Thanki K, Jain S. Solidified self-nanoemulsifying formu-
lation for oral delivery of combinatorial therapeutic regimen: part I
formulation development, statistical optimization and in vitro char-
acterization. Pharm Res 2014; 31: 923-45.
[88] Jain AK, Thanki K, Jain S. Solidified self-nanoemulsifying formu-
lation for oral delivery of combinatorial therapeutic regimen: part II
in vivo pharmacokinetcis, antitumor efficacy and hepatotoxicity.
Pharm Res 2014; 31(4): 946-58.
Received: August 14, 2015 Accepted: October 26, 2015