Advanced Drug Delivery Reviews 63 (2011) 1340–1351

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Polymeric nanohybrids and functionalized carbon nanotubes as drug delivery

carriers for cancer therapy☆
Satya Prakash ⁎, Meenakshi Malhotra, Wei Shao, Catherine Tomaro-Duchesneau, Sana Abbasi
Biomedical Technology and Cell Therapy Research Laboratory, Departments of Biomedical Engineering and Physiology, Artificial Cells and Organs Research Center, Faculty of Medicine,
McGill University, 3775 University Street, Montreal, Quebec, Canada H3A 2B4

a r t i c l e i n f o a b s t r a c t

Article history: The scope of nanotechnology to develop target specific carriers to achieve higher therapeutic efficacy is
Received 25 September 2010 gaining importance in the pharmaceutical and other industries. Specifically, the emergence of nanohybrid
Accepted 27 June 2011 materials is posed to edge over chemotherapy and radiation therapy as cancer therapeutics. This is primarily
Available online 3 July 2011
because nanohybrid materials engage controlled production parameters in the making of engineered particles
with specific size, shape, and other essential properties. It is widely expressed that these materials will
Keywords:
Nanohybrids
significantly contribute to the next generation of medical care technology and pharmaceuticals in areas of
Polymeric nanoparticles disease diagnosis, disease prevention and many other treatment procedures. This review focuses on the
Carbon nanotubes currently used nanohybrid materials, polymeric nanoparticles and nanotubes, which show great potential as
Drug delivery effective drug delivery systems for cancer therapy, as they can be grafted with cell-specific receptors and
Microcapsule intracellular targeting molecules for the targeted delivery of therapeutics. Specifically, this article focuses on
Cancer therapy the current status, recent advancements, potentials and limitations of polymeric nanohybrids and
functionalized carbon nanotubes as drug delivery carriers.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341
2. Nanohybrid drug delivery carriers for cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341
2.1. Polymeric nanohybrid materials as drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1342
2.1.1. Pharmacokinetics and biodistribution of polymeric nanohybrid materials . . . . . . . . . . . . . . . . . . . . . . . . . 1342
2.1.2. Long circulating polymeric nanohybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1343
2.2. Synthesis of polymeric nanohybrid materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1343
2.2.1. PACA nanohybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1343
2.2.2. PLGA/PLA nanohybrids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1344
2.2.3. Polymeric nano micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1344
3. Carbon nanotubes as new drug delivery carriers for use in cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1345
3.1. Functionalization of carbon nanotubes for drug delivery and other applications . . . . . . . . . . . . . . . . . . . . . . . . . . 1345
3.2. Applications of carbon nanotubes in cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1346
3.2.1. Small hydrophobic cancer drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1346
3.2.2. Microencapsulated carbon nanotube delivery devices for cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . 1347
3.2.3. Selective tumor destruction via Near-Infrared radiation of carbon nanotubes . . . . . . . . . . . . . . . . . . . . . . . 1347
3.2.4. In vivo toxicity of carbon nanotubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347
4. Conclusions: toward future perspective, benefits and concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1348
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1348

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Hybrid Nanostructures for Diagnostics and Therapeutics”.
⁎ Corresponding author. Tel.: + 1 514 398 3676; fax: + 1 514 398 7461.
E-mail address: satya.prakash@mcgill.ca (S. Prakash).

0169-409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.06.013
 S. Prakash et al. / Advanced Drug Delivery Reviews 63 (2011) 1340–1351
1. Introduction
Currently available technologies have made enormous advance-
ment in cancer research, but an adequate therapy remains elusive.
Cancer is characterized as a disorder which arises following a number
of mutagenesis steps, allowing cancerous cells to grow and divide
uncontrollably. These processes allow cancer cells to acquire
properties of unlimited proliferation potential, self-sufficiency in
growth signals and resistance to both anti-proliferative and apoptotic
cues which would, otherwise, contain their growth [1]. Tumors have
also evolved methods to gain further support through interactions
with surrounding stromal cells, promoting their angiogenesis, their
evasion of immune detection and their metastasis to distal organs [2].
The Global Cancer Report issued by the World Health Organization
(WHO) estimates that there are over 10 million new cases of cancer
every year with over 6 million annual deaths caused by the disease
[3]. The most frequent types of cancers causing death are, as listed by
the WHO: lung, stomach, liver, colon and breast cancers [4].
Current cancer therapies can be broadly categorized into two
groups: cytotoxic therapies and molecular targeted drugs [5].
Examples of traditional cytotoxic therapies include radiation and
chemotherapeutic compounds such as platinum-based drugs [5,6].
Radiation, utilizing photons, damages the DNA of cancer cells by
creating free radicals, leading to the inhibition of cell division and,
eventually, causing cell death. Cancer cells are most abundantly found
in the mitotic phase, in a state of continuous DNA replication, allowing
radiation to be more toxic to tumor cells than normal cells, providing a
therapeutic window [7]. Platinum-based drugs, such as cisplatin, act
through the formation of DNA-platinum adducts [8]. These adducts
lead to DNA deformations, such as unwinding and bending, while also
being recognized by a number of cellular proteins involved in DNA-
repair pathways [9]. The formation of these adducts ultimately results
in apoptosis, although the mechanism of action has not been fully
defined [8].
The compounds listed in Table 1 rely mainly on one important
characteristic of cancer cells: their rapid and uncontrolled proliferation
and division. Hence, the compounds do show a level of toxicity to non-
cancerous cells since these are still proliferating, albeit at a slower rate
than cancerous cells. There are also a number of compounds currently
undergoing clinical trials, but most of these still rely on the proliferation
properties of cancerous cells, attacking the cell division and apoptosis
pathways [36]. It is, hence, evident that the newly developed
compounds, which still rely on these properties, will also give rise to
serious side effects such as nausea, hair loss, neuropathies, neutropenia
and kidney failure [37]. This is simply due to the fact that these
Table 1
Anti-cancer therapeutics and their mechanism of action.
Compound
Amethopterin/methotrexate
Cisplatin/carboplatin/tetraplatin/oxaliplatin
Daunorubicin/adriamycin/doxorubicin/mitoxanthrone/actinomycin/idarubicin
Etoposide
Fluorouracil
Hydroxyurea
Mercaptopurine
Paclitaxel/ Taxol/ Docetaxel
Tamoxifen
Vinblastine/vincristine/vindesine
Camptothecin
1341
compounds, due to their inability to completely discriminate between
tumor and healthy tissues, have a high toxicity [37].
It can be said that, as of yet, for a number of reasons, an adequate
therapy for cancer has not been developed. Some of these reasons
include: late stage diagnosis, inadequate methods for controlling
aggressive metastasis, and a lack of methods to overcome multi-drug
resistant (MDR) cancer. The current medical anticancer treatments
involve applications where therapies are provided by removing the
diseased cells (surgery), burning them out (radiation therapy), or
poisoning the diseased cells faster than the healthy cells (chemo-
therapy), all of which do cause damage to healthy cells [1,38–40].
Nanotechnology, involving the development of an appropriate
delivery system, is an emerging field of research that attempts to
overcome the challenges associated with designing an anti-cancer
therapy. A number of compounds have been formulated using
nanotechnology methods and combinations of polymers with anti-
cancer drugs to allow for the development of a delivery system.
Table 2 lists some of these anticancer therapeutic formulations and
their current clinical status. The benefits of a nanoscale drug delivery
system are numerous, and can involve, but are not limited to: 1) a
targeted delivery, allowing for an increased drug concentration at the
desired site, reducing systemic exposure to a potentially toxic
compound 2) a constant rate of drug delivery to allow for the
maintenance of a constant therapeutic dose at the site of delivery and
3) an increase in drug stability due to protection from degradation and
loss of drug [37,41].
Recently, nanohybrids and carbon nanotubes (CNTs) have been
proposed as drug delivery carriers. Nanohybrids combine biological or
bio-functionalized molecules giving rise to a system capable of drug
delivery. CNTs, on the other hand, are synthetic nanomaterials, made
from carbon atoms, which can be functionalized to act as a drug
delivery system. This review focuses on polymeric nanohybrid
materials and carbon nanotubes as drug delivery systems, specifically
focusing on their synthesis, their functionalization and their applica-
tions, with an emphasis toward cancer therapy.
2. Nanohybrid drug delivery carriers for cancer therapy
The tumor microenvironment comprises fast-growing, hyperpro-
liferative cancer cells having a high metabolic rate and demand for the
recruitment of new vessels (neovascularization) in order to supply
them with oxygen and nutrients [54]. The pathophysiologic condition
of a tumor is its utilization of the glycolysis pathway to obtain
additional energy, resulting in the generation of an acidic environ-
ment [55]. Tumor cells also release growth factors and enzymes such
Mechanism of action Ref.
Inhibits dihydrofolate reductase, blocking thymidine synthesis and, in turn, DNA [10,11]
and protein synthesis
Platinum-based compounds, adduct formation leading to DNA cross linking, [8,12,13]
inducing apoptosis
DNA intercalating compounds, blocking polymerase activity, inhibiting DNA [14–16]
replication, inducing apoptosis
Forms a ternary complex with topoisomerase II and DNA, leading to errors in [17,18]
synthesis, inducing apoptosis
Pyrimidine analog, inhibiting DNA synthesis, induces p53-dependent apoptosis [19–21]
Inhibits ribonucleoside reductase, inhibiting DNA synthesis, inducing apoptosis [22–24]
Purine analog, inhibiting DNA synthesis, inducing apoptosis [25,26]
Binds β-tubulin, forming highly stable microtubules that resist depolymerization, [27–29]
preventing cell division and inducing apoptosis
Selective estrogen response modifier (SERM), used against estrogen-sensitive [30,31]
breast tumors, competitively inhibits estrogen binding, slowing cell proliferation
Binds tubulin, inducing self-association and depolymerizes pre-existing [32,33]
microtubules, inducing apoptosis
inhibits the catalytic activity of mammalian DNA topoisomerase I, inhibiting DNA [34,35]
synthesis and inducing DNA strand breaks, leading to apoptosis
1342 S. Prakash et al. / Advanced Drug Delivery Reviews 63 (2011) 1340–1351

as matrix metalloproteinases, which lead to an imbalance of
angiogenic regulators dilating the tumor vessels, resulting in large
gap junctions, ranging from 200 to 2000 nm in size, between
endothelial cells [54]. Moreover, the higher interstitial pressure
generated by a compromised lymphatic drainage and a lower intra-
vascular pressure limit the movement of macromolecules/particulate
materials out of the tumor blood vessels into the extra-vascular
compartment [56]. This enhanced vascular permeability and the lack
of adequate lymphatic drainage at tumor sites facilitate passive
targeting using polymeric nanovectors. The phenomenon is termed
the Enhanced Permeability and Retention effect (EPR) [57–59](Fig. 1).
This effect is also attributed to the molecular weight, surface charge
and nature of the polymer. The conjugation of drugs to polymers
avoids the random bioavailability of the low molecular weight drugs
and enables target specificity. However, the molecular weight of the
nanovectors also plays an equally important role in the delivery, as
nanovectors of a molecular weight of less than 50 kDa or of a size less
than 6 nm are rapidly cleared by the kidney following systemic
administration [60–63]. On the other hand, the size is crucial for non-
biodegradable polymers, in order to be eliminated by the renal
system, following drug delivery. In general, cationic nanovectors are
more susceptible to glomerular filtration than anionic nanovectors, as
the negative charge on the glomerular capillary results in a charge-
selective barrier and the nanovectors of larger molecular weight
accumulate in the liver, kidneys, and lungs [64–66]. Thus, the ideal
molecular weight of the polymer depends on the particular
application, but ranges from 30 kDa to 100 kDa. Nanoparticles that
abide the size and surface characteristics mentioned above, escape the
Reticulo-Endothelial System (RES) and are able to circulate longer in
the bloodstream with a greater chance of reaching the targeted tumor
tissues. Drugs conjugated to polymers through peptidyl and ester
linkages allow for a controlled drug release. In some cases, the drug is
released through thiol dependent cleavage by protease cathepsin B
[67]. Other drug release methods involve pH sensitive cis-aconityl,
hydrazone and acetyl linkages [68]. The hydrolysis cleaves the linkage
within the compartment of the endosomes and lysosomes, which
have an acidic pH ranging from 4.0 to 6.5.
2.1. Polymeric nanohybrid materials as drug delivery systems
Polymeric nanohybrid materials comprise a core material, a
therapeutic “payload” and a biological surface modification that aids
in the biodistribution and selective cell targeting moieties, Fig. 2. The
nanohybrid materials/nanovectors in conjunction with drugs are mostly
delivered intravenously, as they bear the key characteristic of their
ability to be tailored to bypass the biological/physiological and
immunological barriers of the body. The use of nanovector drug delivery
vehicles has gained importance in biomedical applications, as they
enable the encapsulation and the successful delivery of drugs with poor
aqueous solubility profiles such as paclitaxel, an antitumor agent [69–
71]. Paclitaxel bound to albumin nanoparticles is an FDA approved
nanoparticle formulation, under the market name Abraxane, for
delivery to metastatic breast cancer patients [72,73]. Another advantage
of utilizing polymeric nanovectors is the potential for non-invasive
targeting to the tumor. Nanohybrid materials exhibit multifunctional
features that facilitate imaging, targeting and drug delivery. Other
polymeric nanovector composites that have received much attention in
cancer drug delivery are polylactide–polyglycolide copolymers entrap-
ping leutinizing hormone releasing hormone (LHRH), marketed as
goserelin (Zoladex) and leuprolide (Leuprone Depot) [74,75] and
liposomes encapsulating daunorubicin and doxorubicin, marketed as
DaunoXome and Doxil/Caelyx respectively [76,77]. Other polymers
include N-(2-hydroxyl propyl)methacrylamide (HPMA) copolymers,
polyglycolic acid (PGA) with paclitaxel, marketed as Xyotax™ [78,79]
and polycaprolactones and natural polymers like albumin, gelatin,
alginate, collagen and chitosan. A detailed overview on clinically
evaluated polymer-drug conjugates has been well documented else-
where [67,80].
2.1.1. Pharmacokinetics and biodistribution of polymeric nanohybrid
materials
The drug polymer conjugates appear to improve a drug's half-life in
plasma due to the larger hydrodynamic volume of polymers which, in
turn, increases the drug's accumulation at the tumor site. For example,
PHPMA copolymer conjugated with doxorubicin has shown a drug
stability of 5 min in plasma when administered alone, compared to 1 h
when administered with polymer which also shows an increased drug
accumulation in solid tumors [81–83]. Antibodies [84,85], peptides [86]
and saccharides [48] have also been attached to PHPMA copolymer.
Galactosamine has been attached as a targeting moiety to the HPMA-
doxorubicin, targeting the asialoglycoprotein receptor present in
hepatocytes [48]. Another example is the styrene maleic anhydride
conjugated with the anti-tumor protein, neocarzinostatin (SMANCS)
used for the treatment of hepatocellular carcinoma [87]. Surface
modifications by various ligands and antibodies such as transferrin,
folate, epidermal growth factor, and arginine–glycine–aspartic acid
(RGD) tripeptide conjugated to the polymer backbone, allow for the
active targeting of the therapeutic to tumor cells, via receptor-mediated
endocytosis [88–95]. Usually it is favorable to use non-cationic or
surface-modified polymers to prevent the adsorption of plasma
proteins onto the surface of the nanoparticles, in order to avoid uptake

Table 2
List of polymer–drug conjugate compounds and their clinical status.

Compound Clinical name Clinical Polymer Drug Ref.

status

Albumin-Taxol Abraxane® Market Albumin Paclitaxel [42,43]

CNT-MTX N/A Preclinical Carbon nanotube Methotrexate [44]
HPMA copolymer doxorubicin PK1, FCE28068 Phase III N-(2-hydroxypropyl) methacrylamide (HPMA) Doxorubicin [45]
copolymer
HPMA copolymer-carboplatin AP5280 Phase II N-(2-hydroxypropyl) methacrylamide (HPMA) Platinum [46]
platinate copolymer
HPMA copolymer-DACH- AP5346, ProLindac™ Phase II N-(2-hydroxypropyl) methacrylamide (HPMA) Platinum [47]
platinate copolymer
HPMA copolymer-doxorubicin- PK2, FCE28069 Phase II N-(2-hydroxypropyl) methacrylamide (HPMA) Doxorubicin and [48]
galactosamine copolymer Galactosamine
PEG-PAA-DOX NK911 Phase III Poly(ethylene glycol) Doxorubicin [49,50]
PEG-PLA-Taxol Genexol-PM Phase III Poly(ethylene glycol) Paclitaxel [51]
Polyglutamate-camptothecin CT-2106 Phase I/II Poly-L-glutamic acid (PGA) Camptothecin [52]
Polyglutamate-paclitaxel CT-2103, Xyotax™, Phase III Poly-L-glutamic acid (PGA) Paclitaxel [53]
OPAXIO™
 S. Prakash et al. / Advanced Drug Delivery Reviews 63 (2011) 1340–1351
by the RES when administering nanoparticles via a systemic route of
administration.
2.1.2. Long circulating polymeric nanohybrids
Hydrophilic polymers with neutral charge like polyethylene glycol
(PEG) or polyethylene oxide (PEO) have been extensively used for
surface modification to increase the systemic retention and circulation
time of nanovectors [96]. Incorporation of PEG imparts a stealth
characteristic to the polymers, reducing the hydrophobic interactions
with the RES. The hydrophilicity is attributed to the hydrogen bonding
of water molecules with the ether oxygen of PEG, creating a hydrating
shell around the nanovector [97]. This further increases the hydrody-
namic size of the polymeric nanovector, decreasing its clearance via the
RES [98,99]. The molecular weight and molar ratio of PEG used impart a
steric character to the nanovector. A recent review on PEG conjugates
with drugs for anti-cancer therapy is described elsewhere [100]. PEO has
been used to modify a Poly(3-caprolactone) (PCL) nanovector to deliver
therapeutic agents, such as paclitaxel. The modification resulted in the
prolonged circulation of the nanovector to 25 h and exhibited a greater
accumulation in the tumor region, as compared to the administration of
free drug [101]. Other hydrophilic polymers used for surface modifica-
tion include polyvinyl alcohol, polyacryl amide, polyvinyl pyrrolidone,
polysorbate-80, and block co-polymers such as poloxomer (Pluronicw)
and poloxamine (Tetronicw) [102–104].
2.2. Synthesis of polymeric nanohybrid materials
Synthetic polymers are developed by two processes; dispersion
polymerization (DP) and emulsion polymerization (EP). In the
process of DP, chains of monomer are formed in an aqueous
continuous phase with the help of an initiator, and precipitate in an
insoluble phase, where stabilization occurs with a polymeric
stabilizer. If the initiator generates ions in inducing the polymeriza-
tion process from a monomer, the mechanism is termed “ionic
polymerization”, which can result in the formation of cationic or
anionic polymers. If a radical is involved in nucleating the monomer,
the mechanism is termed “radical polymerization.” Another method
of synthesis is the EP process wherein the monomer is emulsified in a
Fig. 1. Schematic of tumor targeting by nanohybrids via Enhanced Permeation and Retention (EPR) effect.
1343
nonsolvent-containing surfactant, leading to the formation of mono-
mer-swollen micelles and stabilized monomer droplets. Similar to DP,
the polymerization is performed in the presence of an initiator,
generating radicals or ions, nucleating the monomeric units to initiate
the polymerization process. This process can be performed either in
organic or aqueous media as the continuous phase [105]. The
following sections elaborate on some of the nanohybrid materials
developed using the above two (EP or DP) methods of synthesis.
2.2.1. PACA nanohybrids
The synthesis of Poly(alkyl cyanoacrylate) (PACA) nanoparticles
involves EP in the continuous organic phase and results in the
formation of nanocapsules (shell-like structure, encapsulating a liquid
cavity) [106]. In this case, the drug is dissolved in an aqueous phase
such as iso-octane, cyclohexane–chloroform, isopropyl myristate–
butanol, and hexane, along with surfactants, resulting in a
microemulsion with water-swollen micelles containing the drug. On
the other hand, EP in an aqueous continuous phase is used for the
polymerization of monomers like alkylcyanoacrylates but involves
low quantities of surfactants. It is only used to stabilize the newly
formed polymer particles. Poly(ethyl cyanoacrylate) (PEC) and poly
(isobutyl cyanoacrylate) (PIBC) nanospheres containing metaclopra-
mide have been prepared using this technique. However, it does not
facilitate efficient drug loading as much as the former method. The use
of stabilizers/emulsifiers has a significant role in controlling the size of
the polymer particles. It has been observed that high concentrations of
poloxamer 188, i.e. N2%, reduced the particle size of poly(isobutyl
cyanoacrylate) (PIBC) nanoparticles from around 200 nm to 31–
56 nm [107]. Poly(butyl cyanoacrylate) (PBCA) nanovectors of n-
butyl cyanoacrylate containing methotrexate were prepared by DP
and EP methods using dextran and polaxamer 188 as stabilizers
respectively [108]. Nanovectors prepared by DP showed a higher zeta
potential and a higher rate of drug release when compared to those
prepared by EP. The contrast in the drug release profile is attributed to
the channelizing effect of dextran as a stabilizer.
Drug loading to PACA nanoparticles is primarily performed during
the polymerization process or by absorption onto preformed particles.
In the former case, this can lead to the covalent coupling of the drug to
1344 S. Prakash et al. / Advanced Drug Delivery Reviews 63 (2011) 1340–1351
the polymer. The type of drug loading determines the carrier capacity,
i.e. the percentage of the drug associated with a given amount of
nanoparticles, when compared to the initial concentration of the drug
[109,110] Some examples of drugs adsorbed on the surface of PACA
nanoparticles are betaxololchlorhydrate, [111] hematoporphyrin
[112] and primaquine [113], and the ones that were covalently
bound during the synthesis process are doxorubicin [114] and
actinomycin D. It has been observed that doxorubicin-loaded poly
(alkyl cyanoacrylate) (PACA) nanovectors can overcome multidrug-
resistance-1-type efflux pumps expressed by tumor cells [115].
The drug release kinetics greatly depends on the degradation rate
of the polymer and the type of drug binding to the polymer [109,116].
The interaction between PACA-doxorubicin conjugates occurs via
lipophilic, oligomeric units of PACAs that encapsulate the amphiphilic
doxorubicin during the polymerization process. This conjugation is
driven by hydrogen bonds formed between the N and H functions of
doxorubicin and the cyano groups of alkylcyanoacrylate. The collective
force of dipole–charge interaction, H-bonds, and hydrophobic forces
leads to the cohesion of the drug–polymer conjugate. Another drug
that integrates while in the polymerization process is 5-fluorouracil
(5-FU) [117]. However, it may interfere with the initiation process of
the polymerization, as the amino groups of 5-FU form zwitterions at an
acidic pH of 2–3. Another concept of targeting tumor cells was
developed in which a copolymer poly[aminopoly(ethylene glycol)
cyanoacrylate-co-hexadecyl cyanoacrylate] [poly(H2NPEGCA-co-
HDCA)] was synthesized via nanoprecipitation and conjugated to
folic acid via the amino terminal groups on PEG [118].
2.2.2. PLGA/PLA nanohybrids
Polylactides (PLA) and poly (D,L-lactide-coglycolide) (PLGA) have
been extensively investigated for drug delivery applications because of
their biodegradability via hydrolytic cleavage of the ester linkage
[119,120], because of their biocompatibility and the already present FDA
approval for use in humans as resorbable sutures, bone implants and
screws, contraceptive implants [121,122], as scaffolds in tissue engi-
neering and as graft materials [123–125]. PLGA/PLA hybrid nanovectors
have been utilized for the delivery of anti-cancer agents and other
therapeutic agents [119]. Paclitaxel-loaded PLGA nanovectors conjugat-
ed to transferrin were administered to animal models of prostate
carcinoma via intratumoral injection. An enhanced cellular uptake was
observed by these targeted nanoparticles, resulting in complete tumor
Fig. 2. Schematic of multifunctional polymeric nanohybrid devices for targeted drug delivery.
regression and higher survival rates in the treated animals [126]. It was
observed that the IC50 for paclitaxel with transferrin conjugated
nanovector particles was 5 fold lower than that obtained with
unconjugated nanovectors. Another study demonstrated the enhanced
intracellular delivery of PLGA nanovectors, surface-coated with cationic
di-block copolymer, poly(L-lysine)–poly(ethylene glycol)–folate
(PLL–PEG–FOL) in KB cells, overexpressing folate receptors [127]. In
another similar study, paclitaxel-loaded PLGA nanoparticles were
conjugated to wheat germ agglutinin (WGA) and demonstrated a
greater anti-proliferation activity in A549 and H1299 cells due to a
targeted receptor-mediated endocytosis [128]. Another therapeutic
agent encapsulated in PLGA nanovectors was cystatin which inhibits
tumor-associated activity of intracellular cysteine protease cathepsins B
and L. The cystatin-loaded PLGA nanovector formulation exhibited a
160-fold greater cytotoxic effect in MCF-10A neoT cells than the free
drug [129]. The anticancer agent doxorubicin has been delivered via
PLGA nanovectors by a chemical conjugation through an ester linkage to
PLGA polymer, and showed a sustained drug release over a month, an
increased drug uptake in the HepG2 cell line and exhibited a slightly
lower IC50 value compared to that of free doxorubicin [130].
A recent study reported lipid–polymer nanohybrids, comprising
PLGA as a hydrophobic polymeric core encapsulating the hydrophobic
drug docetaxel (Dtxl). This polymer–drug assembly was encapsulated
in a lipid layer of lecithin, which was further covalently conjugated to
1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-PEG as a
hydrophilic polymer [131]. The lipid–polymer nanohybrids yielded
high drug loading and sustained drug release profiles. Another similar
study demonstrated a paclitaxel carrying lipid–polymer nanohybrid
conjugated to anti-carcinoma embryonic antigen (CEA) half antibody
to target pancreatic cancer [132].
2.2.3. Polymeric nano micelles
Polymeric micelles are another class of nanovectors and have
gained much attention for encapsulating and delivering hydrophobic
drugs. The driving forces of polymeric chains to form micelles are the
hydrophobic, electrostatic, π–π and hydrogen bonding interactions.
Polymeric micelles composed of poly(ethylene oxide–aspartate)
block copolymer conjugated to an anti cancer drug, doxorubicin,
exhibited a sustained systemic circulation [133], reduced uptake by
the RES and a higher accumulation in a tumor bearing mouse model of
Colon-26 [134]. Polymeric micelles have also been employed in active
 S. Prakash et al. / Advanced Drug Delivery Reviews 63 (2011) 1340–1351
Fig. 3. Functionalization of carbon nanotubes via 1,3-dipolar cycloadditions. The 1,3-
dipolar cycloaddition of azomethine ylides on CNT is generated by in-situ thermal
condensation of aldehydes and α-amino acids. Azomethine ylides are very reactive
intermediates and attack efficiently the p-system of the CNT causing large number of
pyrrolidine rings fused to the CNT side wall, which helps in solubilisation of CNTs [135].
targeting applications, wherein the polymeric micelles were prepared
from thermo- [135,136] or pH-sensitive [137] block co-polymers. An
example of a polymeric micelle with pH sensitive solubility properties
was synthesized by conjugating 4,40-trimethylenedipiperidine with
1,4-butanediol diacrylate to form a biodegradable, hydrophobic poly
(b-amino ester) (PBAE) polymer. The nanovectors prepared from this
polymer were loaded with paclitaxel (150–200 nm) and were
modified with Pluronic F-108 (poloxamer 407), a triblock copolymer
of polyethylene oxide/polypropylene oxide/polyethylene oxide
(PEO/PPO/PEO). The PPO attached to the hydrophobic surface of the
nanovectors, and the hydrophilic PEO contributed to the stealth
properties of the polymeric nanovectors.
The pH-sensitive nature of the PBAE nanovectors has been tested
at various pH conditions ranging from 5.0 to 7.4 and was found to
degrade at a pH below 6.5, thereby releasing their contents on
encountering the acidic tumor microenvironment and in the endo-
somes and lysosomes of the cells following internalization; a
condition ideal in anti-cancer drug delivery. The in vitro studies
with PEO–PBAE nanovectors loaded with paclitaxel were performed
on human breast adenocarcinoma cells (MDAMB231) [138,139]. The
surface modification using a triblock copolymer (PEO/PPO/PEO)
enhanced the half life of the nanovectors with a residence circulation
time of 21 h compared to 10 min for the unmodified nanovectors. It
also improved the drug concentration from 5.2 to 23 fold in solid
tumors, monitored 5 h post-administration [140]. Polymeric micelles,
like Pluronics composed of ethylene oxide and propylene oxide have
been shown to overcome MDR but may, however induce complement
activation [141].
Another example of biodegradable polymeric nanovectors is Poly
(3-caprolactone) (PCL), used to encapsulate hydrophobic drugs like
tamoxifen. The nanovectors were synthesized via solvent displace-
ment by utilizing an acetone–water system, facilitating the instant
adsorption of PPO–PEO groups when the organic solution of the
polymer is introduced into aqueous solution in the presence of a
stabilizer, Pluronic [142]. These nanovectors were taken up by the
MCF-7 estrogen receptor-positive breast cancer cells and MDA-
MB231 human breast adenocarcinoma cells within 30 min of
incubation [143]. In another similar study, PEO-modified PCL
Fig. 4. Synthetic scheme of SWNT-PEG graft copolymers. The carboxylic acid functionalized Single Walled Carbon Nanotubes (SWNT–COOH) react with oxalyl chloride to form the
acyl chloride intermediate, which is further reacted with PEG to form SWNT–PEG [131].
1345
nanovectors were used to deliver ceramide with paclitaxel, in
combination to overcome MDR, especially in cases of breast and
ovarian cancers. The co-treatment resulted in enhanced cell death
when compared to the drugs alone and exhibited a 100-fold increase
in chemosensitivity and overcoming of MDR via combination therapy.
3. Carbon nanotubes as new drug delivery carriers for use in
cancer therapy
Carbon nanotubes (CNTs) are synthetic nanomaterials made from
carbon and belong to the family of fullerene. Structurally, carbon
nanotubes can be pictured as rolled sheets of graphene rings built
from sp 2 hybridized carbon atoms into hollow tubes. There are two
categories of carbon nanotubes, single-walled carbon nanotubes
(SWNTs) and multi-walled carbon nanotubes (MWNTs). SWNTs
contain one layer of graphene sheet with a diameter of 1–2 nm with a
length ranging from 50 to several hundred nanometers, whereas
MWNTs are co-axially arranged multiple layers of SWNTs, positioned
within one another with a diameter ranging from 5 to 100 nm [144].
There are various techniques to produce CNTs. The three main
techniques are 1) electric arc discharge [145], 2) laser ablation [146]
and 3) chemical vapor deposition [147]. These methods involve
synthesis at high temperature, pressure and the use of reaction
catalysts, leading to fine structures of CNTs along with some synthesis
induced impurities like graphitic debris and catalytic particles.
Various methods such as oxidation, acid treatment, chromatography,
filtration and functionalization are involved for purification [148]. A
recent review on CNTs and their applications describes various other
processing and purification techniques [149]. Compared to other
nanomaterials, carbon nanotubes have an ultrahigh surface area ratio
and distinct optical properties, such as, high absorption in the near-
infrared (NIR) range and a strong Raman shift, which make them
advantageous for biomedical applications linked to detection and
imaging [150]. CNTs are hydrophobic in nature and thus insoluble in
water, which limits their application in biomedical and medicinal
chemistry. Therefore, various functionalization methods like adsorp-
tion, electrostatic interaction and covalent bonding are being utilized
with a number of compounds and polymers to render a hydrophilic
character to CNTs so as to avoid their aggregation and to facilitate
their use in biomedical applications. Recent developments with CNTs
span the areas of gene therapy, drug delivery, thermotherapy, imaging
and anticancer treatments, as explained in further sections.
3.1. Functionalization of carbon nanotubes for drug delivery and other
applications
The functionalization of carbon nanotubes for biomedical applica-
tions involves covalent or non-covalent modifications. Covalent
modifications are carried out by reacting carbon atoms on the
sidewall of carbon nanotubes to a therapeutic molecule. In biological
applications, oxidation and grafting polymers on the sidewalls of
carbon nanotubes are widely adopted. In the process of oxidation, the
raw (pristine) carbon nanotubes are refluxed in nitric acid, which
results in open tubes and the tips that bear oxygenated functions,
mainly carboxyl acids [151,152]. Another important covalent
1346 S. Prakash et al. / Advanced Drug Delivery Reviews 63 (2011) 1340–1351
modification of carbon nanotubes involves 1,3-dipolar cycloaddition
reactions [153]. Using this method, azomethineylides are added on
the graphitic surface of CNTs, forming pyrrolidine-fused rings, Fig. 3.
These covalent modifications lead to the generation of various
functional moieties on the ends and side wall of CNTs and enable
the conjugation of various fluorescent dyes, drugs, peptides etc.
[154,155].
A detailed review on attaching various compounds and drugs
covalently to CNTs, following the two above mentioned methods have
been described elsewhere [156]. To further improve the solubility of
carbon nanotubes, other biocompatible polymers like polyethylene
glycol (PEG) can be grafted that enhance the solubility of the
nanotubes [157] and has recently been shown to overcome the
problem of multidrug resistance [158]. The grafting of a biocompatible
polymer can be achieved via an acyl chloride intermediate, which
reacts with the hydrophilic polymer PEG to form SWNT-PEG graft
copolymers, Fig. 4. The SWNT-PEG hybrid has been tested for neuron
growth [159,160] and drug delivery [161]. Apart from covalent
modifications, non-covalent functionalization of CNTs has also been
explored with different materials, including surfactants, natural
polymers, synthetic polyelectrolytes and amphiphilic block polymers
or polymeric micelles. Among them, functionalization of carbon with
some amphiphilic polymers provides good serum stability and has
been utilized in many biomedical applications. The hydrophobic
moiety binds to the carbon nanotube sidewalls via π–π interactions
which, in turn, help the CNTs to disperse in aqueous solution. A recent
study demonstrated the non-covalent pyrene conjugation of glyco-
dendrimers via π–π stacking on the sidewalls of CNTs, enhancing their
water solubility [162]. Amphiphilic polymer phospholipid linked PEG
(PL-PEG) was used to non-covalently bind to the sidewall of SWNTs,
which gives rise to a large number of biomedical applications ranging
from gene, peptide, drug delivery and biodistribution studies as well
as biological sensing and imaging [163].
3.2. Applications of carbon nanotubes in cancer therapy
3.2.1. Small hydrophobic cancer drug delivery system
The administration of chemotherapeutic agents often poses a
limitation of solubility and cell-penetration ability. In addition, the
systemic toxicity caused by a lack of selective drug targeting to cancer
cells, limits the clinical applications. The development of an effective
drug delivery system becomes an active area of research. As a new and
Fig. 5. Alginate-poly-L-lysine-alginate (APA) microcapsules encapsulating carbon nanotubes. The calcium ions are responsible for cross-linking of the alginate monomeric units,
trapping the carbon nanotubes into the core of microcapsule.
emerging nanomaterial, the use of CNTs as drug delivery carriers has
brought great attention in recent years. Several small molecules of
anticancer drug were carried to tumor cells by functionalized carbon
nanotubes. Doxorubicin (DOX) is a chemotherapeutic agent and has
been used for the treatment of many human cancers. DOX has been
loaded to branched PL-PEG functionalized SWNTs by π–π stacking to
the sidewall of carbon nanotubes [164]. In this study, the loading ratio
of DOX was evaluated as 2.5 grams per gram of SWNTs. In vivo studies
with an injection of the SWNT formulated DOX in a mouse model of
breast cancer showed significant, enhanced therapeutic efficacy and a
marked reduction in toxicity compared with free DOX and DOXIL. The
same group conducted another study using paclitaxel loaded onto
SWNTs by conjugating the drug to the amino group of the branched
phospholipid-PEG chains via cleavable ester linkages, hydrolysed in
the cellular environment [165]. This resulted in a water soluble
compound: SWNT-PEG–paclitaxel. The obtained SWNT–PTX conju-
gate displayed higher efficacy in suppressing tumor growth than did
clinical Taxol in a murine 4T1 breast cancer model [166]. Furthermore,
the SWNT–PTX showed prolonged blood stability and decreased
toxicity. A similar scheme was developed for the conjugation of the
antitumor prodrug cisplatin to PL-PEG-SWNT [167]. The platinum(IV)
complex, c,c,t-[Pt(NH3)2Cl2(OEt)(O2CCH2CH2CO2H)], was conjugated
to the amino end group of PL-PEG on the carbon nanotubes through
peptide linkages. It was observed that the SWNTs were taken up by
the testicular cancer cells by endocytosis, and the pH drop in the
compartment facilitated the drug release. As well, the SWNT
formulated platinum(IV) complex showed much less toxicity when
compared with the free drug treatment. The targeted delivery of
anticancer agents like cisplatin has also been accomplished using
SWNTs in conjugation with either quantum dots (QDs) or targeting
ligand epidermal growth factor (EGF) to target squamous cancer cells.
The QD luminescence facilitates the tracking of the SWNT formulation
and the conjugation of EGF proves that the formulation was readily
taken up due to the presence of EGF receptors on squamous
carcinoma cells [168]. SWNTs have also been explored to deliver
small interfering RNAs (siRNAs) via non-covalent interactions [169]. A
recent study involved cationic SWNTs and their capability to form
stable complexes with siRNAs with the goal to silence the expression
of telomerase reverse transcriptase (TERT) and inhibit cell prolifer-
ation both in vitro and in vivo in tumor models [170].
The covalent functionalization of CNTs with methotrexate (MTX)
was achieved via a 1,3-dipolar cycloaddition approach. In this study, a
 S. Prakash et al. / Advanced Drug Delivery Reviews 63 (2011) 1340–1351
methodology was developed for the introduction of two linking sites
on the sidewalls of carbon nanotubes for the fluorescent agents FITC
and MTX respectively [44]. The conjugation of MTX to carbon
nanotubes enhanced its cellular internalization. However, the drug
release profiles and their in vitro and in vivo efficacy were not
evaluated. Antitumor agent 10-hydroxycamptothecin (HCPT) was
delivered by a covalently modified MWNT [171]. Diaminotriethylene
glycol was used as a spacer linking the carboxylic groups on the
oxidized nanotube to drug molecules via amidation. The MWNT
formulated HCPT showed an improved antitumor activity both in vitro
and in vivo compared with the clinical HCPT formulation and the
MWNT–HCPT conjugates have a longer blood circulation and a higher
drug accumulation at the tumor site.
3.2.2. Microencapsulated carbon nanotube delivery devices for cancer
therapy
Our research focuses on microencapsulating carbon nanotubes using
biocompatible polymeric membranes, such as alginate-poly-L-lysine-
alginate (APA) for target specific delivery [172]. The purpose of
microencapsulation is to protect the payload from the harsh external
environments while allowing the specific solutes to pass through the
polymeric membrane. It enables the optimum delivery of bioactive
molecules through controlled, sustained and prolonged release of the
therapeutics at the targeted site. The CNT encapsulation was achieved
by mixing a suspension of functionalized SWNTs with a sodium alginate
solution, which was then gelled as beads formed by a microencapsulator
in a calcium chloride solution. The beads were subsequently coated with
a sterile solution of poly-L-lysine which was followed by a sodium
alginate coating, giving rise to SWNT-APA microcapsules, Fig. 5. Our
preliminary studies evaluated the distribution of SWNTs inside the
polymeric core. Based on the optimization and characterization data
obtained with the microencapsulated SWNT formulation, we are
currently focussing on targeting the therapeutic to desired gastrointes-
tinal sites of rodents as a treatment for colon cancer. In a preliminary in
vitro study performed by our group on a colon cancer cell line, SWNTs
were conjugated to pEGFP in order to optimize transfection with
minimal cellular toxicity [173].
3.2.3. Selective tumor destruction via Near-Infrared radiation of carbon
nanotubes
It is known that SWNTs have a very strong optical absorbance in
the NIR (800–2000 nm). This intrinsic property of SWNT has been
exploited for the optical stimulation of nanotubes inside the living
cells, since biological systems remain unharmed and are transparent
to NIR radiation. The photoluminescent property of CNTs in the NIR
region was first discovered in 2002 [171]. This property of CNTs
established a unique sensitive and selective imaging and detection of
biological samples and an application in laser heating cancer therapy,
both in vitro and in vivo. In account of this, a formulation based on
FA-PL-PEG functionalized SWNTs was used for targeting cancer cells,
which over-express folate receptors. Selective cancer cell destruction
was achieved by continuous NIR radiation of SWNTs. The NIR-
triggered cell death has been shown to remain nontoxic for
neighboring normal cells [172]. This research presented a novel
application of carbon nanotubes in cancer therapy. Another study
utilizing the NIR characteristic of CNTs involved the destruction of
breast cancer cells by non-covalently attaching monoclonal antibodies
against membrane markers: insulin like growth factor 1 receptor
(IGF1R) and human endothelial receptor 2 (HER2). The antibodies
were attached using π–π interactions of the pyrene rings onto the side
walls of SWNTs [173].
3.2.4. In vivo toxicity of carbon nanotubes
Nanohybrid materials made of drug–carbon nanotube conjugants
as a potential biotherapeutic candidate for drug delivery would only
be a success if it can provide maximum bioavailability while having
1347
minimum toxicity. As for the concern of the intrinsic toxicity of CNTs,
it has been proposed that CNTs covalently functionalized with phenyl-
SO3H or phenyl (COOH)2 groups pose less toxicity to cells than raw
CNTs stabilized with surfactants, such as, Pluronic F108 [174]. A
detailed account of toxicological studies performed with CNTs has
been well reviewed elsewhere [175]. Functionalized SWNTs have
been used as drug carriers with paclitaxel [161,165]. Paclitaxel, being
insoluble in water, is currently clinically administered as a highly toxic
formulation with Cremophor EL. However, using SWNTs as a carrier
allowed for a prolonged circulation of the drug and a 10-fold higher
uptake by tumor cells [165]. The high uptake of SWNT complexes by
the RES may endanger the liver and spleen, as they may suffer toxic
effects from SWNT deposition and accumulation. One of the main
problems encountered with intravenous administrations is the rapid
clearance through the blood and another is the toxic effects to other
organs and tissues. Another study tested the toxicity of intravenously
administered functionalized SWNTs in mice and demonstrated no
evidence of toxicity [176]. PEG-SWNTs were shown to be gradually
removed from the body following an intravenous administration in
mouse models with no evidence of toxicity during the excretory
process [177].
In many cases, the functionalization of nanotubes is detrimental
for their serum stability and toxicity. SWNTs were made soluble in
physiological solution by first suspending them in Polysorbate-80 and
experiments were performed to investigate their solubility and
toxicity [178]. A low-level of toxicity was observed with high dosages
of SWNT-Polysorbate-80 formulation via intravenous administration.
The dose accumulation was observed in the liver and the lungs [179].
In order to understand the toxic impact of the systemic delivery of
carbon nanotubes in greater detail, additional studies using a variety
of animal models over a longer time frame need to be performed.
However, one way of decreasing the toxicity and the side-effects of
carbon nanotube based drug delivery would be to have targeted
delivery. Zhuang et al. exemplified this idea by conjugating PEGylated
SWNTs to the RGD peptide that specifically binds to integrin αvβ3,
expressed on the surface of numerous tumor cells. The formulation
consisted of RGD-bound SWNTs, which were intravenously injected
into U87MG tumor bearing mice. The RGD-bound SWNTs showed a
higher tumor uptake as compared to SWNTs alone [179].
4. Conclusions: toward future perspective, benefits and concerns
Biomedical applications of nanotechnology have shown a clear
edge over conventional methods. It promises effective treatment in a
cost-effective way, wherein the diseases will be combated with
maximum therapeutic effect and minimum intervention. It will lead
to a decrease in both the time and money invested into developing
new medicines where modeling, targeting and safety assessment of
the drug require a large amount of resources. The use of particles of
the scale of biomolecules will lead to a better interaction and
monitoring of cells, intercellular interactions and intracellular
pathways, thus providing us with an important tool for targeted
drug delivery, in vivo imaging, in vitro diagnostics and regenerative
medicine. It opens an opportunity for “personalized medicine”
through which a therapy/medicine could be suggested according to
the molecular characteristics of the patient.
Current research attempts to fuse all of the desired characteristics
of nanomedicine into one particle, which would perform targeted
drug delivery and monitoring of the induced repair. As with any new
technology, there are concerns over the application of nanomedicine,
stemming from the lack of proper knowledge and the need for the
establishment of regulatory measures. The primary concern with
medical nanodevices is their potential toxicity. For example, the
exposure of human keratinocytes to insoluble SWNTs was associated
with oxidative stress and apoptosis. Further alarming is the fact that
nanoparticles are extremely stable in the body and have been
1348 S. Prakash et al. / Advanced Drug Delivery Reviews 63 (2011) 1340–1351
designed so as to protect them from the immune system. Further-
more, no information is currently available as to how and when they
are excreted. Minimal excretion of nanoparticles could potentially be
harmful due to overdosing. Another concern of nanoparticles is that
they are active and have a large surface area capable of interacting
with unintended sites if not tagged properly with targeting molecules.
Additionally, they are of a size range similar to that of proteins and can
thus interfere with normal and cancerous cell signaling pathways.
Thus, care has to be taken to implement this technology in a way as to
avoid environmental, socio-economic and toxic side-effects. It should
be seen that new regulatory mechanisms are in place prior to the
avalanche of data that is forthcoming.
The efficacy of nanomedicine needs to be analyzed on the basis of
pharmacogenetics due to known population variability in drug
sensitivity. There is a possibility of “varying” specific and non-specific
interactions due to nanoparticle contact based on cell and tissue type.
Currently, there are no established methodologies or model system(s)
to study such intricacies to rule out the possibility of any hazardous
effects of nanoparticles delivered in vivo. In this scenario, vital
questions need to be addressed further: how do these nanomaterials
interact with other types of drugs, foods and secondary metabolites of
a tissue/organ, will there be any induction or interference mediated
by these nanomaterials, and do they influence macromolecular
interactions happening in a cell in response to different signals? An
emphasis on metabolism, degradation, clearance and bioaccumula-
tion of nanomaterials, especially CNTs remains to be addressed.
Moreover, the pharmacokinetic behavior, the production reproduc-
ibility of CNT formulations and their size distribution need to be
validated both in vitro and in vivo before their use is implemented. For
example, proper disposal and use of CNT formulations need to be
determined to prevent environmental and health effects. A multi
dimensional investigation is needed to rule out all of the possible
short-term and long-term toxicological effects.
Efforts to ensure the safety of nanomaterials require manufac-
turers to fully assess how the “nanosizing” of drugs affects dissolution
rate, solubility and therapeutic action. Safety has to be given higher
priority for the in vivo use of nanoparticles, particularly those in the
size of b50 nm, which can enter cells via adsorptive endocytosis.
Validated assays are mandatory for detecting and quantifying
nanoparticles in tissues and medical products. Additional standard
test methods may be needed to ensure the appropriate formulation of
nanoparticles for drugs and biologics. However, a major challenge is
to find a reliable and affordable method of connecting the steering
(delivery) system to the payload (drug). Having described both
nanoparticles and CNTs, each of these should be efficiently used and
functionalized based on the desired applications. The characteristics,
both physical and biochemical, of each delivery system should be
considered in the design and drug functionalization processes.
Furthermore, current preclinical studies focus on a number of
different animal models, including tumor-induced and genetically
encoded cancers. This makes it difficult to compare and contrast the
efficiency of each delivery system and drug combination. In addition,
the route of administration, the targeted site, the stage of the cancer
and the physiological stability of the formulation are all aspects that
need to be addressed to conclude on the efficacy of any developed
therapeutic. For this analysis, established clinical trial methods would
need to be employed.
There are still several questions that remain unanswered concerning
the fate of these nanomaterials in vivo and their long term effects on
gene expression, interaction/interference with the normal physiology,
dose effect and drug–drug interactions. These properties have to be
validated in addition to the conventional methods of ADMETox. The
answers may start coming from the clinical research and trials in cancer
and infectious diseases, provided that the drug manufacturers can
resolve technical challenges, unwanted cellular/immunological reac-
tions, in vivo stability and limitations in delivery. Industrial scale-up of
nanotechnologies is required for future clinical studies. Efficient studies,
using preclinical and clinical studies, as those highlighted in Table 2,
must continue to ensure efficiency and safety of any developed
formulation. One also must consider that drug delivery systems are
inherently limited by the payload they deliver. Anti-cancer drug
research must progress to allow any delivery system formulation,
nanoparticles or CNT, to be effective in the future.
Acknowledgments
The authors would like to acknowledge Canadian Institute of
Health Research (CIHR) grant to Dr. S. Prakash, the support of McGill
Majors scholarship to Meenakshi Malhotra, McGill Provost's Graduate
Fellowship to Wei Shao, Industrial Innovation Scholarship (IIS) BMP
Innovation-NSERC, FQRNT and Micropharma Limited Scholarship to
Catherine Tomaro-Duchesneau and McGill Internal scholarship to
Sana Abbasi. We also acknowledge Dr. V.R. Swamy for assistance with
Fig. 2.
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