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Fullerene Based Materials for Drug Delivery 335
to be 410 and 253 nM, r espectively. The paclitaxel concentration, delivered by C60paclitaxel-DLPC small-particle aerosol to lungs, was enough for potential therapeutic against lung cancer. Zacchigna et al. [97] developed conjugates of warfarin
(anticoagulant) to a series of fullerene derivatives via covalent linkage and succinic
acid as a tether. The stabilityat different pH simulating biological fluids of different
conjugates were tested (in vitro study) for mouse plasma and esterases. When incubated at pH 1.2, the fullerene derivatives were found in the stomach up to 6 h. The
fullerene-warfarin conjugates showed a very good stability at different pH releasing
less than 2% of the warfarin whereas more than 45% of covalently linked warfarin
was released from the multifullerene-warfarin conjugates, within 24 h. Thus, polyfunctional molecules acted as good substrate for the plasma enzymatic complex with
potential of free and active drugs delivery in a prolonged manner. Rybkin et al. [98]
designed two water-soluble hybrids derivatives PAF-FD and PCF-FD using fluorescein (FD), covalently linked to polycationic (PAF) or polyanionic (PCF) fullerene-
respectively. Such derivativesshowed effective photodynamic activity in biolog-
C
60
ical media. A comparison of efficacy of O
−
•
produced by the above two hybrids
2
derivatives was made. In PAF-FD, negatively charged FD and PAF were found to be
spaced apart due to electrostatic repulsion. As a result, PAF-FD exhibited, compared
to PCF-FD, a much lesser fluorescence quenching along with photochemical activity.
The nature of the dye and the charged groups on the fullerene derivative played the
major role in the deactivationprocesses both for non-covalently linked and covalently
linked fullerene–dye derivatives.The findings may be utilized to design fullerene C
conjugates with singlet excited dyes, to be acted as photosensitizers in photodynamic
therapy.
60
Fig. 11.3 Fullerene conjugation with a drug using a linker (C60-paclitaxel). (Adapted with
permission from ACS [96]
336 M. Sarkar and D. Santra
4 Fullerene Based Materials for Drug Delivery
Various types of drug delivery by fullerene based materials are represented in
Fig. 11.4.
4.1 Nucleic Acid Delivery
Deliveryof nucleic acids and other biomolecules directly into cells via cell membrane
is of great importance. Transportation of molecule into the intact cell nucleus through
nuclear, endosomal and cell membrane barriers is a major challenge [9]. Fullerene
and its functionalized derivatives, bearing nanoparticle size range of ~ 1 nm, impart
biological activity and are found effective for biomedical applications. Gene delivery
is the popular approach to transport RNA, DNA, LNA, siRNA, and plasmid DNA, to
specific locations of the cells [99]. Fullerene functionalized with hydrophilic cationic/
anionic species have improved water solubility and form complexes with calf thymus
DNA for desired DNA transfer into living cells. The fullerene-DNA aggregates
morphology in the Green Fluorescent Protein (GFP) expressing cells showedthat the
complex is taken up by cells through phagocytosis [100]. Fullerene based transfection reagent is unique to effect sustained protein expression for a prolonged period,
Fig. 11.4 Fullerene based materials for drug delivery
Fullerene Based Materials for Drug Delivery 337
indicating that plasmid DNA with fullerene complex is stable inside phagosomes.
Wang et al. [101] employed cationic macromolecules for efficient and controllable
siRNA delivery due to their non-immunological behavior and low cost compared to
viral carriers. C
-Dex-NH2), the photosensitive amphiphilic carrier, was designed,
60
as specific amphiphilic skeleton which forms aggregate structures like micelle in
water. The carrier could restrain siRNA from abolishing by ROS. C
-Dex-NH2,on
60
exposure to visible light, triggered controllable generation of ROS that destroyed
the lysosome membrane, promoting lysosomal escape and enhancing in vitro and
in vivo gene silencing efficiency (GSE) of siRNA. In the MDA-MB-231-EGFP cells
the GSE reached a maximum of 53% and 69% in the 4T1-GFP-Luc2 tumor-bearing
mice. A series of fullerene derivatives, bearing amino acid side chains that bind
s to a plasmid vector DNA, were evaluated for their transfection capability and
DNA-binding capacity [102–104]. Chemical and biological studies of Isobe et al.
indicated endocytosis assisted cellular uptake of fullerene/DNA and endosomes internalized DNA protection by the fullerene against enzymatic digestion. The success of
the process was dependent on the toughness of the fullerene/DNA complex. Moreover, DNA-binding studies showed that amino group in fullerene derivatives, would
interact favorably to double-stranded DNA. The fullerene derivatives need to fulfill
certain characteristic structural features to act as effective transfection reagent
s. First,
it must form nanometer or sub micrometer sized aggregates for endocytosis assisted
internalization into mammalian cells. Next, during the movement into the cytoplasm
it must release DNA. Two different pathways may be proposed for this: by losing
amino groups or by converting amino groups to neutral amides from the fullerene
core of the molecule. Isobe et al. [104] identified, a tetrapiperidino fullerene, as more
efficientthan a commonly used lipid-based transfection reagent. Xu et al. [105] chem-
ically synthesized fullerene nano spherical miRNA(C
@SiO2-miR27b), that may
60
deliver miR27b into resistant cancer cells. After escaping from lysosomes, miR27b
was released into cytoplasm. Under the light (365 nm) irradiation and in combination with paclitaxel (drug), it exhibited a strong cell killing effect, induced apoptosis effect, suppressed invasion and anti-cancer effect. The fullerene nano spherical
miRNA can further be applied as an adjuvant therapy agent for overcoming resistant breast cancer. Uritu et al. [106] reported some fullerene conjugates having effi-
cient binding ability with resulting cyto-friendly polyplexes. C
-PEG-PEI (fullerene
60
polyethylene-glycol-polyethyleneimine) polyplexes showed low toxicity and high
transfection efficiencyof nucleic acid, enhancing cell proliferation. DNA binding and
release tests (in vitro) were conducted in two steps. The overall polyplex behavior of
conjugates in salmon sperm dsDNA was verified from N:P (nitrogen to phosphorus)
ratios, in the first step. Next, in cultures of HEK 293 T cells (being able to replicate
SV40 or bearing plasmids), the transfection ability of conjugates, using pEYFP, a
plasmid carrying a reporter gene, was proved. The EYFP (enhanced yellow fluorescent protein) expression in HEK293T cells was estimated to assess the success of
transfection [106]. HEK 293Tis a derivative of the original HEK (human embryonic
kidney) 293 parent cell line. The number 293 indicates Graham’s habit of numbering
his experiments. Sitharaman et al. [107] prepared water-soluble derivatives, having
improved transfection efficiency. Hirsch-Bingel chemistry was applied to evaluate
338 M. Sarkar and D. Santra
in vitro gene-delivery vectors of different water-soluble C60transfecting agents. In
different physiological conditions the C
or charged (negatively, or positively). The capability of C
derivatives yielded were of either neutral
60
derivatives to transfect
60
cells grown in culture of GFP reporter gene carrying DNA was assessed. However,
for in vitro transfection only an octa-amino and a dodeca-amino derivatized, the
two C
exhibited dose-dependent increase in toxicity. Positively charged C
derivatives bearing positive charge, were found efficient. All C60derivatives
60
derivatives
60
were exhibited relatively high levels of cellular toxicity compared to the neutral and
negatively charged C
DNA uptake and gene expression from DNA employing C
a probability of building similar Gd@C
derivatives. The results demonstrated intracellular transport,
60
derivatives, suggesting
60
-based derivatives both as therapeutic and
60
diagnostic agents.
4.2 Peptide Delivery
Efficient intracellular drug delivery decreases nonspecific effects and toxicity, while
increases the effectiveness of drugs unable to r each the therapeutic target (in vivo).
In developing nucleic acid and peptide-based drugs the major drawbacks are their
resistance to enter the cell. An improvement of their pharmacological properties
can be achieved through therapeutic agents to cell penetrating peptides (CPPs)
conjugation. Virus proteins transduction domains derived CPPs were able to transport conjugated species to cell membrane via easy internalization into cells. The
delivery of any compounds via transportation across the nuclear or endosomal
membrane of a cell is a significant challenge [108]. Membrane translocation of
anionic occurs via improvement of CPP uptake through activation process mediated
by counter anions and thus anionic fullerenes find potential application in biological and medicinal fields. Yang et al. [108] investigated the use of “Bucky amino
acid” (Baa), the phenylalanine derived amino acid-fullerene derivative, for the cell
uptake properties of cationic peptides. The fullerene allows peptide sequence to
cross cell membrane, although peptide solubility (aqueous) reciprocated fullerene
transport. The hydrophobic fullerene, and the hydrophilic peptide sequence, may
produce a peptide with penetrating ability for an amphipathic cell. The development
of immunological tools and new anti-infective agents are main concern in biomedical application. Fullerene conjugated with peptides or amino acids was examined for
treatments of Alzheimer, cancer, mixed connective tissue disease, lupus etc. [109].
A potential example is the use of C
applications. The conjugation of peptides in sugars and fullerenes aided structural
diversity, flexibility, charge, and specific recognition properties [110].
-peptide bioconjugate or various biomedical
60
Fullerene Based Materials for Drug Delivery 339
4.3 Topical Drug Delivery
A unique spherical structure and strong apolar character of C60make it suitable
to develop lipid-like structures bearing potential to easily cross cell membranes.
Moreover, C
be multi-functionalized, to act as a drug absorbent [111]. In cosmetic applications,
particularly transdermal delivery, fullerene show huge potential due to their nano
nature, antioxidant property and interactions with epidermal keratinocytes [7]. Thus,
in dermatology the potential of fullerene C
is suggested. In vivo studies of animals and humans revealed no adverse skin reactions for single or repeated topical administration of fullerene. Moreover, in vivo
dermal patch studies of skins, having a history of various irritations and allergic
sensitivities, exhibited no signs of oedema and erythema [112]. Zhou et al. [113]
investigated efficacy of different C
after shaving) and in human (skin sections maintained in culture). The rate of hair
growth as well as the number of hair strands in bald mice and humans was shown
to be increased. Inflammatory skin disorders (alopecia areata, acne vulgaris, psoriasis, etc.) caused by photo damage and oxidative stress including carcinoma, are
the real challenges to tackle in dermatology. ROS-scavenging fullerene is a novel
therapeutic agent in restraining oxidativestress and inflammation and thus find applications in dermatology [112]. Experimental studies revealed cytoprotective ability
derivatives against cellular damage (UV- A & B induced) together with an
of C
60
anti-tanning effect [114, 115]. Thus, C
their anti-inflammatory, inhibitory, protective and stimulating properties [112, 116].
Gupta and Rai [117] reported the mechanism of skin lipid bilayer permeation of
pristine fullerene C
ular dynamics (CG MD) simulations. Different constrained CG MD simulations
were employed to estimate the permeability, diffusion coefficient and free energy of
permeation. Results showed that at low concentration, small clusters of fullerenes
formed in water phase spontaneously spread, through permeation, inside the bilayer.
At high concentration, aggregated fullerenes in the water layer, penetrated inside and
remained in the interior of the bilayer. Significant structural variations in the bilayer
were not induced by lower concentration of C
gurgitation in the bilayer was achieved. Therefore, aggregation, dispersion, and
C
60
optimum fullerene concentration estimated from the results may be applied in effective drug delivery and cosmetic application. Dispersion
in transcutol/isopropyl myristate is suitable for transdermal delivery. Martins et al.
[118] found that C
sion cells and these results were confirmed by transmission electron microscopy and
molecular dynamics simulations. So, transcutol/isopropyl myristate based formulations in absence of organic s olvents exhibited efficient delivery of C
applications and biopharmaceutical. Hadad et al. [119] demonstrated ibuprofen (IBP)
adsorbed (noncovalently) on fullerene C
as well as classical molecular dynamics. The geometry optimization procedures
can be considered as an attractive scaffold for drug delivery. It can
60
derivatives, as novel treatment agents,
60
on hair loss in mice (genetically hairless and
60
derivatives have shown potential use for
60
using coarse-grained (constrained and unconstrained) molec-
60
while at higher concentration of
60
sofC60fullerene molecules
was successfully permeated through pig skin in Franz diffu-
60
for cosmetics
60
for its transdermal delivery using DFT
60
340 M. Sarkar and D. Santra
revealed that IBP-fullerene assumed two different adsorption geometries (A and
B), having similar IR spectrum and binding energies corroborating the stability of
both structures at room temperature. DFT and classical molecular dynamics studies
confirmed two levelsadsorption. In the geometric configuration A, the IBP molecule
was in the internal layer while in the exterior layer in the other geometric configuration B. Raman spectra of A and B was found to be dominated by C
60
normal
modes.
4.4 Infectious Diseases Drug Delivery
Photodynamic therapy (PDT) is proved as a potential tool in alleviation of bacterial
and viral infections, as well as cancer [7]. It involves use of some photosensitizer
(PS), commonly a nontoxic but light-activated dye, and a light source to destroy
bacteria, microorganisms and abnormal cells. Activated PS produces ROS through
either type 1 or type 2 trail. The ROS are highly effective in killing fungi, virus and
bacteria as well as cancer cells [120]. However, poor water solubility of several PSs
puts some limitations on the use of PDT. Some fascinating characteristics viz., visible
light absorption combined with intersystem crossing yielding a triplet state (longlived) and hence producing ROS, makes fullerenes a potential candidate in PDT [21].
Moreover, easy functionalization of fullerene and effective in vivo administration of
the functionalized fullerenes to a site of infection are the added advantages. Subsequently increased generation of
more effective PS [120]. The virucidal activity of a water-soluble fullerene derivative, (fullerene conjugated with methoxy polyethylene glycol amine) was investigated for inactivation of vesicular stomatitis virus (VSV) under illumination [121].
The inactivation of VSV was found to be inhibited by
azide addition or oxygen removal. Tegos et al. [122] investigated the efficacy of six
different functionalized fullerenes, viz., three non-cationic (NCF1, NCF2, NCF3)
and three cationic (CF4, CF5, CF6), against both Staphylococcus aureus and E. coli.
The result revealed that CF4—CF6(having 1- 3 pyrrolidinium groups), on incubation for a short time and subsequent white light illumination developed antimicrobial
activity in killing cells (fungal and bacterial; > 99.99%) in a short period. Further,
with increasing cationic substitution the absorbance decreases, the fullerenes with
increased positive charge bind to cells and cross the microbial permeability barriers.
The antimicrobial photosensitizing ability of cationic fullerenes was found more
compared to that of toluidine blue O.
Cationic fullerene mediated PDT plays an important role to heal burns, skin,
wounds, and mucus membranes in localized infections. Mroz et al. [123] investigated
the efficacy of same series of functionalized fullerenes against Staphylococcus aureus
as well as E. coli. Except CF4, the cationic fullerenes gave dark toxicity at high
level but the di-serinol functionalized C
characteristic light dose-dependent loss in ability of colony formation. However, a
high concentration of 100 μM and high white-light fluences of 120 J cm
1
O2,O
•–
, and OH•make the specific fullerenes as
2
1
O2scavenger through sodium
, rather than dark toxicity exhibited some
60
−2
wasneeded
Fullerene Based Materials for Drug Delivery 341
to destroy Gram-positive S. aureus up to 99.9% (2–3 logs). The cationic fullerenes
at lower concentrations were considered to be strongly effective PS at significantly
lower light doses. Surprisingly, effectivity of CF4 - CF6 in killing (light-mediated)
of S. aureus and E. coli were indicated [120]. However, CF5 and CF6 required
−2
concentration of 1 μM and white light of 1 or 2 J cm
to destroy 4–5 logs of S.
aureus and 10 μM for E-coli (up to 6 logs).
Spesia et al. [124] synthesized dicationic fullerene, viz., N,N-dimethyl-2-
-N,N,N- trimethylamino phenyl) fulleropyrrolidinium iodide (DTC
(4
2+
) and
60
employed it for photodynamic inactivation (in vitro) of a typical Gram-negative
bacterium, E. coli. A ∼3.5 log decrease of cell survival with 99.97% of cellular
inactivation, applying 1 μM of sensitizer and irradiation period of 30 min, was
observed. The E. coli growth was inhibited in presence of cationic fullerene (2 μM)
and subsequent irradiation, whereas N-methyl-2-(4
-acetamidophenyl) fulleropyrrolidine (non-charged) exhibited some negligible effect. In vitro and in vivo studies of
anti-fungal PDT against fungal skin infectionviz., Candida albicans, in mammals,
using highly selective PSs lacking genotoxic and mutagenic activity was reported in
2005 [125]. Milanesio et al. [126] evaluated the photodynamic mechanism induced
2+
by DTC
eration of O
on E. coli and Candida albicans cells induced by DTC
60
•–
2
by DTC
2+
using nitro blue tetrazolium method in reverse micelles
60
in presence of NADH was detected. 10 μMofDTC
2+
wasaneffectivePSinC.
60
2+
. Photogen-
60
albican suspensions, producing a ∼5 log decrease of cell s urvival for cultures irradiated with visible light for 30 min. The cells growth of C. albicans was not detected
2+
in presence of 10 μMDTC
and irradiation.
60
4.5 Anticancer Drug Delivery
Cancer, the uncontrolled body cells proliferation can be linked with the presence
of toxic or chemical compounds, pathogens, ionizing radiation, and human genetics
[127]. Among the different drawbacks in cancer treatment non targeted delivery,
resistance and significant side-effects of the drugs are of critical concerns [7]. In an
aim to investigate the potential of fullerenes, as anti-cancer agent [128, 129], the
biological activities of a water-soluble cationic fullerene derivative, C
dimethyl pyrrolidinium i odide), on human promyeloleukaemia (HL-60) cells were
investigated [130]. The ROS generation by the pyrrolidinium fullerene derivative
was detected by DCFH-DA, a fluorescence probe. The α-tocopherol suppressed
cell death occurred through pre-treatment and intracellular oxidative stress via ROS,
produced by the pyrrolidinium fullerene derivative. A gene responsible mutant, JAK2
V617F, for human myelo proliferative neoplasms (MPNs), in the context of cellular
transformation and resistance to several anti-cancer drugs, was employed [131].
JAK2 indicates the Janus kinase2 (JAK2) and V617For Val617Phe is a mutant that
replaces (amino acid) valine, the protein building block, with the amino acid phenylalanine in the protein at position 617. It was shown that pyrrolidinium fullerene
derivative potently induced apoptosis cells transformed by JAK2 V617F mutant by
-bis(N,N-
60
342 M. Sarkar and D. Santra
inhibiting JNK (c-Jun N-terminal kinase) activation. The study clearly indicated
that the pyrrolidinium fullerene through modification with a suitable length of alkyl
group increased the apoptotic effect through inhibition of the ASK1-MKK4/7-JNK
pathway. Here, ASK1 indicates apoptosis signal-regulating kinase 1 and MKK4/7
represents mitogen-activated protein kinase 4 and 7. Thus, pyrrolidinium fullerene
endohedral fullerene derivatives may be recommended for use as a potent MPN
therapeutic drug.
Thakral and Thakral [66] performed in vitro studied using some water-soluble
fullerenes for cell growth protection from toxins induced apoptosis for RAW 264.7
(leukemic monocyte cell line), epithelial and hepatoma cells in mouse. Castro et al.
reviewed on the different biological aspects of parent and endohedral fullerene
derivatives [132]. In the tumor-bearing mice intraperitoneal injection of Gadolinium
endohedral metallofullerenol nanoparticles [Gd@C
(OH)22]nlowered enzymes
82
activities related with the ROS metabolism [133]. ESR signal of 2,2-diphenyl-1picryhydrazyl radical (DPPH), was also lowered in presence of[Gd@C
Such spin-trapping studies indicated effective scavenging of OH
[Gd@C
of [Gd@C
and Gd@C
(OH)22]n. The study (in vitro and in vivo) revealed antitumor activities
82
(OH)22]n. Further, it was reported that C60(C(COOH)2)2,C60(OH)22,
82
(OH)22could protect H2O2-induced cell oxidative damage, stabilized
82
•
,O
(OH)22]n.
82
•–
,1O2,by
2
the mitochondrial membrane potential and reduced intracellular ROS production
[134]. The derivatives, due to their cytoprotective abilities, inhibited lipid peroxida-
−
•
tion in vitro with scavenging of the stable DPPH radical, ROS, O
,1O2, and HO•.
2
Tokuyama et al. [135] first reported fullerenes mediated phototoxicity in malignant cells. The study consisted of development, biological activity and cytotoxicity of fullerene carboxylic acid together with cleaving ability for some DNA (Gselective) under irradiation with low energy visible light. The biological activity of
these fullerene derivatives was evaluated in a whole cell system. The cytotoxicity
(in vitro) against the HeLa S3 cell line was established through inhibition growth rate
study. Photoirradiation of water-soluble fullerene C
(10−5M) under visible light
60
was carried out using mercury lamp produced some phototoxicity in Ehrlich carcinoma cells and rat thymocytes [136]. Irradiated fullerene C
solution when added
60
to suspension of thymocytes and ascite cells, the number of vital cells was decreased
by 67% and 58% respectively. The water-soluble fullerene C
, via photoirradiation,
60
may be recommended for photodynamic therapy of cancer cells as ROS catalytic
system. The cytotoxic and photo cytotoxic effects of water-miscible functionalized
fullerenes, viz., dendritic
-C60mono-adduct and the malonic acid -C60tris-adduct
were evaluated on Jurkat cells [137]. On irradiation with UV-A or UV-B observed
death of Jurkat cells was due to UV dose-dependent membrane damage. However,
compared to the dendritic derivative,phototoxicity of tris-malonic acid fullerene was
observed. The nanomaterials C
and its derivatives gained fascinating attraction in
70
delivery of drug. Li and Zhao [138] studied adsorption of hydroxyurea (HU), an anticancer drug, on doped and pristine C
fullerene nanomaterial as potential carriers
70
for delivery of drug. Density functional theory (DFT) was applied to follow HU
interactions between hetero fullerene MC
(M = B, Si, Al) along with pristine C
69
considering energy of adsorption, configuration, charge density difference, Hirshfeld
70
Fullerene Based Materials for Drug Delivery 343
charge and frontier molecular orbitals. HU molecule was chemisorbed more on the
,SiC69, and AlC69, rather than pure C70, as evidenced by adsorption energy
BC
69
and charge transfer. Thus, hetero fullerene BC
,SiC69, and AlC69were capable for
69
the HU drug delivery. The structural feature of anticancer drug thiotepa (TP), TP
complexed with iron-doped fullerene (F) cage was investigated, using DFT calculations, to provide a more efficient method of medications [139]. Two configurations
viz., TPN@F and TPS@F corresponding to relaxed TP near the Fe atom through N
and S head, respectively were established. The calculated energy of TPN@F model
was more than that of TPS@F as indicated by the observed energies. The drug carrier
activityof boron fullerene FB
for NU (nitrosourea) was investigatedfollowing DFT
40
[140]. It was revealed that NU tends to be associated with the boron atom of B
fullerene cage via nitrogen and oxygen (adsorption energy -25.18 kcal mol−1) and
high loading capacity (up to five NU simultaneously adsorbed by fullerene B
Further, the effect of atoms (C, N, Al, Ga) substitution in B
nanocage for delivery
40
40
efficiency of drug was explored. The potential for 5-fluorouracil (5FU) delivery
by Li, Na and K (alkali metal; AM) decorated fullerenes C
, as anticancer drug,
60
was investigated [141]. The energy for adsorption of 5FU on such fullerene derivative, C
14.07 kcal mol
decorated with single Li, Na and K were evaluated as 19.33, 16.58, and
60
−1
respectively. Moreover, it was found that different number of
atoms (12 for Li and 6 for Na/K) can be attached simultaneously on the exterior
surface of the C
decorated fullerene, and interact with 5FU molecules. Effective-
60
ness of fullerene/polymer nanoparticles for tumor therapy was reviewed by Youn
et al. [142]. Fullerenes derivatized with several polymers, drugs, proteins, small
molecules, viz., α-Cyclodextrin-C
PEGylated C
acid (DMA)-C
-fluorouracil, C60-peptide, glycol chitosan (GC)-2,3-dimethyl maleic
60
, glycol chitosan (GC)-C60, and hyaluronated C60were investigated
60
-sugar hybrids, C60-PEI-folate/docetaxel,
60,C60
for tumor therapy. However, the toxicological issues need to be fully addressed for
their effectiveness in therapeutic use in the future.
40
).
4.6 Lung-Specific Drug Delivery
Huang et al. [143] synthesized twenty fullerene derivatives with different solubilizing addends and their cytotoxicity was evaluated for A549, H460, and H1299, the
non-small cell lung carcinoma (NSCLC) in lung cancer cells. QSAR models were
evaluated using experimental data. The fullerene-based derivatives bearing aromatic
rings (sulfur containing), aromatic bonds, and oxygen atoms were found to have
favored chemical features to produce inhibitory effects on cells (H460 and H1299)
through thiophene moiety. The observations were further supported by the regression
QSAR models. Berberine (Ber), noncovalently bound to a carbon nanostructure of
fullerene C
against Lewis lung carcinoma (LLC) using C57Bl in mice by Grebinyk et al. [144].
In vivo study,indicated release of Ber from C
LLC cells treatment with C
at several molar ratios (1:2, 1:1 and 2:1) of the components was explored
60
–Ber nanocomplexes in acid medium.
60
–Ber nanocomplexes as well as the cytotoxicity was
60
344 M. Sarkar and D. Santra
indicated by increased intracellular uptake of Ber in comparison to free Ber. In a
mouse having LLC the therapeutic potency of the nanocomplex 2:1 C
–Ber showed
60
50% growth suppression of tumor but nil for free Bar. Minami et al. [145] established
a lung-selective delivery system of siRNA by monitoring the size of tetra(piperazino)
fullerene epoxide (TPFE), a carrier vehicle, in blood vessels. In buffered solution
complexes (sub-micrometer size) formed between TPFE and siRNA were found
to agglutinate to micrometer-sized particles further, in the bloodstream with plasma
proteins. The agglutinate quickly clogged the lung capillaries, the siRNAwas entered
into lung cells, kept expression of target genes silent, and was quickly released from
the lung. Zhao et al. [146] prepared doxorubicin-C
acid (DOXO-C
revealed that DOXO-C
in NSCLC compared to DOXO-C
cytotoxicity at low dose of DOXO-C
-cRGD), for clinical application in lung cancer. In vitro results
82
-cRGD nanoparticles exhibited preferential cellular uptake
82
and DOXO. The cell viability showedsignificant
82
-cRGD to the cells.
82
-cyclic arginylglycylaspartic
82
4.7 Brain Drug Delivery
Deliveryof drug to the central nervous system (CNS) is a big challenge due to limited
penetration of the blood brain barrier (BBB), acting as endothelial tight junctions
(physical boundary) preventing the paracellular permeability [7]. In neuropsycho
pharmacology drug delivery systems required to be capable of transfer of polar
compounds across the BBB to the CNS. Piotrovskiy et al. [147] developed hexam-
ethonium complexes of fullerene C
penetration may antagonize central effects of high doses of nicotine. However,
fullerene C
-hexamethonium complexes were found to be more effective (40 times)
60
for polar drug delivery, because of boosted ability to interact with central nicotine
receptors, compared to the equimolar doses of hexamethonium. Hsieh et al. [148]
synthesized water-soluble derivatives of C
bonds between the fullerene cage and the solubilizing addend. Some fullerene derivativeshaving C–C and C–P linkages induce in vitro proliferation of NSC and recovered
the function of injured CNS in zebrafish. Some fullerene derivatives having C–C,
on the other hand, were found to significantly promote NSC proliferation and neural
repair resisting tumor growth. Derivatives of fullerene containing C–N linkage inhibited in vitro proliferation and growth formation of glioblastoma cell in zebrafish. The
fullerene derivatives with phenylalanine components showed some contrast effects of
significant glioblastoma growth inhibition without any neural repair retardation due
to metabolic changes of mitochondria. In vivostudies, further, revealed that the watersoluble fullerenes with ability to cross the BBB had the potential as antitumor agents
for treatment of brain tumor. Kumar et al. [149] employed Prato reaction to develop
a water-soluble CF-LYS-TEG-MMF, the C
fumarate nanoconjugates as a better drug delivery agent. The conjugate showed
increased cytotoxicity on neuroblastoma cells, and biocompatibility to erythrocytes.
The material showed pH- sensitive release pattern and a minimal leaching of drug at
. Hexamethonium, due to its restricted CNS
60
fullerene having C–C, C–S, C–P C–N
60
-fullerene lysine-based monomethyl
60