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Fullerene Based Materials for Drug Delivery 325
(i) They are stable up to a temperature of 1000 °C. An increased amount of C
and C70are generated at 1000 °C with increased pulse duration [10].
(ii) They can react with nucleophiles. Moreover, rather than electron enriched
aromatic systems possessing extreme conjugation, they behave as electron
impaired alkenes [11].
(iii) They are good lubricants due to their spherical shape.
−1
(iv) They possess low density (1.65 g cc
) than diamond (3.51 g cc−1).
(v) They can undergo different kinds of reactions viz., radical, nucleophilic,
transition metal complex, regioselective as well as oxidation, reduction,
hydrogenation, halogenation, etc. [12].
(vi) In aqueous media C
is insoluble and easily aggregate [13]. Fluorinated
60
derivatives are more soluble while some bromo derivatives are not [8].
In biomedical field, 3-dimensionality, hydrophobicity, length, and electronic
configurations of the molecule yield it as an interesting agent. The typical shape
(cage), development of different synthetic derivatives, builds fullerene a potential
therapeutic agent. Solubility of fullerenes in chloroform, toluene, and benzene is
sufficiently high due to their hydrophobic nature [14], whereas in polar solvents
difficult solubility has created a major issue for medicinal applications. Thus, several
protocols were designed to improve fullerene aqueous solubility via increased
hydrophilicity through modification of fullerene and hence to improve its efficacy in
biomedical applications, specifically for delivery of drugs.
(i) Dispersion of fullerene in aqueous media though improve the hydrophobicity,
but the challenge is in the choice of a dispersant, due to the toxicity of the
dispersants towards organisms. Used as a potential dispersant for C
fullerenes
60
in water tetrahydrofuran (Thf) showed toxicity effect on living organisms [15,
16]. Henry et al. [17] assessed the toxic effectof metabolites of Thf on zebra fish
during the dispersion of C
. Similarly, the gallic acid-stabilized C70(aqueous
60
colloidal suspensions) were found to reduce the fecundity in Daphnia magna
significantly [18]. Fullerenes found to transfer to aqueous phase from an organic
solvent like toluene or benzene [19]. Fullerene dispersal (aqueous) mechanism
could be demonstrated in two ways: (a) hydrogen bonding and charge transfer
and (b) ultrasound treated covalent bond formation in fullerene cage between
hydroxyl groups and carbons [20, 21].
(ii) Chemical modification by carboxylic acids, amino acids, polyhydroxy groups
and amphiphilic polymers increases fullerenes hydrophilicity in biological
systems [22, 23].
(iii) Encapsulation of fullerenes in cyclodextrins, calixarenes, polyvinylpyrroli-
done, micelles and liposomes [9] is another route to facilitate biopharmaceutical applications such as drug delivery. Interestingly fullerenes with lipid
membranes have led to some unique results. Gul and Ileri-Ercan [24] described
the peroxidized lipid membranes-fullerene interactions indicating toxicity.
The extent of peroxidation along with saturation of lipid acyl chains govern
the distribution of fullerenes inside the bilayer. Complete diffusion in Janus
fullerenes though not occurred in micro timescale fullerenes transport through
60
326 M. Sarkar and D. Santra
bilayers was achieved at nano timescale. The clusters of fullerene crumble
entering within the bilayers.
This excellent chemical appearance of fullerene in biological media creates great
interest in biomedical applications involving antiviral, antimicrobial, antioxidant,
anti-HIV activity, along with efficiency in radiation protection, X-ray contrast agent
for magnetic resonance imaging (MRI), photodynamic therapy,nucleic acid and drug
delivery [12]. Various biomedical applications of fullerene are presented in Fig. 11.2.
Derivatization of fullerene is recommended for its use as sustainable drug release
carrier. Due to the characteristic features (all carbon surfaces, presence of double
bonds, electron deficient nature etc.) addition reactions are common for fullerenes.
Fig. 11.2 Biomedical
applications of fullerene
Fullerene Based Materials for Drug Delivery 327
Easy modification of the outer sphere of the carbon cage prompts derivatives formation involving different functional groups [25], following polyaddition of free radicals, nucleophilic attack, Prato reaction [26] and cycloaddition reactions such as
Diels–Alder reactions [27] across the C = C in fullerene cage. The derivatives of
fullerene, depending on the attached functionality, show solubility enhancement in
organic or in aqueous media. Sustained release of drugs covalently attached via a
linker to fullerene derivatives were monitored in lung cancer and compared to the
native drug was found to be more effective [26, 28]. Components in the isomeric
products mixtures, yielded due to addition of more than one groups to the fullerene,
can be separated by chromatography.
2 Types of Fullerene Derivatives
2.1 Exohedral Fullerene Derivatives
Exohedral fullerene, also called functionalized fullerene, is the most versatile and
important type of fullerene and is generally derived from fullerenes interaction with
different functional moieties. Fullerene possesses two types of bonds, one is 1.398(1)
Å long at 6,6 junctions between two hexagons, and the other is 1.455(6) Å long
at 5,6 junctions between pentagons and hexagons [29]. Fullerenes are commonly
involved in simple electron-deficient polyolefin’s addition reactions (cyclo, nucleophilic radical), reduction, halogenations reactions, hydrometallation reactions. Most
of the reactants attack at the 6,6 junctions, forming open or ring (3-, 4-, 5-,
6-membered) structured fullerene [13, 30, 31].
Fullerenes are functionalized mainly by four reactions. First two reactions are
the popular Prato and Bingel reactions [32, 33]. The functionalized fullerenes are
produced easily in one pot process and they show excellent water solubilities. The
others two reactions viz. amination and hydroxylation havemajor drawbackin respect
to uncontrolled attachment of functional groups to the cage of fullerene. Fullerene
functionalization through 1,3-dipolar cycloaddition is a popular choice due to its electron deficient nature. However, open structure adducts of fullerene can be developed
via hydrogenation or nucleophile addition (1,2 and 1,4) followed by an electrophile
or acid quenching [13]. Nucleophiles such as Grignard reagents [34], organolithiumderivatives [34, 35], cyanide ion [36] etc. are successfully employed. Fulleroids
and methanofullerenes, the two different three-member ring structures were yielded
by diazomethane cycloaddition (1,3-dipolar) to fullerene [37]. Three membered rings
on 6,6 junctions of fullerene (methanofullerenes) were obtained by electrochemical reaction or addition of nucleophiles, diazirines, carbenes, and sulfonium ylides
without formation of fulleroids [29]. Interestingly, derivatives like fulleroids and
aza-fulleroids are obtained from reaction of fullerene with substituted diazomethane
and organic azide respectively [13]. Typically, [2 + 2] cycloaddition reaction gives
four-membered ring fullerenes i.e., cyclobutanofullerene derivatives by addition of
328 M. Sarkar and D. Santra
benzyne followed by addition of alkenes or alkynes [38, 39]. Five membered ring
fullerenes are generally prepared by [3 + 2] cycloadditions, which involve pyrrolidines [32], pyrazolines [40], isoxazolines [41], furans [42], and cyclopentane derivatives [43]. Addition of azomethine ylide to fullerene cage [32] produces high yield,
stable pyrrolidino fullerene. The reactiveintermediate, ylide, was in situ generated via
α-amino acid- ketone/aldehyde condensation, and decarboxylation [44]. 1,3-dipolar
cycloaddition via Diels–Alder reaction is highly selective and derivatives of different
geometric shapes built at 6,6 ring junctions of fullerene. Cardona et al. showed that
product formed at 6,6 junction of fullerene is kinetically favored while that at 6,5
junction of fullerene is thermodynamically favored [45]. The [4 + 2] cycloaddition
to fullerene produces six-membered rings fused to 6,6 junctions [39, 46, 47]. Moreover, different dipoles, e.g., nitriles, imines, nitrile oxides, ylides (nitrile, carbonyl,
thiocarbonyl), and isonitriles [48] react with fullerene.
Methanofullerenes are synthesized efficiently by Bingel reaction [33], using stabilized carbanions for nucleophilic cyclopropanation of fullerene [49]. Fullerene was
treated in presence of a base, with 2-bromomalonic ester in the classical version. In
1993, Bingel first reported the nucleophilic cyclopropylation of fullerene at room
temperature employing 2-diethyl bromomalonate, ω-bromoacetophenone, methyl
2-chloroacetoacetate, and desyl chloride using 1,8-diazabicyclo [5.4.0] undec-7-ene
(DBU), potassium tert-butylate, or NaH [33]. Hirsch modified the Bingel reaction
through one-pot synthesis using some suitable substrate (e.g., malonate), CBr
4/I2
and the base DBU. All fullerene functionalization adducts formation occurs at [6,
6]-junction of fullerene. Biglova and Mustafin [49] discussed in details about Bingel-
Hirsch reaction. Further, development, regiochemistry and reactivity of different
supramolecular fullerene adducts are highlighted in current literatures [50–52].
Chiang et al. [53] synthesized fullerols, as the first polyhydroxylated fullerene
derivatives (PHFs, fullerenols and fullerols), and hydrated fullerols, with high yield
by taking a mixture of C
optimum temperature of 85–115°C. Li et al. [54] synthesized C
fullerene and aqueous NaOH employing some catalyst (e.g., tetrabutylammo-
C
60
and C70fullerene sulfuric and nitric acid mixture at
60
fullerol using
60
nium hydroxide TBAH), at ambient temperature under aerobic conditions. In the
absence of oxygen a very slow addition of hydroxyl group to fullerene occurred. A
water-insoluble mass having hydroxyl groups (<10 per C
) was yielded conducting
60
the same reaction under argon. This indicated that oxygen influences the reaction.
The greater number of hydroxyl groups induced more water solubility due to the
presence of greater number of hydrogen bond donors. One-pot direct synthesis of
fullerenols was proposed by Arrais and Diana [55] and the products were differentiated by an extensive hydroxylation. Wudl et al., [37] first employed direct fullerene
amination reaction employing aliphatic amines (n-propylamine, tert-butylamine, ndodecylamine, morpholine). Aliphatic amines (primary and secondary) are attached
repetitively and quickly to C
fullerene yielding several molecules having different
60
structures and isomers. However, characterization of the products mixture was diffi-
cult. Kampe et al. [56] described an easy protocol using N,N
-dimethyl ethylenediamine or piperazine (secondary diamine) for synthesis of distinct amine addition
products. Amination of C
with ethylenediamine yielded water-soluble derivatives
60
)
Fullerene Based Materials for Drug Delivery 329
[37]. The radical ion-pairs formation occurred when C60fullerene was mixed with
aliphatic amine. Detailed mechanism of amination reaction was discussed by Miller
[57]. The amination of fullerene can generate different adducts (diamino, tetraamino
oxide, and pyrrolidine) of different well-defined aminated fullerene structures, with
excellent yield.
2.2 Endohedral Fullerene Derivatives
Endohedral fullerenes, also known as endofullerenes, result when some atoms, ions
or molecules are trapped inside the cavity of a fullerene. Chai et al. [58]firstintroduced endohedral fullerenes with notation of M@C
(M) species, and more complex example denoted as K
one C by B in the geodesic network of C
fullerene cage. Further, one K was trapped
60
inside and another two K were adhered the outside. Endohedral and metallofullerenes
having metals, bearing electroactive, radioactive and magnetic properties, are potentially important, as building blocks, in biomedical fields and nanomaterial sciences.
In bioimaging and drug therapy they also serve as active agents and deliver metal
ions or atoms [59]. Functionalization of endohedral fullerenes, due to insolubility
in common solvents, is tough. Endohedral metallofullerenes (EMFs) and nonmetaldoped fullerenes, varying the moiety inside the cage, are the examples of two different
types of endohedral complexes. Endohedral fullerene synthesis is very tedious and
lack efficiency, with only 1% yield. ‘Molecular surgery’, a newly developed strategy,
has been introduced to accommodate a guest within the sphere of fullerene [60]. The
process initiates with opening of a ring, generally tempted by radical-oxidation or
cycloaddition reactions, specifically to create a ‘hole’ or ‘orifice’ in the sphere and
subsequently to insert ‘S’, the suitable radicals/species including metals. Fullerene
cage reconstitution following encapsulation is accomplished at high temperatures.
Krachmalnicoff et al., [61] followed opening and closing of ring through ‘molec-
ular surgery’ approach, yielding H
and H2O@C60with 60–78% incorporation
2@C60
of single hydrogen and water molecule respectively in C
[62] confirmed the presence of yttrium atom in Y@C
employing synchrotron X-ray powder diffraction analysis. The yttrium atom was
tightly bound to the carbon cage subsequently via displacement from the center of
the C
molecule. Several methods have been proposed for synthesis of endohe-
82
dral fullerene [21]. Mostly, EMFs are prepared through LASER ablation, employing
a composite disk containing graphite and metal oxide located in a furnace at high
temperature (1200°C) [63]. Irradiation of LASER (532 nm) onto the composite under
inert gas flow yielded empty fullerenes and EMFs [64]. However, this process is very
expensiveandwith low yield. The contact arc technique was, however, found effective
for large production of EMFs [65]. An overview on the potential medical applications of different fullerenes is reported by Thakral and Thakral [66]. There are reports
on fullerenes containing radioactive isotopes such as
containing Group IV [67] and Group V elements [68]; EMFs containing Sc, Ca, Y,
, i ndicating C60caged metal
60
(K@C59B), by substituting
2
. Takata and coworkers
60
within the carbon cage by
82
24
34m
Na,
Cl,69Ge; fullerenes
330 M. Sarkar and D. Santra
La, Sr,and Ba; EMFs containing actinides [69, 70]; EMFs containing lanthanides (Ce
to Lu) [71]. Stevenson et al., [72] first synthesized a stable trimetallic nitride encapsulated endohedral fullerene, Er
under low N
atmosphere. Dunsch et al. [73] demonstrated synthesis of different vari-
2
eties of nitride cluster fullerenes viz. Sc
1,2,3), Tb
N@C80,Ho3N@C80and Y3N@C80, with 90% selectivity. Examples of
3
N@C80(x = 0–3), in an electric-arc reactor
xSc3-x
N@C80,Sc3N@C78,Sc
3
3−xErx
N@C80(x =
large band-gap endohedrals are generally nitride cluster fullerenes Due to their high
stability the M
N@C80structures are the right choice for biomedical applications.
3
2.2.1 Magnetic Resonance Imaging Contrast Agents (MRI-CA)
Some metallofullerenes may serve in tumor therapy diagnostic depending upon the
characteristics and contents of metal and the fullerene cage. Currently, gadolinium
(Gd) is used as an MRI contrast agent. However, toxic and/or undesired metals
3+
released from chelates is of serious concerns. Several chelates of Gd
are
employed in good number in MRI scans [26]. Further, confinement of Gd within
carbon cage prevent its release and lessens the toxicity aspect with consequent
changes of hydrophobic cage to potent hydrophilic components through exohedral
functionalization and improves the reactivity [74].
Gd@C
(OH)xand Gd@C60[C(COOH)2]10, the water-soluble endohedral gado-
60
fullerene derivatives [75], were developed, characterized and used as MRI contrast
agent. These two compounds showed proton relaxivity. At high magnetic fields of
−1S−1
30–60 MHz proton relaxivity of 10.4 mM
−1S−1
38.5 mM
for Gd@C60(OH)xwas observed at 299 K. Moreover, the pH depen-
for Gd@C60[C(COOH)2]10and
dent proton relaxivities makes them suitable as pH-dependent MRI contrast agent.
Laus et al. [76] further studied the relaxivity of gadofullerenes by addition of salt in
1
aqueous solution through
H NMRD (nuclear magnetic relaxation dispersion/DLS
(dynamic light scattering) study.
N@C80, an example of trimetallic nitride EMFs (Trimetasphere), cluster
In Gd
3
N is encapsulated inside a C80carbon cage. The advantages of these EMFs,
of Gd
3
compared to small Gd
minimal toxic effects. Murphy et al. [77] evaluated the potential of Gd
3+
chelates, include high proton relaxivity, together with
N@C80as
3
positive contrast agent for imaging (in vitro) and tracking (in vivo) in amniotic fluidderived stem cells within human lung tissue. Functionalization of Gd
N@C80by
3
poly(ethylene glycol) (PEG) units, and hydroxylation of the carbon cage enhanced
water solubility as well as biodistribution [78]. The product was investigated as MRI
contrast agent. The distribution of the produced derivative for agarose gel infusions (in vitro and in vivo) in rat brain was followed. The study indicated that
functionalized EMFs are infused directly into a tumor-bearing brain providing a
3+
better tumor description in contrast to the conventional Gd
inserted. Zhang et al. [79] prepared egg-shaped structured Gd
chelate, intravenously
N@Cs-C84, bearing a
3
fused pentagon, as a lower-symmetry EMF. They are considered to serve as excellent
3+
candidate for MRI contrast agent with preventing Gd
vironment. Li et al. [80] prepared Gd@C
(O)10(OH)16nanoparticles having a high
82
ion release into the bioen-
Fullerene Based Materials for Drug Delivery 331
effective magnetic moment (μ
to μ
(6.4μB) of Gd@C82the higher μ
eff
;8.98μB) using solid–liquid reaction. Compared
eff
of Gd@C82(O)10(OH)16, was due to
eff
functionalization on the carbon cage with highest occupied π-states of carbon. The
resulted in vitro and in vivo MRI improvement indicates it a strong candidate for
MRI contrast agent.
(OH)yand Gd@C82Ox(OH)y(x = 0, 3; y = 8, 16, 24, 36, 44) complexes
C
82Ox
were synthesized by Shakirova et al. [81] for use for biomedical application. The reac-
tivityof endohedral Gd@C
(OH)ywas evaluated from χ, the absolute electroneg-
82Ox
ativity and ω, the chemical electrophilicity indices. The presence of Gd (guest atom)
was indicated to enhance the reactivity of endohedral complexes with some reactive
oxygen species. The theoretical along with experimental investigations proposed
suitability of Gd@C
(OH)24for various MRI biomedical applications. Zhao
82Ox
et al. [82] developed a more effective and safe MRI contrast agent viz. GF-OH
for the early diagnosis of hepatocellular carcinoma. Xiao et al. [83]usedsomeGd
nanoparticle MRI probe, characterized by XPS, to detect chronic post-traumatic
osteomyelitis in mouse tibia. The probe was found to bind to LPS (lipopolysaccharides) stimulated macrophages. Moreover, in the infected tibia the metallofullerene significantly describe the hyper-intense MRI signal. Li et al. [84] synthe-
sized Gd
EMF, bearing NH
(IL-13-Gd
N@C80(OH)x(NH2)y, a functionalized trimetallic nitride template (TNT)
3
N@C80O12(OH)10(NH2)7(NO2)2the hydrophilic nanoparticle showed a
3
+
, on the surface of cage. On conjugation with IL-13-amino-I,
3
higher targeting of U-251GBM cell lines. Moreover, compared to a carboxyl-surface
functionalized nanoparticle, the positively charged (amino)-I nanoparticle showed
boosted attraction for glioblastoma cellular endocytosis on the surface of EMF. Li
et al. [85] showed an enhanced relaxivity of GO-Gd@C
(graphene oxide nanosheets
82
modified with Gd-EMF derivatives. Relaxivity can be enhanced by physicochemical properties and due to structure of the carbon nanohybrids. The enhanced proton
relaxation was thought to be due to electron transfer between GO nano sheet and the
Gd@C
.
82
2.2.2 Radiopharmaceuticals
EMF can find application also in radioimmunotherapy. Metallofullerenes can show
radionuclide’scarbon-cage captivity but not through detachment of isotopes from the
chelate. Radioisotopic EMFs can be produced by different methods viz., (i) neutron
activation of metallofullerenes, (ii) ion implantation, (iii) implosion of nuclear recoil
and (iv) direct arc synthesis using radioisotope doped graphite rods.
In metallofullerene radioimmunotherapy, Bolskar [26] employed radioactive
166
Ho@C82, derived from non-radioactive
165
Ho@C82, via neutron activation. The
water solubilization of the radio EMF through surface polyhydroxylation, was investigated in mice for its biodistribution by radiochemical methods [26]. Diener et al.
212
[86], reported
Pb@C60synthesis by recoil of water solubilized
acids. In β-decay of
212
Pb to
212
Bi the stability of the radio metallofullerene was
212
Pb@C60malonic
investigated. In mice the preliminary biodistribution study was conducted with the
332 M. Sarkar and D. Santra
untargetedwater-soluble radio metallofullerenes. Contrary to polyhydroxylated radio
212
fullerenes and conventional polyaminocarboxylate chelators
Pb from
malonic acids, administered as an EMF, was not found in bone, indicating that
212
Pb@C
212
Pb,
in the fullerene, was held more strongly than in other methods. This suggested a
212
significant role of fullerenes in
sized β-emitting TNT endohedral
was successfully encapsulated into the EMF
177
fullerene cage
Further,
177
Lu is not readily removed for at least one-half-life period (6.7 days).
LuxLu
N@C80, conjugated with an interleukin-13 peptide, form radio
3−x
Pb targeted delivery. Shultz et al. [87] synthe-
117
Lu EMFs for nuclear medicine agents.
177
LuxLu
N@C80(x = 1 − 3). In this
3−x
177
Lu
EMF, a potent agent for brain cancer.
225
Mwakisege et al. [88] synthesized
having half-life (t
of “preformed” C
of α-emitter
) of 10 days using an electrical arc discharge between a thin coat
1/2
on an Al disk (C60thickness of ∼0.25 mgcm−2) and a source
60
225
Ac (∼1 mCi, electroplated on a Pt disk). The malonic esters were
added to the surface of the radio fullerenes for stabilization of
225
repeated washing, the
Ac activity retained in the organic phase was found to be
Ac@C60the endohedral fullerenes of
225
Ac@C60.After
around 45%. Its extraction in the aqueous phase was resisted, proving that
225
225
Ac,
Ac was
located inside the fullerene. Chromatographic analysis (TLC and HPLC) indicated
225
that endohedral encapsulation of
225
structural stability of
Ac@C60malonate.
Ac within the C60cage was due to improved
2.3 Surface Derivatized Fullerenes
60
Surface-derivatizedfullerene- drug nanomaterial builds with functionalized fullerene
without external covalent attachment of drug molecules/agents or non-covalent
association and shows biological activity. The characteristic size, electronegativity,
reactivity, photochemistry, etc. of fullerenes promote such biological action.
Fullerene derivativesfind potential biomedical applications and are used as antioxidants [89]. Due to their promptly react with free radicals and efficiently scav-
1
enge the ROS targeting the antioxidants. Oxidative stress induced ROS viz.,
HO•, and O
ation, other disease states and cell death. C
malonate C
are implicated in inflammation, ischemia/reperfusion, neurodegener-
2
[C(COOH)2]3, the water-soluble tris-
60
derivative, having C3symmetry, was studied in vivo for its antioxidant
60
O2,,
activity showing neuroprotective and life-extending effects. Moreover, in mutant
rats, with model ALS (amyotrophic lateral sclerosis), life-extending effects were
observed. The superoxide destruction was through catalytic action and not stoichiometric. Carboxylated fullerene, when administered to animals bearing Parkinsonism and other neurodegenerative disorders, exhibited neuroprotective properties
in cell cultures. The antioxidant property evaluation study was extended with different
fullerene derivatives (polyalkylsulfonated, dendrimer-functionalized, malonate and
fullerols). Dendrimer-functionalized C
derivatives, particularly attached with a
60
single dendrimeric group, have been suggested as antioxidants. The potential of
such derivative in live zebrafish embryos, as a radioprotector,was evaluated, showing
Fullerene Based Materials for Drug Delivery 333
protection against ionizing radiation damage (overall and organ specific), similar to
that of a clinically approved drug amifostine. However, an enhanced action was
observed for administered dendrimer-functionalized C
immediately after or before
60
the exposure of radiation. A modest radiation protection in live mice, tumor cells
versus normal cells (free from selective radiation protection) was reported. The free
radical scavenging ability of water-soluble hexasulfobutylated C
derivatives was
60
studied in relation to composition, intermolecular aggregation characteristics considering position of the functional groups. The biological, including antioxidant behaviors of fullerols (C
(OH)x) were demonstrated through some binding interaction
60
blocking the glutamate receptors. Fullerols, due to their radical scavenging ability,
induced acute toxicity lowering of anthracycline DNA-intercalating anticancer drug,
viz,. chemotherapeutic doxorubicin. C
(OH)x, in model mice (live) having tumor
60
(T-cells and macrophages), were indicated to have tumor inhibitory effects through
immuno-stimulation [90]. Several fullerenes produce
1
O2and O
•–
through photo-
2
chemical mechanism (Type I and Type II respectively) that designate them as potential photosensitizing agents for PDT [91]. In vitro studies with C
(cationic pyrro-
60
lidinium) derivatives confirmed their ability in destroying cancer and other types
of cells. Effectiveness of fullerene derivatives induced photochemical ROS production for inactivation (photodynamic) of viruses (influenza, enveloped,HIV protease),
along with antimicrobial potential was also indicated.
3 Interaction of Fullerene Derivatives for Drug Delivery
3.1 Fullerene Derivatives with Non-Covalent Drugs
Interactions
Derivativesof fullerene for the applications in deliveryof drug can be grounded on the
drug’s non-covalent interaction, targeting of substrate, and a protein to the surface of
fullerene derivatives. Fullerene and its derivatives form non-covalent intermolecular
complexes with electron-rich molecules including porphyrins and polyaromatics,
through electrostatic, pi-pi, hydrophobic and van der Waals interactions, along with
hydrogen bonding [26]. Antiviral activity of non-covalent intermolecular complexes
was first time reported by Friedman et al. [92]. The study involved building of
model and simple physico- chemical analysis to assess fullerene C
interaction with HIVP, i.e., the HIV-1 protease active site. The model study indicated that fullerene C
derivatives, due to matched chemical and steric features with
60
the active site, acted as the HIVP inhibitor. A qualitative analysis of hydrophobic
surface transfer in model complexes also corroborated the findings. Diamino C
“second-generation” fullerene C
derivative, was found to form salt bridges with
60
the nonpolar HIVP surface through van der Waals interaction using catalytic aspartic
acids. Fullerene fits well within the protease cavity and the approach of substrates to
enter the enzyme catalytic site was prevented.
derivatives
60
,a
60
334 M. Sarkar and D. Santra
Samanta and Das [93] estimated the noncovalent interactions of optimized structures of C
lomustine) complexes having gas phase adsorption energy of > 6 kcal mol
evaluated from DFT calculation. These C
– chemotherapeutic drug (temozolomide, procarbazine, carmustine, and
60
–chemotherapeutic drug derivatives were
60
−1
,as
found to possess blood brain barriers (BBB) crossing ability. It wasassessed that drug
interaction with C
occurred through π e−s of conjugated (full or partial) rings of
60
temozolomide and procarbazine as well as π-π stacking of parallelly aligned rings (5
or 6 membered) of C
of carmustine and lomustine with C
. The noncovalent interaction (dipole induced dipole coupling)
60
was occurred. The density of states (DOS)
60
spectra revealed that in the composite systems the HOMO–LUMO gaps after the
drug adsorption remained less or similar to that of the pure C
systems the electrical conductivity was found similar to the pristine C
the enhanced polarities of the C
composite systems assisted them to act as probable
60
In the C60composite
60.
. However,
60
vehicles in biological systems for the delivery of drug. The binding characteristics
for non-covalent conjugation of fullerene C
nanocage with three anticancer antibi-
60
otics viz. Epirubicin, Doxorubicin, and Mitomycin was investigated through DFT
calculations [94]. In aqueous as well as in protein core environment the stability and
reactivity studies of the fullerene-C
ated. C
indicating fullerene (C
moiety was found to perturb the features of drug molecular chemistry least,
60
) complexes as potent carriers for anticancer antibiotics
60
complexes, after drug adsorption was evalu-
60
delivery to the target cells. Yamada et al. [95] synthesized a novel series of fullerenearene complexesand evaluated the strength and nature of face-to-face fullerene-arene
noncovalent interactions. The number of arene rings, electronic dipole moments,
anionic charges contributions and polarizabilities for the interactions were experimentally quantified by analyzing the folding equilibrium of the molecular torsion
balances.
3.2 Fullerene Derivatives with Covalently Attached Drugs
Moieties
Zakharian et al. [96] designed a slow-release drug-delivery system viz., C60paclitaxel conjugate (Fig. 11.3) that was applied as a liposome formulation in tissue
culture for potential anticancer activity. The synthesized conjugate was found to be
stable in the solid state, in aqueous media (10% DMSO) and aprotic organic solvents
at physiological pH. The conjugate, incubated at 37 °C with bovine plasma, revealed
paclitaxel release at 80 min half-life of hydrolysis. Dilauroylphosphatidycholine
(DLPC) with C
with human A594 epithelial lung cancer cells to study the antitumor activity. The
(mean) value (drug concentration needed to inhibit a given biological process
IC
50
to half of the maximum) for C
-paclitaxel- liposomes conjugates were synthesized and interacted
60
-paclitaxel-DLPC and paclitaxel-DLPC were found
60