Introduction

1 A role of novel drug delivery system in various diseases
NOVEL DRUG DELIVERY SYSTEM
The method by which a drug is delivered can have a significant effect on its efficacy.
Some drugs have an optimum concentration range within which maximum benefit is
derived, and concentrations above or below this range can be toxic or produceno
therapeutic benefit at all. On he other hand, the very slow progress in the efficacy of
the treatment of severe diseases, has suggested a growing need for a multidisciplinary
approachto the delivery of therapeutics to targets in tissues. From this, new ideas on
controlling the pharmacokinetics, pharmacodynamics, non specific toxicity,
immunogenicity, biorecognition, and efficacy of drugs were generated. These new
strategies, often called drug delivery systems (DDS), are based on interdisciplinary
approaches that combine polymer science, pharmaceutics, bioconjugate chemistry, and
molecular biology.
To minimize drug degradation and loss, to prevent harmful side-effects and to increase
drug bioavailability and the fraction of the drug accumulated in the required zone,
various drug delivery and drug targeting systems are currently under development.
Among drug carriers one can name soluble polymers, microparticles made of insoluble
or biodegradable natural and synthetic polymers, microcapsules, cells, cell ghosts,
lipoproteins, liposomes, and micelles. The carriers can be made slowly degradable,
stimuli-reactive (e.g., pH- or temperature-sensitive), and even targeted (e.g., by
conjugating them with specific antibodies against certain characteristic components of
the area of interest). Targeting is the ability to direct the drug-loaded system to the site
of interest. Two major mechanisms can be distinguished for addressing the desired
sites for drug release: (i) passive and (ii) active targeting. An example of passive
targeting is the preferential accumulation of chemotherapeutic agents in solid tumors as
a result of the enhanced vascular permeability of tumor tissues compared with healthy
tissue. A strategy that could allow active targeting involves the surface
functionalization of drug carriers with ligands that are selectively recognized by
receptors on the surface of the cells of interest. Since ligand–receptor interactions can
be highly selective, this could allow a more precise targeting of the site of interest.
Controlled drug release and subsequentbiodegradation are important for developing
successfulformulations. Potential release mechanisms involve: (i) desorptionof
surface-bound /adsorbed drugs; (ii) diffusion through the carrier matrix; (iii) diffusion
(in the case of nanocapsules) through the carrier wall; (iv) carrier matrix erosion; and
(v) a combined erosion /diffusion process.The mode of delivery can be the difference
between a drug’s success and failure, as the choice of a drug is often influenced by the

way the medicine is administered. Sustained (or continuous) release of a drug involves
polymers that release the drug at a controlled rate due to diffusion out of the polymer
or by degradation of the polymer over time. Pulsatile release is often the preferred
method of drug delivery, as it closely mimics the way by which the bodynaturally
produces hormones such as insulin. It is achieved by using drug-carrying polymers that
respond to specific stimuli (e.g., exposure to light, changes in pH or temperature).
For over 20 years, researchers have appreciated the potential benefits of
nanotechnology in providing vast improvements in drug delivery and drug targeting.
Improving delivery techniques that minimize toxicity and improve efficacy offers great
potential benefits to patients, and opens up new markets for pharmaceutical and drug
delivery companies. Other approaches to drug delivery are focused crossing particular
physical barriers, such as the blood brain barrier, in order to better target the drug and
improve its effectiveness; or on finding alternative and acceptable routes for the
delivery of protein drugs other than via the gastro-intestinal tract, where degradation
can occur.
Drug Delivery Systems
The global market for advanced drug delivery systems was more than €37.9 billion in
2000 and is estimated to grow and reach €75B by 2005 (i.e., controlled release €19.8B,
needle-less injection €0.8B, injectable/impantable polymer systems €5.4B, transdermal
€9.6B, transnasal €12.0B, pulmonary €17.0B, transmucosal €4.9B, rectal €0.9B,
liposomal drug delivery €2.5B, cell/gene therapy €3.8B, miscellaneous €1.9B).
Developments within this market are continuing at a rapid pace, especially in the area
of alternatives to injected macromolecules, as drug formulations seek to cash in on the
€6.2B worldwide market for genetically engineered protein and peptide drugs and
other biological therapeutics.
Drug Delivery Carriers
Colloidal drug carrier systems such as micellar solutions, vesicle and liquid crystal
dispersions, as well as nanoparticle dispersions consisting of small particles of 10–400
nm diameter show great promise as drug delivery systems. When developing these
formulations, the goal is to obtain systems with optimized drug loading and release
properties, long shelf-life and low toxicity. The incorporated drug participates in the
microstructure of the system, and may even influence it due to molecular interactions,
especially if the drug possessesamphiphilic and/or mesogenic properties.

Figure 1. Pharmaceutical carriers
Micelles formed by self-assembly of amphiphilic block copolymers (5-50 nm) in
aqueous solutions are of great interest for drug delivery applications. The drugs can be
physically entrapped in the core of block copolymer micelles and transported at
concentrations that can exceed their intrinsic water- solubility. Moreover, the
hydrophilic blocks can form hydrogen bonds with the aqueous surroundings and form
a tight shell around the micellar core. As a result, the contents of the hydrophobic core
are effectively protected against hydrolysis and enzymatic degradation. In addition, the
coronamay prevent recognition by the reticuloendothelial system and therefore
preliminary elimination of the micelles from the bloodstream. A final feature that
makes amphiphilic block copolymers attractive for drug delivery applications is the
fact that their chemical composition, total molecular weight and block length ratios can
be easily changed, which allows controlof the size and morphology of the micelles.
Functionalization of block copolymers with crosslinkable groups can increase the
stability of the correspondingmicelles and improve their temporal control. Substitution
of block copolymer micelles with specific ligands is a very promising strategy to a
broader range of sites of activity with a much higher selectivity.

Figure 2. Block copolymer micelles.
Liposomes are a form of vesicles that consisteither of many, few or just one
phospholipid bilayers. The polar character of the liposomal coreenables polar drug
molecules to be encapsulated. Amphiphilic and lipophilic molecules are solubilized
within the phospholipid bilayer according to their affinity towards the phospholipids.
Participation of nonionic surfactants instead of phospholipids in the bilayer formation
results in niosomes. Channel proteins can be incorporated without loss of their activity
within the hydrophobic domain of vesicle membranes, acting as a size-selective filter,
only allowing passive diffusion of small solutes suchas ions, nutrients and antibiotics.
Thus, drugs that are encapsulated in a nanocage-functionalized with channel proteins
are effectively protected from premature degradation by proteolytic enzymes. The drug
molecule, however, is able to diffuse through the channel, driven by the concentration
difference between the interior and the exterior of the nanocage.
Figure 3. Drug encapsulation in liposomes.

Figure 4. A polymer-stabilized nanoreactor with the encapsulated enzyme.
Dendrimers are nanometer-sized, highly branched and monodisperse macromolecules
with symmetrical architecture. They consist of a central core, branching units and
terminal functional groups. The core together with the internal units, determine the
environment of the nanocavities and consequently their solubilizing properties,
whereas the external groups the solubility and chemical behaviour of these polymers.
Targeting effectiveness is affected by attaching targeting ligands at the external surface
of dendrimers, while their stability and protection from the Mononuclear Phagocyte
System (MPS) is being achieved by functionalization of the dendrimers with
polyethylene glycol chains (PEG).
Liquid Crystals combine the properties of both liquid and solid states. They can be
made to form
different geometries, with alternative polar and non-polar layers (i.e., a lamellar phase)
where aqueous drug solutions can be included.
Nanoparticles (including nanospheres and nanocapsules of size 10-200 nm) are in the
solid state and are either amorphous or crystalline. They are able to adsorb and/or
encapsulate a drug, thus protecting it against chemical and enzymatic degradation.
Nanocapsules are vesicular systems in which the drug is confined to a cavity
surrounded by a unique polymer membrane, while nanospheres are matrix systems in
which the drug is physically and uniformly dispersed. Nanoparticles as drug carriers
can be formed from both biodegradable polymers and non-biodegradable polymers.
In recent years, biodegradable polymeric nanoparticles have attracted considerable
attention as potential drug delivery devices in view of their applications in the
controlled release of drugs, in targeting particular organs / tissues, as carriers of DNA
in gene therapy, and in their ability to deliver proteins, peptides and genes through the
peroral route.
Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing
large amounts of water or biological fluids. The networks are composed of
homopolymers or copolymers, and are insoluble due to the presence of chemical
crosslinks (tie-points, junctions), or physical crosslinks, such as entanglements or
crystallites.
Hydrogels exhibit a thermodynamic compatibility with water, which allows them to
swell in aqueous media. They are used to regulate drug release in reservoir-based,
controlled release systems or as carriers in swellable and swelling-controlled release

devices.
On the forefront of controlled drug delivery, hydrogels as enviro-intelligent and
stimuli-sensitive gel systems modulate release in responseto pH, temperature, ionic
strength, electric field, or specific analyte concentration differences.
In these systems, release can be designed to occurwithin specific areas of the body
(e.g., within a certain pH of the digestive tract) or also via specific sites (adhesive or
cell-receptor specific gels via tethered chains from the hydrogel surface). Hydrogels as
drug delivery systems can be very promising materials if combined with the technique
of molecular imprinting.
Figure 5. Pegylated and pH sensitive micro- or nanogels.
The molecular imprinting technology has an enormous potential for creating
satisfactory drug dosageforms. Molecular imprinting involves forming a pre-
polymerization complex between the template molecule and functional monomers or
functional oligomers (or polymers) with specific chemical structures designed to
interact with the template either by covalent, non-covalent chemistry (self-assembly) or
both. Once the pre-polymerization complex is formed, the polymerization reaction
occurs in the presence of a cross-linking monomer and an appropriate solvent, which
controls the overall polymer morphology and macroporous structure. Once the
template is removed, the productis a heteropolymer matrix with specific recognition
elements for the template molecule.
Examples of MIP-based drug delivery systems involve: (i) rate-programmed drug
delivery, where drug diffusion from the system has to follow a specific rate profile, (ii)
activation-modulated drug delivery, where the release is activated by some physical,

chemical or biochemical processes and (iii) feedback-regulated drug delivery, where
the rate of drug release is regulated by the concentration of a triggering agent, such as a
biochemical substance, the concentration of which is dependent on the drug
concentration in the body. Despite the already developed interesting applications of
MIPs, the incorporation of the molecular imprinting approachfor the development of
DDS is just at its incipient stage. Nevertheless, it can be foreseen that, in the next few
years, significant progress will occurin this field, taking advantage of the
improvements of this technology in other areas. Among the evolution lines that should
contribute more to enhance the applicability of imprinting for drug delivery, the
application of predictive tools for a rational design of imprinted systems and the
development of molecular imprinting in water may be highlighted.
Figure 6. The volume phase transition of the hydrogel -induced by an external
stimuli (e.g., a change in pH, temperature or electrical field) modifies the relative
distance of the functional groups inside the imprinted cavities. This alters their
affinity for the template.
Figure 7. (A) Induced Swelling - As analyte (A) binds, the enzymatic reaction (E

denotes covalently attached enzyme) produces a local pH decrease. For the cationic
hydrogel, which is weakly basic, the result is ionization, swelling, and release of
drug, peptide, or protein (filled circle). When A decreases in the bulk concentration,
the gel shrinks. (B) Loss of Effective Cross-links - Analyte competes for binding
positions with the protein (P). As free analyte binds to the protein, effective cross-
links are reversibly lost and release occurs.
Conjugation of biological (peptides/proteins) and synthetic polymers is an efficient
means to improve control over nanoscale structure formation of synthetic polymeric
materials that can be used as drug delivery systems. Conjugation of suitable
biocompatible polymers to bioactive peptides or proteins can reduce toxicity, prevent
immunogenic or antigenic side reactions, enhance blood circulation times and improve
solubility. Modification of synthetic polymers or polymer therapeutics with suitable
oligopeptide sequences, on the other hand, can prevent random distribution of drugs
throughout a patient’s bodyand allow active targeting. Functionalization of synthetic
polymers or polymer surfaces with peptide sequences derived from extracellular matrix
proteins is an efficient way to mediate cell adhesion. The ability of cationic peptide
sequences to complex and condenseDNA and oligonucleotides offers prospects forthe
development of non-viral vectors for gene-delivery based on synthetic polymeric
hybrid materials.
Figure 8. Bioconjugates.
The field of in-situ forming implants has grown exponentially in recent years. Liquid
formulations generating a (semi-)solid depot after subcutaneous injection, also
designated as implants, are an attractive delivery system for parenteral application
because, they are less invasive and painful compared to implants. Localized or
systemic drug delivery can be achieved for prolonged periods of time, typically

ranging from one to several months. Generally, parenteral depotsystems could
minimize side effects by achieving constant, ‘infusion-like’ plasma-level time profiles,
especially important for proteins with narrow therapeutic indices. From a
manufacturing point of view, in-situ forming depotsystems offer the advantage of
being relatively simple to manufacture from polymers. Injectable in-situ forming
implants are classified into four categories, according to their mechanism of depot
formation: (i) thermoplastic pastes, (ii) in-situ cross-linked polymer systems, (iii) in-
situ polymer precipitation, and (iv) thermally induced gelling systems.
The ultimate goal in controlled release is the development of a microfabricated device
with the ability to store and release multiple chemical substances on demand. Recent
advances in microelectro-mechanical systems (MEMS) have provided a unique
opportunity to fabricate miniature biomedical devices for a variety of applications
ranging from implantable drug delivery systems to lab-on-a-chip devices. The
controlled release microchip has the following advantages: (i) multiple chemicals in
any form (e.g., solid, liquid or gel) can be stored inside and released from the
microchip, (ii) the release of chemicals is initiated by the disintegration of the barrier
membrane via the application of an electric potential, (iii) a variety of highly potent
drugs can potentially be delivered accurately and in a safe manner, (iv) complex
release patterns (e.g., simultaneous constant and pulsatile release) can be achieved, (v)
the microchip can be made small enough to make local chemical delivery possible thus
achieving high concentrations of drug at the site where it is needed while keeping the
systemic concentration of the drug at a low level and (vi) water penetration into the
reservoirs is avoided by the barrier membrane and thus the stability of protein-based
drugs with limited shelf-life is enhanced.
AdministrationRoutes
The choice of a delivery route is driven by patient acceptability, the properties of the
drug (such as its solubility), access to a disease location, or effectiveness in dealing
with the specific disease. The most important drug delivery route is the peroral route.
An increasing number of drugs are protein- and peptide-based. They offer the greatest
potential for more effective therapeutics, but they do not easily cross mucosalsurfaces
and biological membranes; they are easily denatured or degraded, prone to rapid
clearance in the liver and other bodytissues and require precise dosing. At present,
protein drugs are usually administered by injection, but this route is less pleasant and
also poses problems of oscillating blood drug concentrations. So, despite the barriers to
successfuldrug delivery that exist in the gastrointestinal tract (i.e., acid-induced
hydrolysis in the stomach, enzymatic degradation throughout the gastrointestinal tract
by several proteolytic enzymes, bacterial fermentation in the colon), the peroral route

is still the most intensively investigated as it offers advantages of convenience and
cheapness of administration, and potential manufacturing costsavings.
Pulmonary delivery is also important and is effected in a variety of ways - via aerosols,
metered doseinhaler systems (MDIs), powders (dry powder inhalers, DPIs) and
solutions (nebulizers), all of which may contain nanostructures suchas liposomes,
micelles, nanoparticles and dendrimers. Aerosol products forpulmonary delivery
comprise more than 30% of the global drug delivery market. Research into lung
delivery is driven by the potential for successfulprotein and peptide drug delivery, and
by the promise of an effective delivery mechanism for gene therapy (for example, in
the treatment of cystic fibrosis), as well as the need to replace chlorofluorocarbon
propellants in MDIs. Pulmonary drug delivery offers both local targeting for the
treatment of respiratory diseases and increasingly appears to be a viable option for the
delivery of drugs systemically. However, the pulmonary delivery of proteins suffers by
proteases in the lung, which reduce the overall bioavailability, and by the barrier
between capillary blood and alveolar air (air-blood barrier).
Transdermal drug delivery avoids problems such as gastrointestinal irritation,
metabolism, variations in delivery rates and interference due to the presence of food. It
is also suitable for unconscious patients. The technique is generally non-invasive and
aesthetically acceptable, and can be used to provide local delivery over several days.
Limitations include slow penetration rates, lack of dosageflexibility and / or precision,
and a restriction to relatively low dosage drugs.
Parenteral routes (intravenous, intramuscular, subcutaneous) are very important. The
only nanosystems presently in the market (liposomes) are administered intravenously.
Nanoscale drug carriers have a great potential for improving the delivery of drugs
through nasal and sublingual routes, both of which avoid first-pass metabolism; and for
difficult-access ocular, brain and intra-articular cavities. For example, it has been
possible to deliver peptides and vaccines systemically, using the nasal route, thanks to
the association of the active drug macromolecules with nanoparticles. In addition, there
is the possibility of improving the occular bioavailability of drugs if administered in a
colloidal drug carrier.
Trans-tissue and local delivery systems require to be tightly fixed to resected tissues
during surgery. The aim is to producean elevated pharmacological effect, while
minimizing systemic, administration-associated toxicity. Trans-tissue systems include:
drug-loaded gelatinous gels, which are formed in-situ and adhere to resected tissues,
releasing drugs, proteins or gene-encoding adenoviruses; antibody-fixed gelatinous
gels (cytokine barrier) that form a barrier, which, on a target tissue could prevent the

permeation of cytokines into that tissue; cell-based delivery, which involves a gene-
transduced oral mucosal epithelial cell (OMEC)-implanted sheet; device-directed
delivery - a rechargeable drug infusion device that can be attached to the resected site.
Gene delivery is a challenging task in the treatment of genetic disorders. In the case of
gene delivery, the plasmid DNA has to be introduced into the target cells, which
should get transcribed and the genetic information should ultimately be translated into
the corresponding protein. To achieve this goal, a number of hurdles are to be
overcome by the gene delivery system. Transfection is affected by: (a) targeting the
delivery system to the target cell, (b) transport through the cell membrane, (c) uptake
and degradation in the endolysosomes and (d) intracellular trafficking of plasmid DNA
to the nucleus.
Future Opportunitiesand Challenges
Nanoparticles and nanoformulations have already been applied as drug delivery
systems with great success;and nanoparticulate drug delivery systems have still greater
potential for many applications, including anti-tumour therapy, gene therapy, AIDS
therapy, radiotherapy, in the delivery of proteins, antibiotics, virostatics, vaccines and
as vesicles to pass the blood-brain barrier.
Nanoparticles provide massive advantages regarding drug targeting, delivery and
release and, with their additional potential to combine diagnosis and therapy, emerge
as one of the major tools in nanomedicine. The main goals are to improve their
stability in the biological environment, to mediate the bio-distribution of active
compounds, improve drug loading, targeting, transport, release, and interaction with
biological barriers. The cytotoxicity of nanoparticles or their degradation products
remains a major problem, and improvements in biocompatibility obviously are a main
concern of future research.
There are many technological challenges to be met, in developing the following
techniques:
 Nano-drug delivery systems that deliver large but highly localized quantities
of drugs to specific areas to be released in controlled ways;
 Controllable release profiles, especially for sensitive drugs;
 Materials for nanoparticles that are biocompatible and biodegradable;
 Architectures / structures, such as biomimetic polymers, nanotubes;
 Technologies for self-assembly;
 Functions (active drug targeting, on-command delivery, intelligent drug

release devices/ bioresponsive triggered systems, self-regulated delivery
systems, systems interacting with the body, smart delivery);
 Virus-like systems for intracellular delivery;
 Nanoparticles to improve devices such as implantable devices/nanochips for
nanoparticle release, or multi reservoir drug delivery-chips;
 Nanoparticles for tissue engineering; e.g. for the delivery of cytokines to control
cellular growth and differentiation, and stimulate regeneration; or for coating
implants with nanoparticles in biodegradable polymer layers for sustained
release;
 Advanced polymeric carriers for the delivery of therapeutic peptide/proteins
(biopharmaceutics),
 And also in the development of: Combined therapy and medical imaging, for
example, nanoparticles for diagnosis and manipulation during surgery (e.g.
thermotherapy with magnetic particles);
 Universal formulation schemes that can be used as intravenous, intramuscular or
peroral drugs
 Cell and gene targeting systems.
 User-friendly lab-on-a-chip devices for point-of-care and disease prevention and
control at home.
 Devices for detecting changes in magnetic or physical properties after specific
binding of ligands on paramagnetic nanoparticles that can correlate with the
amount of ligand.
 Better disease markers in terms of sensitivity and specificity.
MedicatedChewing Gum
Now-a-days most of the drugs are formulated into various solid dosage forms
including the most popular ones like Tablets, capsules etc. and semi-solid dosage
forms such as creams, ointments, gels etc. Chewing gum is being used worldwide since
ancient times after man experienced the pleasure of chewing a variety of substance. It
can be used as a convenient modified release drug delivery system. Chewing gum has
been used for centuries to clean the mouth and freshen the breath (Jacobsen et al.,
2004). One thousand years ago the Mayan Indians chewed the tree resin (Chicle) from
the sapodilla tree to clean their teeth and freshen their breath .
The first commercial chewing gum “State of Maine pure sprucegum” was marketed in

1948 in the U.S.A. The first patent was filed in 1869 (Conway et al., 2003). The gum
was intended as dentifrices but it has never been marketed. The first Medicated
chewing gum “Aspergum” was launched in 1928. This chewing gum is still available
and contains acetylsalicylic acid. Another commercially available medicated chewing
gum is dimenhydrinate – containing chewing gum for motion sickness. However,
chewing gum did not gain acceptanceas a reliable drug delivery system until 1978,
when nicotine chewing gum became available.
In 1991, Chewing Gum was approved as a term for pharmaceutical dosageform by
the commission of European Council. Moreover, there is need of reformulation of
existing drug into New Drug Delivery Systems (NDDS) to extend or protect product
patents thereby delaying, reducing or avoiding generic erosion at patent expiry. Today
improved technology and extended know how have made it possible to develop and
manufacture medicated-chewing gum with pre-defined properties. MCG is one of
them. Owing to new social and behavioral trends in the pastmodern age, such as the
growing consumer health awareness and increasing attention to safety products,
chewing gum has been known for a new image and potential. Chewing gum today is
gaining consideration as a vehicle or a delivery system to administer active principles
that can improve health and nutrition.
MCG represents the newest system with potential uses in pharmaceuticals, over the
counter medicines and nutraceuticals (Lee et al., 2001). The drugs intended to act in
oral cavity often have low water/saliva solubility and chewing gum constitute a
valuable delivery system for such drugs.
Definition
Medicated Chewing Gum (MCG) is a novel drug delivery system containing
masticatory gum base with pharmacologically active ingredient and intended to use for
local treatment of mouth diseases or systemic absorptionthrough oral mucosa. MCG is
considered as vehicle or a drug delivery system to administer active principles that can
improve health and nutrition.
Why Use ChewingGum AsA Drug Delivery System?
Chewing gum provides new competitive advantages over conventional drug delivery
system:
Fast onset of action and high bioavailability
Pleasant taste
Higher compliance (easy and discreet administration without water)
Ready for use
High acceptance by children (Lamb et al., 1993)

Fewerside effects
Low dosagegives high efficacy as hepatic first pass metabolism is avoided. The
controlled release rate also reduces the risk of side effects, as high plasma peak
concentrations are avoided.
Systemiceffect
Active substances can be absorbed through the buccal mucosaand/or through the GI
tract when saliva is swallowed. Once the active substance is present in the blood,
systemic affect can be obtained (Lamb et al., 1993).
Fast onset of action
Fast onset of systemic effect is seen for active substances absorbed through the buccal
mucosa, as the active substances pass by the jugular veins directly to the systemic
circulation.
Local effect
Chewing gum is an obvious drug delivery system for local treatment of diseases in the
oral cavity and in the throat, as sustaining the release of active substances may
deliberately prolong exposure.
Effect on dry mouth ( xerostomia)
Dry mouth is a side effect of many types of medicament (e.g. antidepressants) and it is
also part of the symptomatology of several diseases (e.g. sjogren’s syndrome-an
autoimmune disorder characterized by lymphocytic infiltration of the salivary and
lacrimal glands) (Sjögren et al., 2002). Chewing gum stimulates salivary secretion
thereby decreasing dryness in the mouth.
MERITS OF THE MCG (PHARMACOLOGICAL)
The active component absorbed at the oral level avoids the enterohepatic circulation
and the associated metabolism (Conway et al., 2003).
The productis rapidly released from the gum after a short period of mastication; some
absorption takes place directly through the oral mucosa depending upon the active
ingredient. Importantly, not being swallowed, the gum does not reach the stomach,
which means that the GIT suffers less from the excipients and the iatrogenic effects.
(observed with some galenical form) (Conway et al., 2003).

Moreover the stomach does not suffer from direct contactwith high concentration of
the active principle, thus reducing the risk of intolerance of the gastric mucosae
(Conway et al., 2003).
The fraction of the productreaching the stomach is conveyed by the saliva and
delivered continuously and regularly.
Others:
Relaxes and eases tension.
Freshens the breath.
Decreases ear discomfort when flying.
Satisfies snack craving.
Cleans teeth after meals.
It’s fun.
DEMERITS OF THE MCG (PHARMACOLOGICAL)
If you chew gum on a regular basis, please consider the following:
Chewing gum causes unnecessary wear and tear of the cartilage that acts as a shock
absorberin the jaw joints. Once damaged this area can create pain and discomfort for
lifetime (Weil et al., 1978).
You use eight different facial muscles to chew. Unnecessary chewing can create
chronic tightness in 2 of these muscles located close to the temples. This can put
pressure on the nerves contributing to chronic intermittent headaches (Weil et al.,
1978).
You have six salivary glands located throughout mouth that are stimulated to produce
and release saliva whenever you chew. Producing a steady stream of saliva for
chewing gum is a waste of energy and resources that otherwise could be used for
essential metabolic activities.
Most of the chewing gums are sweetened with aspartame: long use causes cancer,
diabetes, neurological disorderand birth defects.
Flavor color etc. may cause allergic reaction. Long term frequent use causes increase
release of mercury vapor from dental amalgam filling. However medicated chewing
gums do not normally require extensive chewing or consumption to a great extent.

MERITS OF THE MCG (OVER OTHER DOSAGE FORMS)
 Dose not requires water to swallow. Hence can be taken anywhere (Morjaria et
al., 2004).
 Advantageous for patients having difficulty in swallowing.
 Excellent for acute medication (Conway et al., 2003).
 Counteracts dry mouth, prevents candidiasis and caries.
 Highly acceptable by children (Morjaria et al., 2004).
 Avoids First Pass Metabolism and thus increases the bioavailability of drugs
(Conway et al., 2003).
 Fast onset due to rapid release of active ingredients in buccalcavity and
subsequent absorptionin systemic circulation (Conway et al., 2003).
 Gum does not reach the stomach. Hence G.I.T. suffers less from the effects of
excipients.
 Stomach does not suffer from direct contactwith high concentrations of active
principles, thus reducing the risk of intolerance of gastric mucosa (Conway et
al., 2003).
 Fraction of productreaching the stomach is conveyed by saliva delivered
continuously and regularly. Duration of action is increased.
 Aspirin, Dimenhydrinate and Caffeine shows faster absorption through MCG
than tablets.
DEMERITS OF THE MCG (OVER OTHER DOSAGE FORMS)
 Risk of over dosage with MCG compared with chewable tablets or lozenges that
can be consumed in a considerable number and within much shorter period of
time (Jacobsenet al., 2004).
 Sorbitol present in MCG formulation may cause flatulence, diarrhoea.
 Additives in gum like flavouring agent, Cinnamon can cause Ulcers in oral
cavity and Licorice cause Hypertension.
 Chlorhexidine oromucosalapplication is limited to short
 term use because of its unpleasant taste and staining properties to teeth and
tongue.
 Chewing gum have been shown to adhere to different degrees to enamel
dentures and fillers.
 Prolong chewing on gum may result in pain in facial muscles and earache in
children.

Mechanism of Drug Transport (Rathbone et al., 1996; Squier et al., 1996)
During the chewing process, mostof the medications contained within the drug
productare released into the saliva and are either absorbed through buccalmucosa or
swallowed or absorbed through GIT.
Major pathways of drug transport across buccalmucosa follow simple fickian
diffusion. Passive diffusion occurs in accordancewithout the pH partition theory.
Some carrier mediated transport also observed. Equation for drug flux is:
J = DKp/ΔCe
Where,
J = drug flux
D = diffusivity
Kp = partition coefficient
ΔCe = concentration gradient
h = diffusional path length
It shows (h) that the flux may be increased by decreasing the diffusional resistance of
the membrane by making it more fluid, increasing the solubility of the drug in the
saliva immediately adjacent to the epithelium or enhancing the lipophilicity through
pro-drug modification. Because of the barrier properties of the tight buccalmucosa, the
rate limiting step is the movement of the drug molecules across the epithelium.
Two pathways of permeation across the buccalmucosa are transcellular and
paracellular. Permeability coefficient typically ranges from 1x10-5 to 2x10-10 cm/s.
The pathway of drug transport across oral mucosa may be studied using:
 Microscopic techniques using fluorescent dyes
 Autoradiography and
 Confocallaser scanning microscopic procedures.
COMPONENTS OF THE MCG
Chewing gum is a mixture of natural or synthetic gums and resins, sweetened with
sugar, corn syrup, artificial sweeteners and may also contain colouring agents and
flavour. The basic raw material for all CG is natural gum Chicle, obtained from the
sapodilla tree. Chicle is very expensive and difficult to procure therefore other natural
gum or synthetic materials like polyvinylacetate and similar polymers can be used as
gum base.
Typically Chewing Gum comprises two parts
 Water insoluble chewable gum base portion (Zyck et al., 2003)

 Water-soluble bulk portion (Zyck et al., 2003)
Waterinsoluble gum base generallycomprises of
(Conway et al., 2003; Zyck et al., 2003)
Elastomers (40-70%by wt. of gum base).
Elastomer provides elasticity and controls gummy texture. Natural elastomer: Natural
rubbers like Latex or Natural gums such as Jelutong, Lechi Caspi, Perillo, and Chicle.
Plastisizers (3-20%by wt. of gum base). These are used to regulate cohesiveness of
product.
These are again divided into Natural and Synthetic. Natural Plastisizers include
Natural rosin esters like Glycerol Esters or Partially hydrogenated Rosin, Glycerol
Esters of Polymerized Esters, Glycerol Esters of Partially dimerized Rosin &
Pentaerythritol Esters of Rosin. Synthetic Plastisizers include Terpene Resins derived
from α-pinene and/or d-limonene.
APPLICATIONS OF THE MCG
The MCGs can also be used as an alternative toolto buccaland sublingual tablets
which are intended to act systemically because active ingredient is released more
uniformly and cover greater area of absorptionin oral cavity. Oral diseases are
prevented or cured with MCG. MCGs can be used for systemic effect in conditions like
vitamin C deficiency, pain & fever, alertness, motion sickness, smoking cessation, as
well as for local effect in conditions like plaque acid neutralization, fresh breath, dental
caries, antiplaque, fungal, and bacterial infections.
Prevention and cure of oral diseases is a prime target for chewing gum formulations.
Local Therapy
Chewing Gum can controlthe release rate of active substances providing a prolonged
local effect. It also re-elevates plaque pH which lowers intensity and frequency of
dental caries. Fluoride containing gums have been useful in preventing dental caries in
children and in adults with xerostomia. Chlorhexidine chewing gum can be used to
treat gingivitis, periodontitis, oral and pharyngeal infections. It can also be used for
inhibition of plaque growth. Chlorhexidine chewing gum offers large flexibility in its
formulation as it gives less staining of the teeth and is distributed evenly in the oral
cavity. The bitter taste of chlorhexidine can be masked quite well in a chewing gum

formulation (Pedersen et al., 1990; Rindum et al., 1993) Clinical trials involving
patients with oral candidiasis have shown that miconazole chewing gum is at least as
sufficient as miconazole oral gel in the treatment of fungal infections in the mouth. A
miconazole chewing gum is yet to be launched (Pedersen et al., 1990; Rindum et al.,
1993)
Systemictherapy
Chewing gum can be used in treatment of minor pains, headache and muscular aches.
Chewing gum formulation containing nicotine (Nemeth et al., 1988) and Lobeline have
been clinically tested as aids to smoking cessation. Active substances like chromium,
guaran and caffeine are proved to be efficient in treating obesity. Chromium is claimed
to reduce craving for food due to an improved blood-glucosebalance. Caffeine and
guaran stimulate lipolysis and have a thermogenic effect (increased energy
expenditure) and reduce feeling of hunger. Xerostomia, Allergy, Motion sickness,
Acidity, Cold and Cough, Diabetes, Anxiety, etc are all indications for which chewing
gum is a means of drug delivery. Medicated chewing gum is used to counteract dental
caries by stimulation of saliva secretion. Non-medicated chewing gums increases
plaque pH, stimulates saliva flow and decrease decay.
FUTURE TRENDS
Chewing gum is no longer seen simply as confectionary. It not only offers clinical
benefits but also is an attractive, discrete and efficient drug delivery system.
A few decades ago, the only treatment for some diseases was surgical procedure but
now more and more diseases can be treated with Novel Drug Delivery Systems.
Generally, it takes time for a new drug delivery system to establish itself in the market
and gain acceptance by patients, however chewing gum is believed to manifest its
position as a convenient and advantageous drug delivery system as it meets the high
quality standards of pharmaceutical industry and can be formulated to obtain different
release profiles of active substances. The potential of MCG for buccaldelivery, fast
onset of action and the opportunity for productline extension makes it an attractive
delivery form. Reformulation of an existing productis required for patent protection,
additional patient benefits and conservation of revenues. Dental health chewing gum is
here to stay, as is medicated gum for smoking cessation and travel sickness. A bright
future for a preparation with a long history.

NANOTECHNOLOGY:
Applications in medicine and possible Side-Effects
Nanotechnology provides the field of medicine with promising hopes for assistance
in diagnostic and treatment technologies as well as improving quality of life. Humans
have the potential to live healthier lives in the near future due to the innovations of
nanotechnology. Some of these innovations include:
• Disease diagnosis
• Prevention and treatment of disease
• Better drug delivery system with minimal side effects
• Tissue Reconstruction
Researchers and scientists alike are constantly searching for new methods to
improve the current medical system to offer patients better care, and to improve the
efficiency of care delivery of physicians. When observed superficially the nano-
technological enhancements seem to be nothing but promising. They will provide
individuals with an improved quality of life, which will most likely lead to greater
lifetime productivity, given that people get more accomplished when they feel their
best. The advancements of nanotechnology will also greatly improve the accuracy of
medicine, which could significantly reduce the number of malpractice lawsuits.
Physicians could revert to the days where they focused more on treating the patient
instead of averting litigation.
Before these advancements occur, the ethical implications must be considered. The
ethical questions presented here, like many others involved in the nanotechnology
debate, are not unanswerable. If the questions presented here are answered
appropriately then nanotechnology and medicine should develop concurrently and
complimentarily. Once the ethicality of nanotechnology is resolved, the pursuit of
developments in this arena will be fruitful and advantageous as long as frequent
checks are made to ensure the development of nanotechnology is not unregulated
chaos.

INTRODUCTION
Nanotechnology is the study, design, creation, synthesis, manipulation, and
application of materials, devices, and systems at the nanometer scale (One meter
consists of 1 billion nanometers). It is becoming increasingly important in fields like
engineering, agriculture, construction, microelectronics and health care to mention a
few. The application of nanotechnology in the field of health care has come under
great attention in recent times. There are many treatments today that take a lot of
time and are also very expensive. Using nanotechnology, quicker and much cheaper
treatments can be developed. By performing further research on this technology,
cures can be found for diseases that have no cure today. We could make surgical
instruments of such precision and deftness that they could operate on the cells and
even molecules from which we are made - something well beyond today's medical
technology. Therefore nanotechnology can help save the lives of many people.
The specific purposeof this report is to explain what nanotechnology is and how it
can be used in the field of health care. Applications such as drug delivery system,
tissue reconstruction and disease diagnosis shall be discussed. In addition to this, the
report will outline some of the problems with using this technology. This report will
be of particular interest to researchers in medicine and electronics and to
undergraduate students from medicine, computer engineering, electrical engineering
and mechanical engineering.
The report contains background information on nanotechnology and its importance.
Then thereport will discuss some of the applications of nanotechnology in the field
of health care. Finally, problems with using nanotechnology will be discussed
Nanotechnology, when used with biology or medicine, is referred to as
Nanobiotechnology. This technology should be used very carefully becausethe lives
of human beings are being dealt with. If used properly, it can be very effective in
providing treatments with minimal side-effects.
Assemblyapproaches
There are two main approaches for the synthesis of nano-engineered materials. They
can be classified on the basis of how molecules are assembled to achieve the desired
product.
1. Top – down technique
The top – down technique begins with taking a macroscopic material (the finished
product)and then incorporating smaller scale details into them. The molecules are

rearranged to get the desired property. This approachis still not viable as many of the
devices used to operate at nanolevel are still being developed. (Silva, 2004)
2. Bottom – up approach
The bottom – up approachbegins by designing and synthesizing custom made
molecules that have the ability to self- replicate. These molecules are then organized
into higher macro-scale structures. The molecules self replicate upon the change in
specific physical or chemical property that triggers the self replication. This can be a
change in temperature, pressure, application of electricity or a chemical. The self
replication of molecule has to be carefully controlled so it does not go out of hand
APPLICATIONIN MEDICAL SCIENCE
This section discusses the applications of nanotechnology in the field of health care.
These applications can remarkably improve the current treatments of some diseases
and help save the lives of many.
A. Drug Delivery System
1. What are nanorobots and why use them?
Nanorobots are robots that carry out a very specific function and are just several
nanometers wide. They can be used very effectively for drug delivery. Normally, drugs
work through the entire body before they reach the disease-affected area. Using
nanotechnology, the drug can be targeted to a precise location which would make the
drug much more effective and reduce the chances of possible side-effects. Figure 1
below shows a device that uses nanorobots to monitor the sugar level in the blood.
Figure 2. Device Using Nanorobots for Checking Blood Contents (Amazing
Nanroobots)

2. Drug delivery procedure
The drug carriers have walls that are just 5-10 atoms thick and the inner drug-filled
cell is usually 50-100 nanometers wide. When they detect signs of the disease, thin
wires in their walls emit an electrical pulse which causes the walls to dissolve and
the drug to be released. Aston Vicki, manager of BioSante Pharmaceuticals, says
“Putting drugs into nanostructures increases the solubility quite substantially”.
3. Advantagesof using nanorobots for drug delivery
A great advantage of using nanorobots for drug delivery is that the amount and
time of drug release can be easily controlled by controlling the electrical pulse.
Furthermore, the walls dissolve easily and are therefore harmless to the body. Elan
Pharmaceuticals, a large drug company, has already started using this technology
in their drugs Merck’s Emend and Wyeth’s Rapamune.
B. Disease Diagnosisand Prevention
1. Diagnosisand Imaging
Nanobiotech scientists have successfully produced microchips that are coated with
human molecules. The chip is designed to emit an electrical impulse signal when
the molecules detect signs of a disease. Special sensor nanorobots can be inserted
into the blood under the skin where they check blood contents and warn of any
possible diseases. They can also be used to monitor the sugar level in the blood.
Advantages of using such nanorobots are that they are very cheap to produceand
easily portable.
2. Quantumdots
Quantum dots are nanomaterials that glow very brightly when illuminated by
ultraviolet light. They can be coated with a material that makes the dots attach
specifically to the molecule they want to track. Quantum dots bind themselves to
proteins unique to cancer cells, literally bringing tumors to light.

Figure 3. A LIGHT IN DARK PLACES: Spectral imaging of quantum dots.
Orange-red fluorescence signals indicate a prostate tumor growing in a live mouse
3. Preventing diseases
a. heart-attack prevention
Nanorobots can also be used to prevent heart-attacks. Heart-attacks are caused by
fat deposits blocking the blood vessels. Nanorobots can be made for removing
these fat deposits (Harry, 2005). The following figure shows nanorobots removing
the yellow fat deposits on the inner side of blood vessels.
Figure 4. Nanorobots Preventing Heart-attacks (Heart View)
b. frying tumors
Nanomaterials have also been investigated into treating cancer. The therapy is
based on “cooking tumors” principle. Iron nanoparticles are taken as oral pills and
they attach to the tumor. Then a magnetic field is applied and this causes the
nanoparticles to heat up and literally cookthe tumors from inside out.

Figure 5. Cancer Cooker- Triton BioSystems is developing an anticancer therapy
using antibody-coated iron nanoparticles.
C. Tissue Reconstruction
Nanoparticles can be designed with a structure very similar to the bone structure.
An ultrasound is performed on existing bone structures and then bone-like
nanoparticles are created using the results of the ultrasound (Silva, 2004). The
bone-like nanoparticles are inserted into the bodyin a paste form (Adhikari, 2005).
When they arrive at the fractured bone, they assemble themselves to form an
ordered structure which later becomes part of the bone Another key application for
nanoparticles is the treatment of injured nerves.
Samuel Stupp and John Kessler at Northwestern University in Chicago have made
tiny rod like nano-fibers called amphiphiles. They are capped with amino acids and
are known to spur the growth of neurons and prevent scar tissue formation.
Experiments have shown that rat and mice with spinal injuries recovered when
treated with these nano-fibers.
D. Medical Tools
Nano-devices are nanoparticles that are created for the purposeof interacting with
cells and tissues and carrying out very specific tasks . The most famous nano-
devices are the imaging tools. Oral pills can be taken that contain miniature
cameras. These cameras can reach deep parts of the bodyand provide high
resolution pictures of cells as small as 1 micron in width (A red blood cell is 7
microns wide) . This makes them very useful for diagnosis and also during
operations. Figure 4 below shows such cameras working with other nanoparticles
to get rid of a disease.

Figure 6. Miniature Cameras Inside Blood Vessels(Blender Battles)
An accelerometer is a very useful nano-device that can be attached to the hip, knee
or other joint bones to monitor movements and strain levels. Dressings can be
coated with silver nanoparticles to make them infection-resistant. The
nanoparticles kill bacteria and therefore reduce chances of infection.
PROBLEMS WITHUSING NANOTECHNOLOGY
Environmental Problems
The greatest risk to the environment lies in the rapid expansion and development of
nanoparticles using large scale production . A recent Rice University study showed
that certain nanoparticles have a tendency to form aggregates that are very water
soluble and bacteriocidal(capable of killing bacteria) and that can be catastrophic
as bacteria are the foundation of the ecosystem.Scientists also fear that
nanoparticles may damage the ozone layer . Many people fear that nanoparticles
may self-replicate and cover the earth’s landscape with ‘grey goo’. However
scientists assure that this cannot happen and is a scientific fantasy.
B. Health Problems
The risk of nanoparticles to the health of human beings is of far greater concern.
James Baker, director of the Center for Biologic Nanotechnology at the University
of Michigan, says “ Any time you put a material into something as complex as a
human being, it has multiple effects ” (Perkel, 2004). Nanoparticles are likely to
make contact with the bodyvia the lungs, intestines and skin.
1. Risk to Lungs
Nanoparticles are very light and can easily become airborne. They can easily be
inhaled during the manufacturing process where dust clouds are a common
occurrence. Particles passing into the walls of air passage can worsen existing air
disease such as asthma and bronchitis and can be fatal.

The following illustration shows how nanoparticles can be inhaled and travel
throughout the body.
Figure 8. Tracing how nanoparticles can be inhaled and travel to the brain, lungs
and the bloodstream
2. Effects on Brain
Some nanoparticles that are inhaled through the nose can move upward into the
base of the brain. This may damage the brain and the nervous system and could be
fatal.
3. Problems in Blood
Nanoparticles flowing thorough the bloodstream may affect the clotting system
which may result in a heart-attack. If these nanoparticles travel to organs like the
heart or the liver, they may affect the functionality of these organs.

A BUCKY BALL: AS NOVEL NANOMATERIAL
Buckyball as a novel nanomaterial was discovered by Scientist Fuller, hence
termed as Fullerenes. This new allotrope forms an extensive series of polyhedral
cluster molecules, Cn (n even), comprising fused pentagonal and hexagonal rings
of C atoms, which becomes baseof nanotechnology. Pure fullerenes, derived
fullerenes, metal endohedral fullerenes and carbonnanotube fullerenes are
available for nanoscience.
They have different shapes showing surprising physical and chemical
characteristic. The natural sources and synthetic sources are available for their
production. They show many biomedical, therapeutic, diagnostic and
miscellaneous applications. Enviromental toxicity and biological toxicity are also
reported. The global market for fullerenes in 2005 worth over $60 million.
Fullerenes are the futurefor nanomedicine and nanosurgery.
The notion of nanotechnology has evolved since its inception as a fantastic
conceptual idea to its current position as a mainstream research initiative with
broad application among all division of science. As the name indicate the
nanoparticle form the base of nanotechnology and nanosciences.
These minute particles about 100Ato 2000Ain diameter were introduced by
Krenter and Speiser in the 1970s as a controlled release drug carrier.[1] The
nanomaterials currently being employed in pharmaceuticals includes: Micelles,
Liposomes, Dendrimers, Fullerenes, Hydrogels, Nanoshells, Smart Surfaces,
Quantum Dots, Colloidal Gold, Polymeric nanoparticles etc. Buckyballs are an
integral and newly emerging part of nanomaterials. This new allotrope forms an
extensive series of polyhedral cluster molecules, Cn (n even), comprising fused
pentagonal and hexagonal rings of C atoms. The first member to be characterized
was C60, which features 12 pentagons separated by 20 fused hexagons. It has full
icosahedral symmetry and was given the name buckminsterfullerene in honour of
the architect R. Buckminster Fuller whose buildings popularized the geodesic
dome, which uses the same tectonic principle.

Fuller, who is shown on the cover of Time Magazine of January 10, 1964, was
renowned for his geodesic domes that are based on hexagons and pentagons. The
group actually tried to understand the absorption spectraof interstellar dust, which
they suspected to be related to some kind of long-chained carbonmolecules.
Initially, C60 could only be produced in tiny amounts.
So there were only a few kinds of experiments that could be performed on the
material. Things changed dramatically in 1990, when Wolfgang Krätschmer,
Lowell Lamb, Konstantinos Fostiropoulos, and Donald Huffman discovered how
to producepure C60 in much larger quantities. This opened up completely new
possibilities for experimental investigations and started a period of very intensive
research. Nowadays it is relatively straightforward to mass-produceC60.
It opened up the new branch of Fullerene-Chemistry, which studies the new
families of molecules that are based on Fullerenes. Knowledge of chemical
modification, biological significance and materials application of functionalized
fullerenes is growing rapidly and these compounds are emerging as new tools in
the pharmaceutical field.
Classification
Fullerenes can be classified into following ways –
A. Pure Fullerenes:
1. Fullerene C60 or Buckminsterfullerene:
Molecular wt: 720.66, Appearance: Granular, dark-brown powder. Sublimed
appears as deep blue-black needle-like crystals. The diameter of a C60 molecule is
about 1 nanometer. The C60 molecule has two bond lengths. The 6:6 ring bonds
(between two hexagons) can be considered "double bonds" and are shorter than the
6:5 bonds (between a hexagon and a pentagon) given in Figure 1.

Figure 1: Fullerene C 60 or Buckminsterfullerene
2. Fullerene C70:Molecular wt: 840.77, Appearance: Granular, Sublimed black
powder (Figure 2).
Figure 2: Fullerene C 70
3. Fullerene C76: Molecular wt: 912.84, Appearance: Granular, dark-brown
powder.
4. Fullerene C78: Molecular wt.: 936.86, Appearance: Granular, black powder
(Figure 3).
5. Fullerene C84 : Molecular wt.:1008.92, Appearance: Granular, brown-black
powder (Figure 4).
Derived fullerenes(functionalizedfullerenes):
Chemical groups can be attached to a fullerene carbon atom and this process is
called functionalization, used for modifying the properties. The number of carbon
atoms available to do this had led to the epithet “molecular pincushion”, especially
within the context of medical application such as those being developed by the
company C60.
Ferrocenes are compounds containing iron and organic groups that have attracted
much interest in the decades since their discovery. The hybrids might create
vesicles for drug delivery.

C. Metal Endohedrals:
An area of research that has been as active as functionalization of fullerenes is that
of putting atoms inside them. The results are called endohedral fullerenes (Figure
5). A huge number of elements have been encapsulated in fullerenes, including the
noble gases, which have no desire to bond with surrounding carbonatoms but can
be used in application such as magnetic resonance imaging (MRI).
D. Carbon Nanotubes:
Nanotubes are cylindrical fullerenes. These tubes of carbon (Figure 6) are usually
only a few nanometers wide, but they can range from less than a micrometre to
several millimetres in length.
Figure 6: CarbonNanotube
Description
Shapes of Fullerenes:
The structural motif of the fullerenes is a sequence of polyhedral clusters, Cn, each
with 12 pentagonal faces and (1/2 n-10) hexagonal faces. C60 itself has 20
hexagonal faces. C70 has 25 hexagonal faces with 5 types of carbon atoms and 8
types of C-C bonds.
SystematicNames:
Systematic names for the icosahedral C60 and the D5h (6) C70 fullerenes are
(C60-Ih) [5,6] fullerene and (C70-D5h (6))[5,6] fullerene. Systematic Numbering
is given in both 3-D and Schlegel format .

Production
I. Natural sources :
C60 and C70 have been detected in several naturally occurring minerals e.g. In
carbon-rich semi-anthracite deposits from the yarrabee mine in Queens land,
Australia. In Shungite, a highly metamorphosed metaanthracite from Shunga,
Kerelia, Russia. Most recently, significant findings of naturally occurring
fullerenes have been made in Sudbury (Canada) and New Zealand.
II. Synthetic Sources :
They were first produced byman (at least knowingly) in the sootresulting from
vaporizing graphite with a laser. The earliest bulk production process is the arc
discharge (or Krätschmer-Huffman) method, using graphite electrodes, developed
in 1990.
Other Routes:
Heating naphthalene vapor (C10H8) in argon at about 1000oC followed by
extraction with CS2. Burning sootin a benzene/oxygen flame at about 1500oC
with argon as diluent.
Applications
A. BiomedicalApplications:
Fullerenes unique qualities have promise for certain type of drug design. The small
size, spherical shape and hollow interior all provide therapeutic opportunities.
Moreover, a cage of 60 carbon atoms has 60 places at which chemical groups can
attach in almost any configuration. Such opportunity has led to the development of
not only drug candidates for treating diseases including HIV, cancer and neurological
conditions but also new diagnostic tools.
B.TherapeuticApplications:
The relatively high tolerance of biological systems to carbon is one of the reasons for
the potential of buckyballs in medical applications, in addition buckyballs are small
enough to pass through kidneys and be excreted. The ability to chemically modify the
sidewalls of buckytubes also leads to biomedical applications such as neuron growth
and regeneration.

Self Assembled DNA Buckyballs for drug delivery
Tiny geodesic spheres that could be used for drug delivery and as containers for
chemical reactions have been developed. About 70% of the volume of the DNA
buckyball is hollow and drugs can be encapsulated in it to be carried into cells, where
natural enzymes break down the DNA, releasing the drug. They might also be used as
cages to study chemical reactions on the nanoscale.
Buckyballs to fight allergy
The buckyballs are able to interrupt the allergy/immune responseby inhibiting a
basic process in the cell that leads to release of an allergic mediator. Essentially, the
buckyballs are able to prevent mast cells from releasing histamine. These findings
advance the emerging field of medicine known as nanoimmunology.
Buckyballs as antioxidants:
The unique structure of buckyballs enable it to bind to free radicals dramatically
better then any
antioxidant currently available, suchas vitamin E. Free radicals are molecules that
cause oxidative stress, which experts believe may be the basis of aging therefore
finds use in cosmetics.
Buckyballs as Passkeyinto Cancercells
Drugs are far more effective if they are delivered through membrane, directly into the
cells. The passkey developed contain a molecule called Bucky amino acid based on
phenylalanine that are strung together like a beads on a necklace to build all proteins
The peptides were found effective at penetration the defenses both liver cancer cells
and neuroblastoma cells.
Buckyballs are the first targetedantibiotic ( New Defense AgainstBioterrorism)
A new variant of vancomycin that contains buckyballs -- tiny cage-shaped molecules
of pure carbon could becomethe world's first targeted antibiotic, creating a new line
of defense against bioweapons like anthrax.
Buckyball as HIV ProteaseInhibitor:
C Sixty's drug targets the human immunodeficiency virus (HIV) that causes AIDS by
latching onto the enzyme necessary for viral reproduction. The fullerenes deactivate
both the HIV-1 and HIV-2 types of virus, and don't seem to harm cells or organs,
which is a problem with some other HIV inhibitors. Since a C60 molecule has
approximately the same radius as the cylinder that describes the active site of HIVP
and since C60 and its derivatives are primarily hydrophobic, an opportunity exists for

a strong hydrophobic Vander Waals interaction between the nonpolar active-site
surface and the C60 surface (Figure 8). In addition, however, there is an opportunity
for increasing binding energy by the introduction of specific electrostatic interactions.
One obvious possibility involves salt bridges between the catalytic aspartic acids on
the floor of the HIVP active site and basic groups such as amines introduced on the
C60 surface. The key to exploiting this promising system will be the development of
organic synthetic methodology to derivatize the C60 surface in highly selective ways.
Buckyballs as Neuroprotectants:
Buckyball act as neuroprotectants-a drug that prevents or repair neurological damage.
Diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's
disease and Parkinsonism are under trial.
Buckyball as Cytoprotective agent
The Water-soluble Buckyball derivative RadicalSponge exerts cytoprotective action
against UV
irradiation without visible light catalyzed cytotoxicity toward human skin
keratinocytes.
Buckyball C60 α Alanine Adduct As RadicalScavenging Agent
Water-soluble C60 α Alanine Adduct has been synthesized and scavenging ability
for super oxide anion O- 2 (-) and hydroxyl radical has been demonstrated. It shows
excellent efficiency in eliminating these anions and radicals and will be useful in
radical related biomedical field.
DiagnosticApplications
Buckyballs may be especially useful for shuttling metal contrast agents through the
bodyfor magnetic resonance imaging (MRI) scans. Bolskar, Lon Wilson of Rice
University in Houston, and other researchers have designed carbon-60 and other
fullerene molecules with an atom of gadolinium inside and with chemical appendages
that make them water-soluble. In typical MRI contrast agents, the metal
gadolinium is linked to a non fullerene molecule. Formost diagnostic tests, this
molecule is excreted from the bodyquickly. However, fullerene-encapsulated
gadolinium might one day be a safer option for certain diagnostic tests in which
doctors leave the contrast agent in longer time.
Trimetaspheres are a larger version of the buckyball, with 80 carbons caging up to
three metal or rare earth atoms, such as scandium, lanthanum or yttrium, which are
covalently bonded to nitrogen. In trimetaspheres the nitrogen complex spins freely
within the larger cage of carbons.Theyhave potential uses as contrast agents for

medical magnetic resonance imagining, as light emitting diodes, and potentially for
molecular electronics and computing.
D. MiscellaneousApplication
There is a wealth of other potential applications for Buckytubes, such as solar
collection; nanoporous filters; and coatings of all sorts. Following are certain
example:
1) Data storage devices: fullerene have interesting electrical properties’, which
have led to the suggestion for use in a number of electronics related areas from
data storage devices to solar cells.
2) Fuel cells: another use of electrical property of fullerene is in fuel cells
exploiting their ability to help protonmove around.
3) Memory devices: fullerene have been inserted into nanotube, the result
sometime referred to as
‘peapods’,the properties can be modified by moving the location of the enclosed
fullerens and research has even suggested using this to create memory devices.
4)Photonicdevices
5) Telecommunication devices
6) Supreconductingdevices
7) Fullerene can also be used as precursor for other materials such as diamond
coating or nanotubes.
8) Liquidcrystal display these have potential in liquid crystal application which
goes beyond Liquid crystal displays as there is growing interest in there use in
areas such as non linear optics, photonics and molecular electronics.
Fullerenes are effective at mopping up free radicals, which damage liver tissue.
This had led to the suggestion that they might protectthe skin in cosmetics, or
health hinder neural damage caused by radicals in certain diseases, research on
which on rats has already shown promise.
The size of C60 is similar to many biologically acting molecules, including drugs,
such as Prozac and steroid hormone. This gives it potential as a foundation for
creating a variety of biologically active variants. Buckyballs have a high physical
and chemical affinity for the active site on an important enzyme for HIV, called
HIV protease, and block the action of enzyme. Buckyballs target HIV protease
differently so their effect should not be subject to resistance already developed.

The neuroprotective potential for C60 has already been demonstrated, and vesicles
made out of them could be used to deliver drugs. Applications for buckyballs with
other atoms trapped inside them, referred to as endohedral fullerenes.
Toxicities
Although C60 has been thought in theory to be relatively inert, the studies suggest
the molecule may prove injurious to organisms.
I. EnvironmentalToxicity
An experiment by Eva Oberdörsterat Southern Methodist University, which
introduced fullerenes into water at concentrations of 0.5 parts per million, found
that largemouth bass suffered a 17-fold increase in cellular damage in the brain
tissue after 48 hours. The damage was of the type lipid peroxidation, which is
known to impair the functioning of cell membranes. There were also inflammatory
changes in the liver and activation of genes related to the making of repair
enzymes. The overwhelming evidence of the essential non-toxicity of C60 (not
nC60) in previously peer-reviewed articles of C60 and many of its derivatives
indicates that these compounds are likely to have little (if any) toxicity, especially
at the very low concentration at which it is≈ used (~1-10 μM).
Desorption behavior of carbonnanotubes shows that high adsorptioncapacity and
reversible adsorption of poly aromatic hydrocarbons on nanotubes imply the
potential release of PAHs. If PAH-adsorbed CNTs are inhaled by animal and
human beings it may lead to a high environmental and public health risk.
II. Biological Toxicity
A study published in December 2005 in Biophysical Journal raises a red flag
regarding the safety of C60 when dissolved in water. It reports the results of a
detailed computer simulation that finds C60 binds to the spirals in DNA molecules
in an aqueous environment, causing the DNA to deform, potentially interfering
with its biological functions and possibly causing long-term negative side effects in
people and other living organisms.
Despite of the hydrophobic behavior fullerenes strongly bound to the nucleotides.
C60 bind single
stranded DNA and deform the nucleotides significantly.unexpectedly,when double
stranded DNA is in A form ,fullerene penetrate into the double helix from the end,
form stable hybrids, and frustrate the hydrogen bond between endgroup basepair in
the nucleotide. The simulation results suggest the C60 molecules have potentially

negative impact on the structure, stability and biological functions of DNA
molecule.
Demerits
BuckyballsHurtCells
A new study of the revolutionary nano-sized particles known as 'buckyballs'
predicts that the molecules are easily absorbed into animal cells, providing a
possible explanation for how the molecules could be toxic to humans and other
organisms. "Buckyballs are already being made on a commercial scale for use in
coatings and materials but we have not determined their toxicity studies showing
that they can cross the blood-brain barrier and alter cell functions, which raise a
lot of questions about their toxicity and what impact they may have if released into
the environment." The resulting model showed that buckyball particles are able to
dissolve in cell membranes, pass into cells and re-form particles on the other side
where they can cause damage to cells .

Buckyballs'HaveHighPotential ToAccumulateIn LivingTissue
Synthetic carbon molecules called fullerenes, or buckyballs, have a high potential
of being accumulated in animal tissue, but the molecules also appear to break
down in sunlight, perhaps reducing their possibleenvironmental dangers "Because
of the numerous potential applications, it is important to learn how buckyballs
react in the environment and what their possible environmental. The researchers
mixed buckyballs in a solution of water and a chemical called octanol, which has
properties similar to fatty tissues in animals. Findings indicated buckyballs
have a greater chance of partitioning into fatty tissues than the banned pesticide
DDT. However, while DDT is toxic to wildlife, buckyballs currently have no
documented toxic effects... When nanotechnology is referred to relative to
therapeutics, it generally means that the active agent is targeted to specific
locations in the bodyand that we are working on the molecular basis or with
very small particles, suchas, for example, gold nanoparticles .
Difficultyof targeting drug deliveryto the location
One major problem for current therapeutics is the difficulty of targeting drug
delivery to the location where it is desired. The result of non-targeted delivery is
that the drug can be active all over the bodythat means that large doses, larger than
would otherwise be required, must be used, or that we realize a lot of peripheral
damage to otherwise healthy parts, killing healthy cells or causing immune
reactions. A second major problem for therapeutics is delivery of the active agent.
This issue is related to the targeting problem but is broaderthan just that.

Currently, we design active drugs and expect them to circulate through the body,
pass through barriers such as the digestive system, the cell, and the blood-brain
barrier, and still to be active as a drug after doing all that and it is not surprising
that many drugs cannot effectively do this.
The issue is even more critical for cancer treatment where drugs often do great
damage at the wrong locations. We are all aware of the major side effect problems
with most cancer drugs. This issue will have to be solved by new delivery agents,
materials which will do several jobs—that will direct the drug to the desired
location, that will help the active agent get through the barriers, that will protect
the drug from degradation during delivery, and, finally, that will release the drug
once it is inside the cell or in the preferred location .
Uses
Carbon nanotubes can be modified to circulate well within the body. Such
modifications can be accomplished with either covalent or non-covalent bonding.
And the modifications can be suchthat they increase or decrease circulation time
within the body. Many current drugs, especially for cancer treatment, circulate for
only short times before excretion.
Carbonnanotube drug complexes are readily excreted from the body. Long-term
data will be required, but initial studies indicate acceptable excretion.
Carbonnanotubes show no significant toxicity when they have been modified so
as to be soluble in aqueous, body-typefluids.
Carbonnanotubes readily enter cells.
A wide range of active agents can be attached to carbon nanotubes and carried
into cells along with the nanotubes. It appears that stable structures are formed
which protect the active agents during transport. The active agents which can be
carried by carbonnanotubes include many cancer drugs and also include short
interfering RNA, which may be the hottest current area within therapeutics
research.
Cancer cells in tumors are larger than normal cells and also exhibit leakage. This
means that there is both leakage out of and leakage into the cells.

MesoporousSilica Nanoparticles
Recent breakthroughs in the synthesis of mesoporous silica materials with
controlled particle size, morphology, and porosity, along with their chemical
stability, has made silica matrices highly attractive as the structural basis for a wide
variety of nanotechnological applications such as adsorption, catalysis, sensing,
and separation.[1–6] In addition, we and others have discovered
that surface-functionalized mesoporous silica nanoparticle (MSN) materials can be
readily internalized by animal and plant cells without posing any cytotoxicity issue
in vitro.
These new developments render the possibility of designing a new generation of
drug/gene delivery systems and biosensors for intracellular controlled release and
imaging applications.
Herein we review recent research efforts in developing new MSN-based materials
with different surface functionalities targeted for the abovementioned applications.
Characteristics of Mesoporous Silica Nanoparticles
Since the discovery of MCM-41 by Mobil scientists, significant research progress
has been made in controlling and modifying the properties of mesoporous silica
materials.
For example, several key structural characteristics of the material, including the
size and morphology of pores and particles[ can be regulated. For example, we
have synthesized MCM-41- type MSNs with a variety of shapes and sizes ranging
from 20 to 500 nm, and with pore sizes ranging from 2 to 6 nm,.
Functionalization of these materials with a variety of organic groups inside of the
mesopores or on the external surface of the particles[10,11] have been
demonstrated.

Figure 1. Transmissionelectron microscopyimages of three spherical
MSNs with differentparticle and pore sizes: a) Particle size ca. 250 nm;
pore diameterca. 2.3 nm. b) Particle size ca. 200 nm; pore diameter ca.
6.0 nm. c) Particle size ca. 50 nm; pore diameter ca. 2.7 nm. Figure 1a
reproduced with permissionfrom [10]. Copyright 2003 American
The cylindrical mesopores of MSNsare arranged in a hexagonal structure, forming
well-defined channels that are parallel to each other. These characteristics are
typically observed by powder X-ray diffraction and transmission electron
microscopy.
Such unique features lead to high surface areas (900–1500 cm2 g–1), and large
accessible pore volumes (0.5– 1.5 cm3 g–1), usually measured by nitrogen
sorption analysis. The simple polycondensation chemistry of silica allows for
covalent attachment of a wide variety of functional groups, commercially available
as substituted trialkoxy- or trichloro-silanes, either by co-condensationduring the
initial synthesis of the material, or by post-synthesis grafting. By using these
different methods, the loading and location of functional groups can be controlled.
Decoration of the mesoporous channels and/or the external particle surface of
MSNs with various functionalgroups allows a wide range of manipulation of the
surface properties of these materials for controlled release delivery and biosensing
applications.
CellularUptakeof MSNs
After our first study showing that MSNs were readily internalized by eukaryotic
cells without detectable toxic effectsin vitro (Fig. 2), further studies were
performed in order to understand the mechanism of cellular uptake of these
materials. Mou and co-workers have shown that the endocytosis of fluorescein-
labelled MSNs by 3T3L1 and mesenchymal stem cells was clathrin-mediated and
that the particles were able to escapethe endolysosomal vesicles. Our recent work

with HeLa cancer cells has demonstrated that the uptake efficiency and the uptake
mechanism of the MSNs can be manipulated by the surface functionalization of the
nanoparticles.
We observed that functionalization of the external surface of MSNs with groups
for which cells do express specific receptors, like folic acid, notably enhances the
uptake efficiency of the material by cells. We also found that the functionalization
of the particles with groups that alter their f-potentials affects not only the
efficiency of their internalization, but the uptake mechanism and the ability of the
particles to escape the endolysosomal pathway.
Hoekstra and co-workers have shown previously that nonphagocytic eukaryotic
cells can endocytoselatex beads up to 500 nm in size, and that the efficiency of
uptake decreases with increasing particle size.They demonstrated that the highest
efficiency was achieved with particles sized around 200 nm or smaller, whereas
little, if any, uptake was observed for particles larger than 1 lm. Such information
leads us to believe that MSNs can be efficiently employed as carriers for
intracellular drug delivery as well as cell tracers and cytoplasmic biosensors.
Mesoporous Silica for Drug/Gene Delivery
It is well recognized that an efficient delivery system should have the capability to
transport the desired guest molecules without any loss before reaching the targeted
location. Upon reaching the destination, the system needs to be able to release
the cargo in a controlled manner. Any premature release of guest molecules poses
a challenging problem. For example, the delivery of many toxic antitumor drugs
requires “zero release” before reaching the targeted cells or tissues. However, the
release mechanism of many current biodegradable polymer-based drug delivery
systems relies on hydrolysisinduced erosion of the carrier structure.
The release of matrixencapsulated compounds usually takes place immediately
upon dispersion of these composites in water. Also, such systems typically require
the use of organic solvents for drug loading that can trigger undesirable
modifications of the structure and/or function of the encapsulated molecules, such
as protein denaturation and aggregation. In contrast, surface functionalized
mesoporous silica materials offer, as mentioned before, several unique features,
such as stable mesoporous structures, large surface areas, tunable pore sizes and
volumes, and well-defined surface properties for site-specific delivery and for
hosting molecules with various sizes, shapes, and functionalities.

Nanotubes:A New Carrier for Drug Delivery Systems
Nanotubes (NTs), nanometer-scale hollow cylinders, are emerging as promising
drug vehicles offering many advantages over spherical particles .NTs are
interesting for drug delivery for several reasons: (1) NTs have open mouths, which
makes the inner surface accessible and incorporation of species within the tubes
particularly easy; (2) There are no swelling or porosity changes with changes in
pH, and they are not vulnerable to microbial attack. Therefore, the NTs are able to
effectively protectentrapped molecules (enzymes, drugs, etc.) against denaturation
induced by external environmental deterioration; (3) NTs have large inner volumes
(relative to the dimensions of the tube), which can be filledwith any desired
chemical or biochemical species ranging in size from proteins to small molecules,
and allow for loading more one therapeutic agent in the same nanocarrier so that
targeting molecules, contrast agents, drugs, or reporter molecules can be used at
the same time; (4) The inner diameter and length of NTs can be precisely
controlled to allow for altering the drug release profile and extending the
effectiveness of drugs without increasing potency; (5) Two separated surfaces of
NTs and facile surface functionalization create the possibility, for example, of
loading and concentrating the inside of NTs with a particular biochemical payload
but imparting chemical features to the outer surface that render it recognition
capacity to allow for site-specific drug delivery to reduce toxic side effects .
This paper briefly highlights the recent performance of NTs in drug delivery. This
discussionis by no means intended to be complete, an attempt is made to provide
some illustrative examples on the basis and application of the NT delivery systems.
The NT systems discussed includes silica NTs, self-assembling lipid NTs and
polymer NTs as well as natural halloysite NT. Though it is still too early to
establish NTs for clinical use, these novel carriers are undoubtedly interesting and
deserve further investigation. As carbon NTs as biomolecule vehicles have been
extensively reviewed ;the related content is not involved here.
There are several ways to fabricate NTs. The template synthesis is a general
approachthat involves chemical synthesis or electrochemical deposition of the
desired material within the pores of a nanopore membrane such as alumina or
polycarbonate . This method has been widely used to prepare NTs composed of
many types of materials, including metals, polymers, semiconductors, carbons and
compositenanostructures. One advantage of the template method is
that the template is tuneable, which means the outside diameter of the NT can be
controlled by varying the pore diameter of the template membrane, the length of
the NT can be controlled by varying the thickness of the template membranes, and

the inside diameter of the NT can be controlled by varying the immersion time of
precursors. Another advantage is that template method provides a particularly
easyroute to accomplish differential functionalization on inner and outer surfaces.
Silica NTs are well known as an ideal vehicle for drug delivery and controlled
release becausethey are easy to make, readily suspendable in aqueous solution and
are of biocompatibility.
They are usually prepared using a sol�gel template synthesis procedure.The
template membrane is immersed into a silica precursorsuch as
tetraethylorthosilicate sol so that the sol fills the pores. After the desired emersion
time, the membrane is removed, dried in air, and then cured at 150 °C. This yields
silica NTs lining the pore
walls of the membrane plus silica surface films on both faces of the membrane.
The surface films are removed by briefly polishing with slurry of alumina particles.
The NTs are then liberated by dissolving the template membrane and collected by
filtration.
Martin’s group elegantly demonstrated the smart NTs for bioseparations. Antibody
functionalized silica NTs can provide the ultimate in extraction selectivity�the
extraction of one enantiomer of a racemic pair .The Fab fragments of an antibody
against the drug 4-[3-(4 fluorophenyl)-2- hydroxy-1-[1,2,4]-triazol-1-yl-propyl]-
benzonitrile (FTB) were immobilized to both the inner and outer surfaces of the
silica NTs. This was accomplished by dispersing silica NTs into a solution of the
aldehyde-terminated silane trimethoxysilylbutanal.
The NTs were then dispersed into a solution of the Fab fragments, which resulted
in attachment of the Fab to the NTs via Schiff base reaction between free amino
groups on the protein and the surface-bound aldehyde. The Fab-functionalized NTs
were added to racemic mixtures of the SR and RS enantiomers of the FTB. The
tubes were then collected by filtration.
As the Fab fragment selectively binds the RS relative to the SR enantiomer, 75%
of the RS enantiomer and none of the SR enantiomer was removed by the NTs.
With the procedure described in,they also attached the Fab to only the inner
surfaces of the NTs using the well-known glutaraldehyde coupling reaction. When
these interior-only Fab-modified NTs were incubated with racemic mixture of the
drug, 80% of the RS (and none of the SR) enantiomer was extracted.

Design of novel drug carriers with multi-functionalities is the key to the success of
the drug delivery and controlled release field. Magnetic particles have been
extensively studied in the field of biomedical and biotechnological applications,
including drug delivery. By using an external, highgradient magnetic field, one can
concentrate the nanocarriers of drugs at a particular point, such as a tumor site, to
increase their possibility to interact with the targeted cells, and then release the
loaded drug. However, conjugation of the magnetic nanoparticles to the
conventional drug carriers is not easy to realize. Thanking to the large volume, the
hollow cylinder of NTs are able to facilely load the magnetic NPs.
Son et al synthesized magnetic NTs (MNTs) with a layer of magnetite (Fe3O4)
nanoparticles on the inner surface of the silica NT [12]. To do that, silica NTs still
embedded in porous alumina film was dip-coated with a mixture solution of FeCl3
and FeCl2, dried in an Ar stream, immersed in NH4OH. They treated the inner NT
surfaces of MNTs with octadecyltriethoxysilane (C18-silane) while MNTs were
still embedded in the pores of the alumina template to obtain hydrophobic inner
surface .
MNTs with C18- functionalized inside were added to a solution of 1,1’-
dioctadecyl-3,3,3’,3’ tetramethylindocarbocyanine perchlorate (DiIC18) in
water/methanol. These dye molecules was extracted into the MNTs by the strong
hydrophobic interaction. The loaded MNT was then separated from the solution
with a magnetic field. More than 95% of the dye was removed from the solution.
MNTs functionalized with human IgG inside show a magnetic bioseparation for
red Cy3- labeled anti-human IgG from the solution using antigenantibody
interaction. 84% of Cy3-labeled anti-human IgG can be separated. The magnetic
property of MNTs can also facilitate and enhance biointeractions between the outer
surfaces of MNTs and a specific target surface. MNTs with an FITC-modified
inner surface and a rabbit IgG-modified outer surface were incubated for 10 min
onto the anti-rabbit IgG-modified glass slide with and without magnetic field from
the bottom of the glass slide. About 4.2-fold binding enhancement was observed
for the antigen-antibody interactions in the presence of magnetic field. This
phenomenon implies that the magnetic field will improve the drug delivery
efficiency.
The MNT also shows the controlled-release behavior with 5-Fluorouracil (5-FU),
4-nitrophenol, and ibuprofen as model drug molecules. The amine�functionalized
MNTs were immersed in the hexane (ibuprofen) or ethanol (5-FU, 4-nitrophenol)

solutions of drugs. The amine functional groups make strong ionic and/or
hydrogen-bonding interactions with the acid functional groups of drug molecules.
It was observed that less than 10% of ibuprofen was released in 1 h, and 80% was
released after 24 h. In the cases of 5-FU and 4-nitrophenol, however, more than
90% was released in 1 h. These results conclude that the carboxylic acid group of
ibuprofen makes the strongest interaction with the amine group inside MNT and
ibuprofen released with a slow rate.
Heterostructured MNTs were also fabricated by the layer-by-layer (LBL)
deposition of polyelectrolytes and magnetic Fe3O4 nanoparticles in the pores of
track-etched polycarbonate membranes .Multilayers composedof poly(allylamine
hydrochloride) (PAH) and poly(styrene sulfonate) (PSS)at high pH (pH > 9.0)
were first assembled into the pores of track etched polycarbonate membranes, and
then multilayers of magnetite nanoparticles and PAH were deposited .
The surface of the MNT were further modified by adsorbing a block copolymer,
poly(ethylene oxide)-b-poly(methacrylic acid)(PEO-PMAA), to improve Fig. (1).

Fig. (2). Formation of LbL-assembled magnetic hollow tubes via the template
method. (a) Assembly of multilayers on track-etched polycarbonate (TEPC)
membranes. (b) Plasma etching of each surface of the multilayer-modified TEPC
membranes. (c) Adsorption of Fe3O4 nanoparticle/PAH multilayers. (d)
Dissolution of TEPC membranes. (e) Surface modification of magnetic hollow
tubes with a PEO-PMAA block copolymer. An axial cross sectionof a typical NT
is shown in the lower right corner. Reproduced with permission from Langmuir
2007, 23, 123. Copyright 2007 Am.
the colloidal stability of the MNTs. The MNTs proved to remove a large amount of
an anionic dye (i.e., rose Bengal from solutionafter acid activation. Immobilization
on silica can markedly improve the stability of enzymes under extreme condition .
Chen and coworkers carried lysozyme on a template-synthesized silica NT .Under
the neutral conditions of the experiment, boththe negatively charged outer and
inner surface of silica NTs could adsorb positively charged lysozyme via
electrostatic interaction.
The lysozyme forms a multilayer adsorption with the weight ratio of
lysozyme/silica 1:1 and 1:5 while a monolayer adsorption with lysozyme/silica
1:10 and 1:20. The enzymatic catalysis experiment shows that the lysozyme’s
enzymatic activities first increased and then decreased with increasing surface
coverage, in contrast to the common result, i.e enzymatic activity largely depends
on the degree of adsorbent surface coverage; the specific activity decreases with
decreasing surface coverage .This result reveals that the overlap and aggregation of
the lysozyme molecules may reduce enzymatic activities at high surface coverage.

Lipid is the basic building blocks of biological membrane. In liquid media, lipid
molecules self-assemble into diverse aggregate morphologies, depending on the
molecular shape and solution condition such as lipid concentration, electrolyte
concentration, pH, and temperature .
Many lipid molecules can self-assemble into open ended, hollow cylindrical
structures, named lipid NTs (LNTs), which are composed ofrolled-up bilayer
membrane wall .
The self assembly process involves a solid bilayer ribbon structure as an
intermediate through fusion of vesicles in cooling process. Thesolid bilayer ribbon
then twists into an open helix, which eventually closes to yield NTs in the way of
either widening of the tape width and maintaining a constanthelical pitch or
shortening of the helical pitch of the ribbon and maintaining a constant tape width.
In addition to the twisting-induced LNT, there is another route based on packing
directed self-assembly without forming helically twisted or coiled ribbons during
the course of self-assembly .
While LNTs have been widely utilized as scaffolds for synthesis of structured
nanomaterials ;these biocompatible nanochannels are getting more and more
intension as drug vehicles. Price et al loaded antibiotics used to prevent marine
fouling into LNTs of 1(8,9)by capillary force . The tubes were then incorporated
into a paint. This NT�based paint successfully proved to inhibit marine fouling
during 6 months in ocean water. The applied biocides include bactericides,
herbicides, molluskicides, insecticides, pesticides. Encapsulation of the biocides
was accomplished by dispersing the desired biocide into a fluidic carrier. The
selection of the carrier is determined by the viscosity of the carrier and the
solubility of the active agent in the carrier. The carrier must possessa sufficiently
low viscosity so that it can fill the lumen of the tubule as a result of capillary
action. This carrier may be a monomer, a linear polymer or a polymerizable cross-
linking material.
The release rate for a given agent is determined by the average inner diameter and
length of the LNT, the viscosity of the carrier, the relative solubilities of the agent
in the carrier and in the surrounding matrix (if present), and molecular weight of
the active agents as well as that of the carrier. If the agent is soluble or mobile in
the carrier, then the rate of release will mainly depend on the diffusion rate and
solubility of the agent in the carrier and in the external matrix. If the agent is
insoluble or immobile in the carrier, then the rate of release will mainly depend on

the rate of release of the carrier itself from the tubule. As another example of
application of LNTs as a drug deliver nanocarrier, Kulkarni utilized the LNTs for
topical delivery of drug into skin.
It is well known that skin is an excretory organ that often causes topical delivery of
pharmacological or cosmetic agents difficult to penetrate against the natural ex-
cretory forces. Moreover, the skin surface is enriched with sweat, bacteria, and
cells that have been damaged or killed by ultraviolet light, creating a harsh
environment for drug molecules and making the drug susceptible to degradation
before reaching their target. The delivery system with LNTs confers special
advantages for topical delivery of agents to the skin over other delivery vehicles.
The diameter of human skin pores has been estimated to about 40 nm .Unlike
traditional liposomal systems, LNTs have a significant size population under 100
nanometers in diameter, while still carrying significant quantities of active
ingredient. These LNTs are therefore particularly useful as topical drug delivery
vehicles because their small size permits rapid dermal penetration. In addition, the
tubular delivery system described in Kulkarni’s work consists of lipids compatible
with lipids in stratum corneum, which further facilitates skin penetration.
Furthermore, the delivery system with LNTs is capable of transporting a multitude
of active ingredients, including drugs, genetic material or cosmaceuticals deep into
the skin. Fluorescent LNTs can be used simultaneously as drug carriers and
biomarkers to track and diagnose effectiveness of the treatment. We have made
fluorescent NTs from a synthetic peptide lipid, the sodium salt of 2-(2-(2-
tetradecanamidoacetamido) acetamido) acetic acid 2, which consistof
CdS�embeddedbilayer membranes . The lipid 2 can self-assemble in aqueous
solutions into a hollow cylindrical structure in the presence of proton(H+)
(H�LNT) or a series of transition metal cations (M�LNT) . As illustrated in
coordination of Cd2+ to two negatively charged COO� groups of the lipid 2
allows it to form a Cd�complexed LNT (Cd�LNT). Upon exposure to H2S vapor,
the Cd2+ in the Cd�LNT were released as a result of competitive binding of the
protonto the COO� group, resulting in the formation of H�LNT. The released
Cd2+ subsequently reacted with S2� to initiate CdS nuclei, and finally grew into
the CdS nanoparticles in all over the lipid bilayer membranes.
The CdS nanoparticles have an average diameter around 4�5 nm with narrow
distribution and separate from one another without any aggregation. The tubular
nanocomposites clearly exhibited distinguishable fluorescfluorescence originating
from electronic transition of the CdS nanoparticles. The fluorescence is resistant to
photobleaching compared to other organic moiety-based fluorescence, and enables
one to visualize for long time and to trace the localization in biological systems.

Introduction

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Introduction