Nanomedicine+for+Targeted+Drug+Delivery

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Nanomedicine for targeted drug delivery

Do Kyung Kim* and Jon Dobson*

Received 9th February 2009, Accepted 24th April 2009

First published as an Advance Article on the web 4th June 2009

DOI: 10.1039/b902711b

In recent years, nanoparticles have played an ever increasing role in biomedical research and clinical

applications. The unique physical properties of nanomaterials are being exploited in the field of

nanomedicine for applications as diverse as drug delivery and targeting, MRI contrast enhancement,

gene therapy, biomarkers, targeted hyperthermia and many others. This review focuses on the design,

synthesis and unique properties of nanoparticles used in nanomedicine as well as on clinical uses for

both diagnosis and treatment of disease.

1. Introduction

The application of nanotechnology to biology and medicine

bionanotechnologyis a growing field. Though research in this

area has undergone rapid expansion in the last decade, manyapplications have not yet made it to routine clinical use.

However, the potential impact of nanotechnology is broad as

nanoscale structures are sufficiently tiny to facilitate unique

interactions with most biological components (e.g., viruses,

organelles, proteins, DNA) at the molecular level. Particularly

impressive achievements are being made in the fields of diagnosis

and detection by MRI1 and fluorescent quantum dots,2 targeted

and controlled drug/gene delivery,3 and cancer treatment by

hyperthermia,4 and this work has given rise to a new, emerging

discipline known as nanomedicine.

Within the field of cancer research, there is great scope for

applying new techniques in nanomedicine to the diagnosis and

treatment of these diseases. Conventional anticancer modalities

such as surgery, radiotherapy, chemotherapy, hormones and

immunotherapy have provided improvements to the successful

treatment of neoplastic disease. However,each of these treatments

has advantages and disadvantages, consequently combined treat-

ment modalities are often recommended to achieve the optimum

effects. Chemotherapy, for example, is a whole body treatment

which is administered either orally or intravenously. This results in

the systemic distribution of cytotoxic, chemotherapeutic

compounds which canbe moreeffectivefor thetreatment of micro-

metastases. Unfortunately, the systemic distribution of cytotoxic

compounds usually results in more serious side-effects (anemia,

vomiting, diarrhea, nausea, decreased infection resistance, and an

increased likelihood of hemorrhaging, hair loss), some of which

can be life-threatening, compared to surgery or radiotherapy, and

these treatments are often used in combination. The major goal of

targetedtherapies is to reduce the side-effects which result from

systemicdistributionof cytotoxic drugs in order to more effectively

control cancer cell proliferation or tumor angiogenesis.5

The past few decades have seen great improvements in

chemotherapy, leading to increases in survival rates, but there is

Institute for Science & Technology in Medicine, Keele University,Stoke-on-Trent, United Kingdom ST4 7QB. E-mail: [email protected]; [email protected]

Do Kyung Kim received the

Ph.D. degree in materials

chemistry (nano-bio) from the

Royal Institute of Technology

(KTH) in Sweden, 2002. He

was a Postdoctoral Fellow in the

Department of Electrical Engi-neering and Computer Science,

Massachusetts Institute of

Technology (MIT), in 2003. He

is currently a lecturer in the

Institute of Science and Tech-

nology in Medicine (ISTM,

rated 5A in the 2001 RAE

exercise), Keele University,

U.K. His research interests include target oriented drug delivery

systems, nanocomposites, quantum dots, and bulk production of

nanomaterials for energy applications.

Jon Dobson received a B.Sc. and

M.Sc. from the University of

Florida, and a Ph.D. from the

Swiss Federal Institute of Tech-

nology (ETH-Zurich) in 1991.

He did his postdoctoral research

in the Department of Physics,Institute of Geophysics, ETH-

Zurich, before taking a lecture-

ship in Biophysics in the

Department of Physics at the

University of Western Australia.

He is currently a Professor in

Biophysics and Biomedical

Engineering at Keele University

and Eminent Scholar/Visiting Professor at the University of

Florida.

6294 | J. Mater. Chem., 2009, 19, 62946307 This journal is The Royal Society of Chemistry 2009

FEATURE ARTICLE www.rsc.org/materials | Journal of Materials Chemistry


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still a critical need to develop more refined therapies which

increase survival and the quality of life for cancer patients. The

enormous technical advances that have occurred in the area of

basic cancer research have not yet been paralleled by similar

improvements in treatment results. Thus, current research is

more focused on a better understanding of the pathophysiology

of neoplastic diseases at the cellular and molecular level in

order to develop more specific cellular and molecular targeting

therapies.Despite advances in cancer therapies, side effects of systemi-

cally administered drugs repeatedly remain a dose-limiting factor

in therapeutic protocols. Self-directed localization of therapeutic

agents to the disease-affected target tissue has been proposed to

overcome this problem. For tumor targeting, disease-specific,

tumor-associated antigens have been exploited for this purpose,6

but the selective uptake of chemotherapeutic agents by tumor

tissues remains a great challenge. For this reason, massive efforts

have been devoted to the development of smart drugs that can

be directed to tumor cell-specific enzymes and surface receptors.

This is an area where bionanotechnology is making great strides.

At present, there are numerous anticancer agents available in

the clinic. These anticancer agents/drugs have an eliminationhalf-life which results in a decrease of the therapeutic potential

and side-effects such as bone marrow depression and gastroin-

testinal damage. Novel strategies have been suggested to decrease

the toxicity of active molecules by targeting the specific tumor

site, where the drug can selectively bind to the targeted tissue at

a cellular and/or sub-cellular level to influence its therapeutic

effects. Chemotherapeutic activity can be enhanced by using

macromolecules as a vector to control the release rate of anti-

cancer agents. For example, polyalkylcyanoacrylate nano-

particles as drug delivery systems (DDSs) play an important role

in the incorporation of anticancer drugs as they can enhance the

drugs concentration in the tumor sites and decrease drug levels

in the heart, thus avoiding some side-effects.7 Polymericnanoparticles are being used to control the loaded anticancer

agent/drug at the targeted site. In a general sense, polymeric

nanoparticles as used in nanomedicine consist of core-shell

nanocapsules that may incorporate therapeutic agents either

within the particle or attached to the outside. Several kinds of

more basic inorganic and metallic nanoparticles without the

sophisticated structures may also be used since their intrinsic

physical properties may be exploited for targeting. Super-

paramagnetic iron oxide nanoparticles (SPION) in particular can

be used as both a targeting agent and a therapeutic by combining

their responses to external AC and DC magnetic fields.8

In spite of major advances in the development of small-scale

devices, however, the majority of DDSs continue to employ smallmolecules administrated orally, transdermally, parenterally, or

through the nose or lung. Target-oriented DDSs, due to their

specificity, should allow for the use of lower doses of anti-cancer

agents, reducing the side-effects associated with systemic distri-

bution.9 The development of novel, smart biomaterials is already

beginning to have an enormous effect on nanomedicine.10

Many synthesis techniques used to produce nanoparticles for

cancer therapy have focused on empirical analysis for the

development of controlled-release anticancer agents and the

increasing demand for multi-functional vectors in nanomedicine

still represents a major fabrication challenge. However, design

criteria can be proposed which integrate several aspects;

(i) theoretical and practical consideration of the novel

phenomena resulting from the particles composition and small

size, (ii) design of complex or composite structures with specific

morphologies and surface chemistry required for multi-func-

tionality, (iii) generation and assembly of new molecular and

macromolecular structures using suitable processing methods,

(iv) methods of incorporation of pharmaceutical agents to be

delivered to the target cells by active or passive targeting, and (v)modification of the particles surfaces and interfaces which

render them suitable for interaction with the pathological sites.

Moreover, novel concepts are needed for the development of

nanoparticles for cancer-oriented drug delivery systems

(CoDDS) with core-shell or mesoporous structures. These carrier

vectors then can be programmed to respond in a variety of ways

to external stimulation, e.g. pH, ionic strength, temperature,

ultrasound, radiation, magnetic fields, UV-light etc. The devel-

opment of suitable nanostructures, methodologies for drug

incorporation, methodologies for controlling release rates, toxi-

cology and biological activity therefore should be considered

during the design phase.

2. Design of nanoparticles for cancer therapy and

their prerequisites

2.1 Nanomaterials in biological systems

Nanomedicine is concerned with the development of advanced,

multifunctional, and even smarter smart materials for specific

applications in this highly integrated field. Recently, these

interdisciplinary concepts have been converging at the intersec-

tion of nanotechnology and molecular biotechnology. They are

closely associated with surface chemistry and the physical

properties of nanomaterials, the topics of bio-organic and bio-

inorganic chemistry, and the various aspects of molecularbiology, recombinant DNA technology and protein expression,

and immunology.

The development of micro/nanospheres has become an

important area of research as such systems enable the

controlled-release of cytotoxic drugs directly into the patho-

logical sites. They also make it possible to transport therapeutic

agents into sites of inflammation or neoplastic diseases. The in

vivo application of nanomaterials require an understanding of

the fundamental mechanisms of their behavior in biological

systems. The effectiveness of targeted nanomedicine can be

evaluated by considering several phenomena depending on

injection sites or extravascular routes. For intravenous injection

the primary factors will be the distribution, elimination andmetabolism of nanomaterials in vivo, whereas extravascular

injection includes more factors such as cellular uptake (endo-

cytosis; phagocytosis and pinocytosis, receptor-meditated

endocytosis).

Endocytosis is a process whereby cells absorb materials

(small particles, molecules and liquids) from the extracellular

space by engulfing them with their cell membrane. This mech-

anism is used by all cells in the body as many substances

important to cellular function are polar and consist of large

molecules, and thus cannot pass through the hydrophobic

plasma membrane. Internalization of the nanomedicine at

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undesired sites due to endocytosis can be eliminated by

applying stealth coatings on the surface of nanomaterials via

manipulation of the surface chemistry. Generally, when these

nanoparticles are injected intravenously, they will be captured

by macrophages of the mononuclear phagocyte system (MPS;

liver, spleen, lungs and bone marrow). Once in the blood-

stream, surface non-modified nanoparticles (conventional

nanoparticles) are rapidly taken up and massively cleared by

the macrophages.11 The stealth coating can both enhance theantitumor efficacy, with a high concentration of the therapeutic

agents localized in pathological sites, and prolong the agents

half-life in the blood.

One of the most important characteristics for nanomedicines is

their biocompatibility, especially with respect to their surface

chemistry. Biocompatibility of nanomaterials can be improved

by modifying the terminal groups on the surface of the nano-

materials as well as their constituents. Obviously, it is important

to stabilize the nanomaterials sterically by chemical modification

or by attaching an outer shell, which minimizes the recognition

by the mononuclear phagocyte system (MPS) in the reticuloen-

dothelial system (RES).12

Essential properties of any multifunctional nanomedicinecarrier are its durability and long-circulating pharmaceutical

effects. One of the main reasons for producing long-circulating

drugs is to maintain the required therapeutic level of the phar-

maceutical agent in the blood for extended time periods.

Subsequently, long-circulating, drug-containing micro-

particulates or large macromolecular aggregates will accumulate

slowly (the enhanced permeability and retentionEPR effect

also termed passive targeting or accumulationvia an impaired

filtration mechanism) in pathological sites with affected and

leaky vasculature, and facilitate controlled release in those areas.

In addition, the prolonged circulation half-life produces better

targeting effects for specific ligand-modified drugs and drug

carriers allowing more time for their interaction with the path-ological sites due to the larger number of passages of pharma-

ceuticals through the target.13

2.2 Nanomaterials as potential carrier vectors of therapeutic

agents

The extracellular matrix biology, cell receptors and immunology

should be considered during the development of artificial

synthetic nanomedicines for CoDDSs, together with an under-

standing of how the human body reacts to the specific

substances. It should be possible to incorporate hydrophobic/

hydrophilic drugs with active surface modifications into thenanomedicine by the attachment of active functional ligands for

targeting specific organs, receptors,etc.

Nanoparticles (Fig. 1A). Colloids are representative of nano-

materials stabilized in solution to prevent uncontrolled size growth,

aggregation, and flocculation. Utilization of colloidal processing

leads to attractive novel concepts for the preparation of advanced

nanostructured materials. Several parameters of the colloidal

systems have been considered,such as temperature, osmolality and

pH of the polymerization medium, which could influence the

characteristics (morphology and morphometry, drug content,

melting point transition or the enthalpy of transition) and stability

of the nanoparticles. Based on their unique mesoscopic physical,chemical, thermal and mechanical properties, nanoparticles offer

great potential for many biomedical applications, including bio-

analysis and bioseparation, tissue-specific drug therapy applica-

tions, gene and radionuclide delivery.14

Many studies have been focused on colloidal processing of

polymeric, inorganic and metallic materials through chemical

methods. The candidate nanoparticles for nanomedicine may be

either amorphous or crystalline and may have particular physical

characteristics, such as optical, magnetic, fluorescence, and elec-

tric properties. With semiconductor Quantum Dots (QDs), i.e.

CdS/CdSe, as the particle sizes decrease, quantum effects cause

the material to fluoresce under ultra-violet or infrared light. By

modifying the functional groups on the surface, the bioactivity ofQD nanocrystals can be directed. Consequently, the luminescent

effects of QDs can contribute to fluorescence-based techniques in

Fig. 1 Generalized schematic representation of nanomedicine constituents. For example, A can be a nanomaterial core such as an iron oxide, B

represents surface functional groups, C is a biocompatible layer such as polymer or novel metal, and D is a functional group to conjugate further active

targeting agents such as an antibody. Any flexible combination such as A + B, A + B + C, A + D and A + B + C + D provides the potential to construct

a nanomedicine.



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biomedicine. A major drawback, however, is that compounds

containing cadmium are cytotoxic, even at low concentrations,

and will accumulate in organisms and ecosystems. One possible

explanation for its cytotoxicity is that it interferes with the action

of zinc-containing enzymes and the cytotoxic effects of the

nanomaterials themselves is a rather controversial and topical

issue at present.15 Thus the potential cytotoxicity of the corematerials should be considered when developing nanomedicines.

Table 1 gives an overview of some of the examples of nano-

particles being developed for use as nanomedicines.

Magnetic nanoparticles or QDs are particularly attractive as

core materials when there is a requirement to monitor the

distribution of the sample after injecting intravenously or via an

extravascular route. Furthermore, magnetic nanoparticles can be

non-invasively traced byin vivoMRI techniques and QDs can be

monitored by in vivo/vitro near-IR. Consequently the experi-

mental/therapeutic aims and conditions, such as in-vivo/in-vitro

and instrumentation techniques, should be considered during the

design of proper nanomedicines.

After selecting suitable core materials, the colloidal behaviorof the nanoparticles in the dispersion medium should be

considered. They can be constructed to absorb, conjugate and

encapsulate therapeutic agents inside or outside. The nano-

particles can be prepared by various chemical synthesis routes,

such as microemulsion, chemical co-precipitation, thermal

reduction and polymerization etc. Although the as-prepared

nanoparticles may be dispersed within the colloid, the particles

may agglomerate and precipitate when transferred into PBS

buffer solution due to the presence of different ion species in the

medium and changes in the zeta-potential of the particles. When

the particles are designed for intravenous injection, the surface

charge of the particles in the biological media is an important

parameter to be considered.

Surface modifications (Fig. 1B and D).Uncoated nanoparticles

as carrier vectors are not highly suitable due to concerns asso-

ciated with the complicated preparation of stable colloidal

suspensions with low cytotoxicity. As a consequence, surface

modification with biocompatible substances is essential.

Integrating organic molecules with inorganic nanostructureshas yielded exciting results in the field of nanomedicine. Organic

molecules have been used as surface coatings to prevent unnec-

essary nanoparticle aggregation, as molecules to direct nano-

particle assembly, and as homing devices to target

nanostructures to specific biological sites. Furthermore, organic

molecules can enhance functional capabilities in nanostructured

materials.

The ability to assemble nanostructures requires accurate

control of the particles surface chemistry, where functional

molecules (carboxyl, hydroxyl, thiol, or amine) can be directly

assembled onto the surface of nanomaterials. The surface of

metallic nanoparticles such as Au or Pt colloids can be easily

modified with recognition biomolecules such as weak ligandsthat can be easily desorbed onto the surface. For instance,

proteins and transferrin can be physically adsorbed onto the

surface of citrate-stabilized Au nanoparticles through ionic and

hydrophobic interactions as well as dative binding. However,

modification of the surface structure of most inorganic nano-

particles is rather more complicated than metallic nanoparticles,

thus additional coating steps with dual functional agents like

a (3-aminopropyl) trimethoxysilane (APTMS) have been

proposed to activate the reactive amine groups. An amphiphilic

polymeric layer has been introduced onto the surface of QDs to

activate the carboxyl groups. The primary amine group in

biomolecules can be covalently bonded to the amphiphilic

polymer with a crosslinking agent, EDC (1-ethyl-3-(3-dimethy-laminopropyl)-carbodiimide), forming an amide bond linkage

between the QDs and the biomolecules.

Three different types of magnetic colloids can be prepared

through various stabilization methods (Fig. 2). The first

Table 1 Examples of nanoscale platforms for nanomedicine (Fig. 1A)

Composition Size (nm) Applications Ref.

MetalsAu 2150 Drug and gene delivery 16Ag 180 Antibody tagged marker 17Pt 120 Sensors and electrodes 18Co 150 Magnetic separation,

drug targeting19

Semiconductors (Quantum Dots)CdX(X S, Se, Te) 120 Fluorescent labeling 20ZnX(X S, Se, Te) 120 Fluorescent labeling 21PbS 218 Infrared photodetectors 22TiO2 350 Biomedical devices for

nerve tissuemonitoring

23

ZnO 130 Photoluminescence 24GaAs, InP 115 Nonlinear optics 25Ge 630 Photoluminescence 26MagneticFeO 640 MR contrast agent,

Drug Delivery,Hyperthermia

27

FePt 210 MR contrast agent,Drug Delivery

28

Nanotube (NT)Carbon NTs 110 Drug/Gene delivery 29PolymerLiposomes 100250 Drug/Gene delivery 30Dendrimer 110 Drug/Gene delivery,

MR contrast agent31

Fig. 2 Schematic representation of three different types of magnetic

colloids: (a) small (typically 12 nm) core-shell structure magnetite

nanoparticles with their magnetic dipoledipole interactions screened by

a layer of surfactant; (b) prepared in a polymeric matrix with a primary

agglomeration size of 35 nm; (c) MPEG modified SPION (primary

agglomeration size is 120 nm).3234



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magnetic colloid is prepared by coating the magnetic core with

a suitable surfactant such as sodium oleate (anionic surfactant,

CH3(CH2)7CH]CH(CH2)7COONa). The second stabilization

method is produced by the formation of nanocomposites con-

sisting of magnetic nanoparticles distributed throughout

a matrix and then the grafting of a non-magnetic coating, e.g.

polymeric starch. The presence of polymeric starch hinders the

cluster growth after nucleation during the formation of SPIONs.

These polymeric networks cover a large number of continuouslyformed iron oxide monodomains and hold them apart against

attracting forces by surface tension. In addition, the formation of

a polymeric layer on the surface of the magnetite nanoparticles

prevents further crucial oxidation, which affects phase trans-

formation. The third magnetic colloid suspension is stabilized, in

a similar manner to that of starch, by MPEG immobilization on

the SPION surface.

The introduction of amine groups on the surface of SPION has

been performed by the two procedures depicted in Fig. 3:

(a) silanization and (b) chemisorption processes. The silanization

process is based on the covalent binding of APTMS to SPION.

The silane coupling agent, usually called an organosilane, has the

following structure: RxSiY(4x). Silicon is located at the centre ofthe molecule and contains organic functional groups R (vinyl,

amine, chloro etc.) and other functional groups Y (methoxy,

ethoxyetc.). The inorganic groups Y of the molecule hydrolyze

to silanol and form a metal hydroxide or siloxane bond with the

inorganic material. The organic group can be connected cova-

lently with organic materials, such as proteins, PEG, biomole-

cules etc. The surface modification with LAA is based on the

chemical adsorption process. LAA is an amine acid and is used as

a chelating agent in SPIONs. LLA on the surface of SPIONs acts

as a small intermediary molecule that can ensure the availability

of a complementary attachment site for functional biomolecules.

After LAA is chemisorbed onto the surface of the SPION, the

coupling between amine acid and the biomolecules can involve

chemical bonds. With this procedure, a number of biomolecules

can be grafted onto the SPION. Fig. 3 (c) and (d) also show

schematic views of the BSA immobilization process. The BSA-

coated SPION prepared by direct coprecipitation is based on the

adsorption of protein followed by covalent binding via carbo-

diimide activation (Fig. 3c). An attempt to immobilize BSA on

APTMS-functionalized SPION has also been performed(Fig. 3d).

The surface layer (few or several monolayers) is distinctly

different from that of the core material in both composition and

structure. Again, such particles are categorized as core-shell

structures. The thickness of the surface layer may be thin or thick

depending on the functionality required. In a broad perspective

these particles can also be considered as composite nanoparticles.

However, the term nanocomposite generally refers to materials

consisting of a dispersion of nanoparticles within a suitable

matrix. The most common example of nanocomposites is the

precipitation of core nanoparticles within a nanoporous polymer

structure. It is interesting to note that the fundamental properties

of the polymeric materials can be dramatically altered as a resultof the dispersion of few percent of inorganic nanoparticles.

Polymeric nanomaterials.There has been considerable interest

in developing biodegradable nanoparticles as effective drug

delivery devices.35 Biodegradable polymers are polymers that can

be degraded and/or catabolized, eventually to carbon dioxide

and water, by microorganisms (bacteria, fungi, etc.) under

natural environments.36 However, due to the development of

a wide variety of synthetic biocompatible polymers, the defini-

tion has been altered to include many artificially synthesized

polymeric materials. Needless to say, components of the

Fig. 3 Schematic view of surface modification of magnetic nanoparticles: (a) silanization process; (b) chemisorption process; (c) carbodiimide acti-

vation; (d) immobilization of BSA on APTMS-modified SPION.



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degraded polymers should not be toxic and should not promote

the generation of harmful substances within the body.

Biodegradable polymers can be classified into three major

categories: 1) polyesters produced by microorganisms; 2) natural

polysaccharides (i.e. chitosan,3741 dextran42); 3) artificially

synthesized polymers, especially aliphatic polyesters (i.e. poly

lactide (PLA),43,44 poly (lactide-r-glycolide) (PLGA),45 and poly

3-caprolactone (PCL)44), polyamide (i.e. poly L-lysine,46) and

others such as poly(methylmethacrylate) (PMMA)47 and poly-(ethyl-2-cyanoacrylate) (PECA)48 which are also being developed

as nanoparticles for the same purpose.

Biodegradable polymers are not only limited to medical

devices and wound dressings, but are also used for the fabrica-

tion of scaffolds in tissue engineering,49 and as DDSs for

controlled-release of 5-fluorouracil,37 cisplatin,50 lidocaine,5153

indomethacin,44 taxol,54 4-nitroanisole,55 dexamethasone,56

radioactive compounds,57 peptides,58 and proteins5964 with

characteristic release rates at the specific target sites. For the

purpose of DDSs, interest has focused on the use of particle

formulations prepared from aliphatic polyesters due to their

biocompatibility and resorbability. Chemical modification of

pharmaceutical nano-carriers with certain synthetic polymers,such as poly(ethylene glycol) or PEG, is the most frequently used

way to prolong their circulation time as drug carriers. On a bio-

logical level, coating nanoparticles with PEG sterically hinders

the interactions of blood components with their surface and

reduces the binding of plasma proteins with PEGylated nano-

particles. This prevents drug carrier interaction with opsonins

and slows down their fast capture by RES.65

Multifunctional smart nanoparticles.These have been designed

in order to meet the need for the fabrication of nanoparticles with

a higher degree of complexity. Further to the core-shell structure,

nanoparticles with structures similar to nanocomposites have

been fabricated (nanobeads). The single bead consists ofa nanocomposite core, where one or fewer nanoparticles are

dispersed into the matrix. Several possible combinations of

organic and inorganic particles can be dispersed within the core

matrix structure. Each of the dispersed components can be

selected to achieve a specific function or property of the particle.

The surface layer can combine both physical (e.g. diffusion

control) and chemical (e.g. allowing certain conjugation chem-

istries) functionality to the particles. In this way, it is possible to

program the nano-carriers with multiple functionalities suit-

able for performing tasks that can be triggered under specific

conditions. For example, it is possible to fabricate such nano-

carriers that can be magnetically stimulated or localized for

target oriented controlled drug release. The release rate of thetherapeutic drug can be controlled by changing the matrix of the

nano-carriers or through the control of the porosity of a suitable

shell layer on the surface of the bead. The nanobeads can be

programmed to be responsive to the environment, e.g. small

variations in temperature, or pH. Though the fabrication of these

advanced generation nanoparticles is complex they have great

potential for DDSs.

The design and fabrication of biochemically functionalized

superparamagnetic iron oxide nanoparticles and near-infrared

light absorbing nanoparticles is of particular interest for cancer

targeting and therapy applications. The processing of

nanoparticles with controlled properties, such as chemical

properties (composition of the bulk, interaction between the

particles, and surface charge) and structural properties (crystal-

line or amorphous structure, size, and morphology), is the main

feature in designing the nanoprecursors (nanoparticles/nano-

tube/nanolayer). The development of supramolecular, biomo-

lecular, and dendrimer chemistries for engineering substances of

Angstrom and nanoscale dimensions has been encouraged for

requirements in nanotechnology. The emerging disciplines ofnanoengineering, nanoelectronics, and nanobioelectronics

require suitably sized and functional building blocks to construct

their architectures and devices.66

Magnetic nanoparticles are also of particular interest as high-

gradient external magnetic fields exert a force on them, and thus

they can be manipulated or transported to specific pathological

sites by applying an external magnetic field.60 They also have

tunable sizes, so their dimensions can match either that of a virus

(20500 nm), a protein (550 nm) or a gene (2 nm wide and 10

100 nm long). In addition, superparamagnetic particles are of

interest because they do not retain any magnetism after removal

of the magnetic field, thus reducing the potential for aggregation

and blockage within the vasculature.The most promising candidates for smart drug carriers as

nanomedicines are polymeric nanomaterials. In general, a poly-

mer which tends to lose mass over time within a living organism

is called an absorbable, resorbable, or bioabsorbable, as well as

a biodegradable polymer. In comparison with the strict defini-

tion, biodegradable polymers require the enzymes of microor-

ganisms for natural hydrolytic or oxidative degradation.

Regardless of the degradation behavior, this terminology applies

to both enzymatic and non-enzymatic hydrolysis. The physi-

ochemical properties of the materials should be considered to

remove toxins from the drugs in the patients body as quickly as

possible. Such engineered smart nanomaterials are strong

candidates for drug detoxification because the size and surfacemodification of the nanomaterials are the key factors in pre-

venting further damage to the patients healthy organs.45

As one of the stimuli-sensitive polymers (SSPs), poly(N-iso-

propylacrylamide) (PNIPAAm) is well known as a thermosensi-

tive polymer due to its distinct phase transition at a specific

LCST at 32 C in water.6771 PNIPAAm is hydrophilic below the

lower critical solution temperature (LCST); however, it becomes

hydrophobic when it is heated up above the LCST. PNIPAAm

has been consistently investigated as it has smart characteristics

and it is being developed for nanomedicine in the form of

micelles,67 tablets,70 and hydrogels.

A new class of temperature-programmed shell-in-shell

structures with two different copolymers synthesized by a modi-fied-double-emulsion method (MDEM) was reported as an

advanced generation nanocarrier.43 Thermosensitive inner shells

composed of poly(N-isopropylacrylamide-co-D,L-lactide)

(PNIPAAm-PDLA) with a lower critical solution temperature

(LCST) can be fabricated. This novel technique allows for the

construction of a delivery vector with programmable release

rates for any kind of hydrophilic chemotherapeutic agents into

the polymeric nanocapsules. The drug release rates are governed

by several parameters which only involve the PLLA-PEG outer

shell, such as the volumetric ratio between the organic phase and

aqueous phase, the interaction parameters between the



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therapeutic agents and the core domain, tacticity of the copoly-

mer, the encapsulation efficiency, and so on.

Generally, a hydrophilic protein such as BSA can be encap-

sulated in the polymeric spheres using a double-emulsion method

(DEM), a so-called water-in-oil-in-water (w/o/w) emulsion

method.61,71,72 However, the DEM has a disadvantage with

respect to the stability of amphiphilic polymer spheres because

both the inner shells and the outer shells are composed of the

same species of copolymer. As for the MDEM, two differentkinds of copolymers are sequentially incorporated in the organic

phase to promote an enhanced stability of the spheres. In this

way, the inner shells can be prepared with PNIPAAm-PDLA

diblock copolymers and the outer shells can be prepared with

PLLA-PEG diblock copolymers respectively.

For another class of thermosensitive nano-carriers, poly-

[(NIPAAm-r-AAm)-co-lactic acid] (PNAL) has been reported.73

Au nanoparticles can be directly self-assembled on the surface of

PNAL nanospheres by virtue of primary amino groups coming

from acrylamide (AAm) molecules of PNAL diblock terpolymer.

The primary amino groups can be strongly bound to noble

metals such as gold or silver. Therefore, the shell domain of

Au@PNAL becomes an affinity site for biomolecules to beconjugated. Furthermore, the LCST of poly(N-iso-

propylacrylamide-r-acrylamide) (PNA) was modulated from 32C up to approximately 36 C through the manipulation of the

ratio between NIPAAm and AAm units. This nanostructure is

expected to serve as a synchronous delivery system by virtue of its

Au-modified surface and hydrophobic inner core site.

3. Active targeting of tumors/cancer cells

In general, the surface molecules of tumors/cancer are overex-

pressed compared to normal, healthy cells. The exhibiting

surface-specific molecules could be used to regulate cellular

processes and are therefore referred to as tumor associatedantigens. These overexpressed antigens differ from those on the

normal cells and thus can be targeted and used for therapy by an

antibody or a receptor ligand to which a toxic substance has been

coupled. Antibodies, most frequently monoclonal antibodies

(mAbs), are used to target tumor-specific structures in several

ways (Fig. 4). Generally, antibodies conjugated to a DDS, which

can load the chemotherapeutical agents such as ricin, genistein

and pseudomonas exotoxin A (ETA) in nanocapsules, have been

suggested to effectively eradiate tumor cells. Additionally,

a superantigen-conjugated antigen can be used to enhance the

immunoreactions toward the pathological cells. However, the

use of antibodies (most mAbs are derived from mice) can

provoke an immune response. Consequently, a humanizedchimeric antibody is produced by modifying the non-binding

part of the antibodies with human parts to enhance tolerance. In

some cases, when a smaller targeting agent is preferred, only the

binding part of the antibody, the Fab fragment75 can be used.

The smallest parts of the antibody, the variable regions, or so-

called single-chain fragments (ScFv), are among the most

frequently used ligands. Because mAb fragments lack the Fc

domain that binds to Fc receptors on phagocytic cells (resulting

in the RES scavenging particles bearing whole mAbs), particu-

lates derivatized with mAb fragments have increased circulation

times in the blood compared to particulates derivatized with

whole mAbs.76 The frequent use of mAbs or mAb fragments as

ligands for particulate drug carriers is the result of a well estab-

lished and relatively facile conjugation chemistry that produces

derivatives that retain full binding activity. mAb fragments have

the additional advantage that they can be expressed as

recombinant proteins in prokaryotic cells, a procedure that

facilitates a more cost-effective massive production than the

production of whole mAbs in eukaryotic cells.77

Targeting toxic therapeutic agents to pathological sites or tosites of inflammation of the endothelium through binding to

receptors over-expressed on the surface of cancer cells can

diminish the systemic toxicity and enhance the effectiveness of

the targeted compounds. Small molecule-targeted therapeutics

have a number of advantages over toxic immunoconjugates;

better tumor penetration, lack of neutralizing host immune

response and superior flexibility by selecting the proper drug

components with optimal specificity, potency and stability

during circulation.78

Therefore, actively targeted particulates represent the second

generation of particulate drug carriers; the first comprises parti-

cles not derivatized with a ligand. Non-targeted particle-drug

formulations demonstrate relative tumor selectivity as a conse-quence of passive targeting, and several have already been

approved for clinical use. As a resultof theincreased permeability

of endothelial barriers in tumor blood vessels and the lack of

effective lymphatic drainage from the tumor, passive targeting

results in the selective extravasation and accumulation of

particulates or other macromolecules in tumor tissues. However,

active targeting is expected to lead to higher intratumoral accu-

mulation and, in the case of targeting with internalizing ligands,

to higher intracellular concentrations of the drug.79

For the potential targeting of liver cancer cells, a novel carrier

was prepared with paclitaxel-loaded nanoparticles (P/NPs)

composed of poly(g-glutamic acid) and poly(lactide) and further

conjugation of galactosamine on the prepared nanoparticles(Gal-P/NPs). In in vitro studies, both the P/NPs and the Gal-P/

NPs had a similar release profile to paclitaxel. The inhibition of

HepG2 cell growth by the Gal-P/NPs was comparable to that of

a clinically available paclitaxel formulation (Phyxol), while the

P/NPs displayed significantly less activity (p


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Homing and binding to tumor-derived cell suspensions indi-

cated that LyP-1 also recognizes an osteosarcoma xenograft, and

spontaneous prostate and breast cancers in transgenic mice, but

not other tumor xenografts. These results suggest that tumor

lymphatics carry specific markers and that it may be possible to

specifically target therapies into tumor lymphatics.83

Certain tumors, including many that are found in the lung,

overexpress the CD44 cell surface marker. CD44 is a receptor

that binds to hyaluronan (HA), a carbohydrate consisting ofb1,3

N-acetyl glucosaminyl-b1,4 glucuronide. Eliaz and Szoka have

shown that the incorporation of phosphatidylethanolamine lipid

derivatives-containing HA oligosaccharides (HA-PE) into lipo-

somes could target drug-containing liposomes to tumor cells that

express CD44. HA targeted liposome (HAL)-delivered Doxo-

rubicin (DOX) was significantly more potent than the unencap-

sulated DOX in cells expressing high levels of CD44. This

suggests that HALs can be a functional targeted drug carrier for

treatment of CD44 expressing tumors.84

Liposomal nano-carriers loaded with Doxorubicin and

bearing controlled numbers of both folic acid and a monoclonal

antibody against the EGFR were designed as a dual-ligand

system which can target tumor cells while sparing off-target cells.

Typically overexpressed multiple types of surface receptor were

designed to enhance the selectivity of the targeted nano-carriers.

This approach was examined in the human KB cell line, which

over-expresses both folate receptor (FR) and the epidermal

growth factor receptor (EGFR).85 EGF-conjugated magneto-

liposomes were used to target the overexpressed EGFR in tumor

cells. These are liposomes that have magnetic nanoparticles

embedded in their bilayer, allowing for selective heating and

release of a drug when the magnetoliposome is exposed to an AC

magnetic field. If a tumor cell overexpresses EGFR by 5-fold,

then each of its endosomes will have five times more receptors

than those of a normal healthy cell. Therefore, the tumor cells

endosome has a five times greater chance of containing one EGF-

bound component and a 25 times greater chance of containing

both components.74

4. Passive targeting of tumors/cancer in vivo

The coupling of low molecular weight drugs with a high molec-

ular weight polymer provides for so-called passive tumor tar-

geting. This strategy increases drug accumulation in solid

tumors generally governed by the enhanced permeability and

retention (EPR) effect. The passive targeting system does not

require a special targeting moiety and is therefore substantially

simpler to construct compared to DDSs. Instead, passive tar-

geting can be applied based on specific conditions at the targeted

site (tumor or tumor-bearing organ).86

Tumor vessels have a wide lumen, whereas tumor tissues have

poor lymphatic drainage. This anatomical defect, along with

functional abnormalities, results in extensive leakage of bloodplasma components, such as macromolecules, nanoparticles and

lipid particles, into the tumor tissue. Moreover, the slow venous

return in tumor tissue and the poor lymphatic clearance mean

that macromolecules are retained in the tumor, whereas extrav-

asation into tumor interstitium continues, a process termed the

enhanced permeability and retention effect.87

By harnessing this unique characteristic (the EPR effect) of

solid tumors, the selective delivery of macromolecular anticancer

agents to the pathological sites has become a reality. The disor-

ganized pathology of angiogenic tumor vasculature with its

discontinuous endothelium leads to hyperpermeability to circu-

lating macromolecules, and the lack of effective tumor lymphatic

drainage leads to subsequent macromolecular accumulation.88

Chemotherapy with HT-1080 bearing mice was used to

investigate this drug targeting strategy and the cause of side

effects of dextran-peptide-methotrexate conjugates. In these

experiments, passive targeting was facilitated by the prolonged

plasma circulation and higher tissue accumulations of both types

of conjugates compared to free methotrexate. Independent of the

peptide sequence of the linker, the ratio of drug accumulation at

the tumor versus drug accumulation at the major site of side

effects (small intestine) for either conjugate was increased by the

EPR effect. The tumor targeting effect of the dextran-peptide-

methotrexate conjugate was dominantly due to passive targeting

and EPR.89

The antitumor effect of poly(ethylene glycol)camptothecinconjugate (PEGCPT) was studied in a nude mouse model of

human colon cancer xenografts. The conjugation of the low

molecular weight anticancer drug CPT with low solubility to

high molecular weight, water-soluble PEG polymer provided

several advantages over the native drug. It offered better uptake

by the targeted tumor cells and substantially enhanced apoptosis

and antitumor activity of the conjugated drug in the tumor along

with decreased apoptosis in the liver and kidneys as compared

with the native drug.86

In addition to the molecular manipulation of therapeutic

agents, surface-modified nanoparticles with stealth coatings can

be used as passive targeting agents. This allows them to selec-

tively extravasate in pathological sites, like tumors or inflamedregions with a leaky vasculature. As a result, such long-circu-

lating nanoparticles are able to directly target most of the tumors

outside the MPS regions.90 The core nanomaterials can be

prepared with mesoporous structures using MCM41 or CNT.

This system could incorporate the low molecular weight

chemotherapeutic agents such as DNA/RNA and can be applied

to gene therapy. Antifouling polymer, poly(TMSMA-r-

PEGMA),-coated SPIONs were also synthesized.

Another passive EPR approach is to exploit the clear visuali-

zation of leaky areas at the early stages of cancer/tumor growth

by injecting superparamagnetic iron oxides (SPION) as MR

Fig. 4 Tumor cell with some of the targeted structures and examples of

their targeting moieties.74



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contrast agents in vivo. When the anti-biofouling polymer-coated

SPIONs were incubated with macrophage cells, uptake was

significantly lower in comparison to that of the popular contrast

agent, Feridex I.V., suggesting that the polymer-coated SPION

can circulate for longer periods in the plasma, escaping uptake by

the RES such as macrophages. Indeed, when the coated SPIONs

were administered to tumor xenograft mice by intravenous

injection, the tumor could be detected in T2-weighted MR

images within 1 h as a result of the accumulation of the nano-magnets within the tumor site. Although the poly(TMSMA-r-

PEGMA)-coated SPIONs do not have any targeting ligands on

their surface, they are potentially useful for cancer diagnosis in

vivo.1

Dextran and its derivatives have been used as attractive

coating materials for inorganic nanoparticles such as SPIONs

due to their biocompatible and hydrophilic characteristics. For

example, Palmacci and Josephson91 synthesized cross-linked

superparamagnetic iron oxides (CLIOs) with epichlorohydrin,

which makes a continuous coating of SPIONs. CLIOs show

good stability and biocompatibility while the cross-linking

process does not affect particle size and magnetic properties of

the colloids. However, the conjugation of bioactive molecules todextran-coated SPIONs such as CLIOs is still very difficult and

strongly relies on the generation of additional functional groups

such as amine and carboxyl groups. In order to generate amine

groups on a dextran coating, cross-linked superparamagnetic

iron oxides (CLIOs) have been aminated by adding concentrated

ammonia at 37 C overnight for further attachment of Tat

peptides, a membrane translocation signal, through N-succini-

midyl3-(2-pyridyldithio)propionate (SPDP). However amine

groups generated by this method are unstable, which may result

in release of the attached Tat peptide.

Versatile, ultra-small superparamagnetic iron oxides (VUS-

PIOs) based on maghemite and partially oxidized dextran, have

been conjugated to poly(ethyl glycol) (PEG), a protein resistantmolecule. But generation of aldehyde groups breaks the glucose

unit of the dextran backbone. Carboxymethyl dextran (CMD)

that contains carboxylic groups as functional groups can be

easily modified with versatile bioactive molecules such as

peptides, proteins and oligonucleotides. Therefore, CMD is of

particular interest as a coating material for SPIONs.

Though the use of magnetic micro- and nanoparticles as drug

carriers for cancer therapy was first proposed decades ago, 92 the

technology has yet to prove effective in the clinic. Early animal

studies were promising using magnetic nanoparticles as both

drug carriers and for targeted magnetic fluid hyperthermia.93

Following on from the success of magnetic targeting and

hyperthermia in animal trials, there has been a handful of clinicalstudies aimed at moving the technology into humans.94

One of the main reasons for the lack of clinical success of

magnetic targeting is that the forces required to trap and target

magnetic nanoparticle carriers circulating in the bloodstream are

difficult to achieve for tumors deep in the tissue.9597 Recent

efforts to overcome this obstacle have focused on such novel

variations as implantable magnets98 and, more recently,the use of

magnetic nanoparticle-loaded macrophages to enhance targeting.

In this latter approach, the innate propensity of macrophages to

respond to chemical signals from tumors was harnessed to

increase the proportion of magnetic nanoparticle-loaded

macrophages which can carry associated chemotherapeutic

compounds and/or apoptosis genes.99 By increasing the propor-

tion of therapeutically armed macrophages, it should be possible

to target the non-vascularized hypoxic core of solid tumors100 and

subsequently employ magnetic fluid hyperthermia to destroy the

carriers and remaining tumor cells.

5. Nanomedicine for controlled release oftherapeutic agents at the target site

Although biomaterials (biologically derived components) are

useful for new medical treatments, critical problems with

biocompatibility, mechanical properties, degradation and

numerous other issues remain. Stealth properties and respon-

siveness such as pH, temperature, specificity and other critical

problems should be resolved in order to satisfy the prerequisites.

Generally, the drug release mechanisms from micro/nano-

particles should consider the following factors: (1) surface

desorption; (2) diffusion through particle pores; (3) diffusion

through intact polymers; (4) diffusion through water swollen

polymers; (5) surface or bulk erosion of the polymeric matrix.101

In addition, certain stimuli-sensitive functions such as pH

sensitivity,73 redox potential, external magnetic field,97 tempera-

ture,67 ionic strength and ligandreceptor interactions could be

introduced to enhance the long-circulating and targeted phar-

maceutical nano-carriers. For example, the intratumoral pH

value in solid tumors may drop to 6.5, i.e. one pH unit lower than

in normal blood (7.4) because of hypoxia and massive cell death

inside the tumor, and drops still further inside cells, especially

inside endosomes (5.5 and even below).102 Enzymes can catalyze

the cross-linking of the polymer chains to form a continuous,

three-dimensional matrix for hydrogels for tissue engineering,

wound healing, and DDSs. In addition, enzyme-responsive

surfaces can direct the attachment of cells, and enzyme-respon-sive polymeric hydrogel beads have potential as a matrix for

DDSs.103 The possibility of delivering cytotoxic agents directly

into tumor cells gives several advantages: loss of the drug in the

bloodstream and upon the liposomecell interaction are mini-

mized and the preparation of drug-loaded nanoparticles becomes

simpler.

To be effective, there are a number of attributes that the

material must possess, including the ability to condense thera-

peutic molecules to a size of less than 150 nm so that it can be

taken up by receptor-mediated endocytosisthe ability to be

taken up by endosomes in the cell and to allow therapeutic

molecules to be released in active form, and to enable it to travel

to the cells nucleus. Moreover, gene therapy is gaining popu-larity as a medical treatment for cancer, tumors, Alzheimers

disease, diabetes etc, however, the clinical efficacy is lower than

expected due to the detergent effect. When it is administered

directly into the blood vessel or lesion, the therapeutic molecules

are taken up by other healthy organs/cells and the residual time

in biological systems is less than 24 h, thus the pharmacological

action is diminished. Also, it has been reported that the thera-

peutic molecules taken up by healthy organs/cells undergo

mutation and may cause other, more serious diseases, such as

cancer. Most antitumor agents are hydrophilic compounds and,

therefore, cannot be retained within the membrane. Thus, the use



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of prodrug forms of anticancer agents to alter the phase behavior

of the chemicals is becoming more popular.

5.1. Alkylating agents

Alkylating reagents are chemical reagents that have an alkyl

group such as propyl in place of a nucleophilic group in a mole-

cule. Alkylating reagents include a number of cytotoxic drugs,

some of which react specifically with N7 of the purine ringresulting in depurination of DNA. These alkylating drugs

interact with DNA and prevent the division of the cells.

The alkylation of DNA bases can cause disruption of the

replication mechanism of the cell. The nitrogen bases in DNA

molecules are nucleophilic and can be easily alkylated. If the

NH groups are replaced by NR groups then the DNA base

pairing is disrupted and can lead to cellular dysfunction. This

should have an effect on the replication of cancerous cells, thus

leading to a slow-down or stoppage of the growth of the cancer.

Chlorambucil is one of the well-know anticancer agents for

blood cancers and acts to reduce the number of blood cells. It is

also used to treat other cancers such as lymphomas. The chemical

structure of Chlorambucil is an aromatic derivative of mech-lorethamine and is closely related in structure to melphalan. Its

therapeutic effects are the slowest acting and it is generally least

toxic among the alkylating agents. Alkylation of DNA results in

breaks in the DNA molecule as well as cross-linking of the twin

strands, thus interfering with DNA replication and transcription

of RNA. Like other alkylators, chlorambucil is cell cycle phase-

nonspecific.104,105

Lerouxet al.demonstrate that polymeric nanoparticles can be

loaded with chlorambucil (8.52% m/m) with an entrapment

efficiency of 60%. Nanoparticles as small as 70 nm in diameter

can be produced by increasing the percentage of poly(vinyl

alcohol) to 27.5% in the external phase. The particle size can be

controlled by using gelatin instead of poly(vinyl alcohol) and thesmallest nanoparticles, with an average size of 700 nm, can be

obtained.106

Chitin-based biodegradable microspheres also have been

investigated for their ability to encapsulate chlorambucil as

a model drug. The polymer sphere can be prepared by directly

blending chitin with different contents of poly(D,L-lactide-co-

glycolide 50:50) (PLGA 50/50) in dimethylacetamidelithium

chloride solution, followed by coagulating in waterviawet phase

inversion. In the initial stage, the drug-release rate increases with

increased chitin content due to the hydration and surface erosion

of the hydrophilic chitin phase; however, the following stage of

slow release is sustained for several days, mainly due to the bulk

hydrolysis of hydrophobic PLGA phase.27

Cyclophosphamide is a cyclic phosphamide ester of mechlor-

ethamine. It is transformedviahepatic and intracellular enzymes

to active alkylating metabolites, acrolein and phosphoramide

mustard. Cyclophosphamide causes prevention of cell division

primarily by cross-linking DNA strands. This anticancer agent is

applicable to breast cancer, lung cancer, multiple myeloma,

mycosis fungoides, neuroblastoma and retinoblastoma etc. It

must be handled carefully as it is considered to be highly carci-

nogenic in humans. Cyclophosphamide-loaded poly-

butylcyanoacrylate nanospheres were investigated to obtain

a suitable and tolerated ocular delivery device for therapeutic

applications involving treatment of severe ocular inflammatory

processes that localize in the anterior chamber of the eye.107,108

Local delivery of 4-hydroperoxycyclophosphamide (4HC

derived from cyclophosphamide), was achievedvia a controlled-

release biodegradable polymer to determine whether the use of

a polymer vector can enhance efficacy. Ninety Fischer 344 rats

implanted with 9L or F98 gliomas were treated with an intra-

cranial polymer implant containing 0% to 50% loaded 4HC in

the polymer. Long-term survival for more than 80 days was 40%in the 4HC-treated ratsversus30% in the BCNU-treated rats. It

can be concluded that 4HC-impregnated polymers provided an

effective and safe local treatment for rat glioma.109

Carmustine (BCNU, 1,3-bis(2-chloroethyl)-l-nitrosourea) is

a highly lipophilic nitrosourea compound which undergoes

hydrolysis in vivoto form reactive metabolites. These metabolites

cause alkylation and cross-linking of DNA. Nitrosoureas

generally lack cross-resistance with other alkylating agents.104,105

The US Food and Drug Administration (FDA) approval of

Gliadel in 1996 represents the first new treatment approved for

brain tumors in over 20 years. It has also been approved by

numerous regulatory agencies worldwide. Gliadel is a polymer

drug combination that delivers the chemotherapeutic agentcarmustine directly to the site of a brain tumor via controlled

release from a biodegradable matrix.110

In order to compare the effectiveness of lipid microspheres to

Gliadel, Takenaga incorporated BCNU into lipid microspheres

by homogenizing a soybean oil solution of BCNU with egg yolk

lecithin. Compared to the corresponding conventional dose of

BCNU, the lipid microsphere-encapsulated BCNU significantly

enhanced antitumor activity with reduced toxicity in mice with

L1210 leukemia. [14C]Triolein uptake by L1210 leukemia cells

was increased by incorporation into microspheres. The nano-

spheres showed longer in vivo half-life due to the avoidance of

cellular uptake by the reticuloendothelial system, resulting in

higher accumulation at the tumor sites.111

5.2. Antimetabolic agents

Cytarabine is metabolized intracellularly into its active triphos-

phate form (cytosine arabinoside triphosphate). This metabolite

then damages DNA by multiple mechanisms, including the

inhibition of alpha-DNA polymerase, inhibition of DNA repair

through an effect on beta-DNA polymerase, and incorporation

into the DNA. The latter mechanism is probably most impor-

tant. Cytotoxicity is highly specific for the S phase of the cell

cycle.104,105

Ellena et al. investigated the distribution of phospholipid and

triglyceride molecules in the membranes forming a non-concen-tric vesicular network within a multivesicular lipid particle

(MLP). MLP formulations exhibited controlled release of

encapsulated pharmaceuticals on timescales of a few days to

a few weeks. The MLP can be synthesized by a double emulsi-

fication process with a neutral lipid such as a triglyceride. MLP

formulations with the antineoplastic agent cytarabine encapsu-

lated in the aqueous compartments were prepared that further

contained [C-13]carbonyl-enriched triolein. This rational

approach can be used to develop MLP formulations with vari-

able rates of sustained release, modulated by changes in the

distribution of various phospholipids and triglycerides.112



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Fluorouracil (FU) was developed in 1957 based on the obser-

vation that tumour cells utilized the base pair uracil for DNA

synthesis more efficiently than did normal cells of the intestinal

mucosa. It is a fluorinated pyrimidine that is metabolized intra-

cellulary to its active form, fluorodeoxyuridine monophophate

(FdUMP). The active form inhibits DNA synthesis by inhibiting

the normal production of thymidine. Fluorouracil is cell cycle

phase-specific (S-phase).104 5-Fluorouracil (5-FU)-loaded poly

(L-lactide) (PLLA) or its carbonate copolymer microsphereswere prepared by a modified oil-in-oil (o/o) emulsion solvent

evaporation technique. Using this modified process, micro-

spheres with various particle sizes can be prepared with high 5-

FU entrapment efficiency (about 80%). In vitro drug release

experiments showed a burst release of 5-FU from PLLA

microspheres, followed by a sustained release over 50 days. In the

case of other vectors, poly (L-lactide-co-1,3-trimethylene

carbonate) (PLTMC) and poly (L-lactide-co-2,2-dimethyl-1,3-

trimethylene carbonate) (PLDTMC), the drug release rate can be

prolonged to more than 60 days.113

Roullin et. al. developed 5-FU-loaded poly(L-lactide-co-gly-

colide) (PLGA) microspheres to deliver the therapeutic agents

into the CNS for stereotactic intracerebral implantation.37

In-vivo experiments with C6 glioma-bearing rats showed prom-

ising resultsthe median survival time was doubled.114 A phase

III pilot study was conducted on 8 patients with high-grade

glioma who underwent surgical removal before 5-FU-loaded

microspheres were implanted. After 18 months the patients

survival rate and welfare was improved.115 Microsphere fate and

the 5-FU diffusion area from these particles in the brain was also

investigated depending on the locations of the inserted drug-

loaded microspheres. [3H] 5-FU microspheres were used to

evaluate diffusion areas from the implantation site.37

Another approach for controlled DDSs into the brain has been

developed using implantable, biodegradable microspheres. The

strategy was evaluated initially to provide localized and sus-tained delivery of the radiosensitizer 5-FU after patients under-

went surgical resection of malignant glioma.116

Methotrexate and its active metabolites compete for folate

binding sites of the enzyme dihydrofolate reductase. Folic acid

must be reduced to tetrahydrofolic acid by this enzyme in order for

DNA synthesis and cellular replication to occur. Competitive

inhibition of the enzyme leads to blockage of tetrahydrofolate

synthesis, depletion of nucleotide precursors, and inhibition of

DNA, RNAand protein synthesis.Methotrexateis cellcyclephase-

specific (S phase).104,117 Methotrexate can be widely employed for

breast cancer, bladder cancer and head and neck canceretc.

ABA-type triblock copolymers of poly(trimethylene carb-

onate)-poly(ethylene glycol)-poly (trimethylene carbonate) weresynthesized by ring-opening polymerization. The anticancer drug

methotrexate was loaded into the core-shell structure of poly-

meric nanoparticles with a diameter of 50160 nm. Generally, the

release rate of methotrexate from the nanoparticles was shown to

be comparatively faster than that of microsphere systems due the

higher surface area and smaller particle size.118

Hydrophilic gelatin nanoparticles were also prepared which

incorporated the methotrexate by solvent evaporation techniques

based on single water-in-oil (W/O) emulsion with glutaraldehyde

as a cross-linking agent. The methotrexate loaded gelatin particles

were in the range of 100200 nm mean diameter.119

5.3. Anticancer antibiotics

At low concentrations actinomycin D inhibits DNA-directed

RNA synthesis and at higher concentrations DNA synthesis is

also inhibited. All types of RNA are affected, but ribosomal

RNA is more sensitive. Actinomycin D binds to double-stranded

DNA, permitting RNA chain initiation but blocking chain

elongation. Binding to the DNA depends on the presence of

guanine. It is applicable to the treatment of testicular, ovarian,and germ cell cancers. Isobutylcyanoacrylate nanoparticles

loaded with actinomycin D were shown to concentrate prefer-

entially in rat mesangial cells and to increase the drugs uptake in

these cellsin vitroandin vivo, as compared to the free drug. Drug

targeting by nanoparticles of renal cells and macrophages may be

possible, resulting in a lowering of the critical level of drug

dosage in tubular cells and a reduction of tubular toxicity.120

The effects of actinomycin D-loaded polymethylcyanoacrylate

nanoparticles on the growth of a transplantable soft tissue

sarcoma were also investigated in a rat model. Actinomycin D-

loaded polymethylcyanoacrylate nanoparticles showed a greater

inhibitory action than the free drug on the growth of the S250

sarcoma but the nanoparticles alone did not demonstrate anysignificant antitumor effect.121 This study demonstrated that 24 h

after injection, adsorbed actinomycin D is 5.6-, 44- and 64-fold

more concentrated than the free drug in muscle, spleen and liver

respectively.122

Bleomycin is an antineoplastic antibiotic. It is used to treat

several types of cancer, including cervical and uterine cancer,

head and neck cancer, testicular and penile cancer, and certain

types of lymphoma. Bleomycin causes DNA strand scission

through formation of an intermediate metal complex requiring

a metal ion cofactor such as copper or iron. This action results in

inhibition of DNA synthesis, and to a lesser degree, in inhibition

of RNA and protein synthesis. The drug is cell-cycle specific for

G phase, M-phase and S phase.123 The manipulation of thephysicochemistry of water-soluble polymers such as glyco-

lchitosan can be used to create hybrid materials for drug delivery

and gene delivery with biocompatibility. Glycol chitosan modi-

fied by the attachment of a strategic number of pendant fatty acid

groups (1116mol%) assembles into unilamellar, polymeric

vesicles in the presence of cholesterol. An ammonium sulphate

gradient bleomycin (MW 1400), for example, can be efficiently

loaded onto these polymeric vesicles to yield a bleomycin-to-

polymer ratio of 0.5 units mg1.124

Bleomycin has been conjugated to carbon nanoparticles as

a new DDS for the treatment of digestive cancer. In this way,

higher levels of anticancer drug can be localized to the regional

lymph nodes and the injection site compared to distribution ofthe drug in aqueous solution. In 12 patients with histologically

proven carcinoma, bleomycin-conjugated carbon nanoparticles

were injected endoscopically into the primary lesions. Endo-

scopic injection of this dosage formulation shows that it can

control these digestive cancers in patients in whom operation is

contraindicated.125

Formulations of ultra-deformable liposomes containing

bleomycin (Bleosome) also have been reported and proposed

for topical treatment of skin cancer.126 Bleosome exerted

a lethal effect on human keratinocytes cell lines and a cell line

derived from a primary carcinomain vitrowhen it is loaded with



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sufficient bleomycin. The cell line, derived from squamous cell

carcinoma, seemed to be more susceptible to Bleosome than

HPV-immortalised keratinocytes (NEB-1).127

Daunorubicin is an anthracycline antibiotic which damages

DNA by intercalating between base pairs resulting in uncoiling

of the helix, ultimately inhibiting DNA synthesis and DNA-

dependent RNA synthesis.128 A tumor-targeting daunorubicin

liposome, DaunoXome, is commercially available and its

beneficial effects are well reported. The daunorubicin liposomeproduct, (DaunoXome) is a formulation of daunorubicin in

small unilamellar vesicles (SUVs) composed of highly pure dis-

tearoylphosphatidylcholine (DSPC) and cholesterol in a 2:1 mole

ratio. Several countries have approved DaunoXome for use in

treating Kaposis sarcoma (KS) in HIV-positive patients.

Preclinical investigations indicate that DaunoXome increasesin

vivo daunorubicin tumor delivery by about 10-fold over

conventional drugs, yielding a comparable increase in thera-

peutic efficacy.129

6. Conclusions

Nanomaterials can contribute enormously in the area of nano-medicine and this contribution is likely to become more signifi-

cant in future. Specific, target-oriented DDSs are showing

promising results along with diminished side-effects and

increased therapeutic effects. Both active and passive targeting

techniques will enhance the localization of the therapeutic agents

in pathological sites. Furthermore, degradation/release rates,

and surface activation/functionalization is being actively inves-

tigated for optimization of these systems.

The selective uptake of chemotherapeutic agents by tumor

tissues is a great challenge since anticancer agents themselves are

not specific to target sites. Active targeting techniques using

nanomaterials as carrier vectors can and will be improved via

focused design, the incorporation of theoretical considerations,and logical approaches to the production of more specific cancer

cell recognition systems. New design strategies for nanovectors

as nanomedicines should be developed in order to move these

systems into the clinic and to realize their main benefits

decreased side-effects and more effective treatment. Novel tech-

niques for the effective loading of active molecules and surface

activation (i.e. antibodies and functional groups) for active tar-

geting are essential to improve the therapeutic effectiveness. As

we write this, the next generation of intelligent smart biomate-

rials for use in nanomedicine are being intensively investigated

and developed and this research is already having an enormous

effect on nanomedicine as a new research field.

Acknowledgements

This work was financially supported by Engineering and Physical

Sciences Research Council (EPSRC) CoDDS projects (EP/

E016944/1).

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