R Subbiah Et Al - Curr Med Chem

Current Medicinal Chemistry, 2010, 17, 4559-4577
4559
Nanoparticles: Functionalization and Multifunctional Applications in

Biomedical Sciences
R. Subbiah, M. Veerapandian and K.S. Yun*
College of Bionanotechnology, Kyungwon University, South Korea
Abstract: Rapid innovations in nanomedicine have increased the likelihood that engineered nanomaterials will eventually
come in contact with humans and the environment. The advent of nanotechnology has created strong interest in many
fields such as biomedical sciences and engineering field. Central to any significant advances in nanomaterial based applications will be the development of functionalized nanoparticles, which are believed to hold promise for use in fields such
as pharmaceutical and biomedical sciences. Early clinical results have suggested that functionalization of nanoparticles
with specific recognition chemical moieties indeed yields multifunctional nanoparticles with enhanced efficacy, while simultaneously reducing side effects, due to properties such as targeted localization in tumors and active cellular uptake. A
prerequisite for advancing this area of research is the development of chemical methods to conjugate chemical moieties
onto nanoparticles in a reliable manner. In recent years a variety of chemical methods have been developed to synthesize
functionalized nanoparticles specifically for drug delivery, cancer therapy, diagnostics, tissue engineering and molecular
biology, and the structure-function relationship of these functionalized nanoparticles has been extensively examined. With
the growing understanding of methods to functionalize nanoparticles and the continued efforts of creative scientists to advance this technology, it is likely that functionalized nanoparticles will become an important tool in the above mentioned
areas. Therefore, the aim of this review is to provide basic information on nanoparticles, describe previously developed
methods to functionalize nanoparticles and discuss their potential applications in biomedical sciences. The information
provided in this review is important in regards to the safe and widespread use of functionalized nanoparticles particularly
in the biomedicine field.
Keywords: Asymmetric group, Bio-functionalization, Cancer therapy, Drug delivery, Functionalized nanoparticles, Postpolymerization, Thiol group, Tissue engineering.
1. INTRODUCTION
Nanotechnology is the study of functional systems at the
molecular level and it is one of the fast growing areas of research in many scientific disciplines. Work in the nanotechnology field began as early as 1959. The theoretical capability of building things with atomic precision was initially envisioned by the physicist Richard Feynman who stated that
There is plenty of room at the bottom [1]. Nanoparticles
(NPs), which range in size from 1-100 nm, are attractive
multifunctional materials due to their unique size, chemical
and physical properties. Several advances have been made in
the past years in regards to the synthesis of NPs, which has
opened up the door to numerous original applications in
many different fields including nanomedicine, biomedical
sciences and engineering. The literature on NPs is already
very dense and well investigated starting from metal NPs to
polymer NPs among which gold (Au), silver (Ag), silica (Si),
PEG, PLGA, PCL (see the summary of abbreviations in Table 1) have been extensively studied and are already found in
various applications such as catalysis, chemical sensing, biolabeling, photonics and nanocarrier for drug and biomolecules delivery [2-7]. Potential biomedical applications
of NPs have increased in the last decades due to their resistance to oxidation, easy synthesis, and optical properties and
if appropriate ligands functionalization is used they can be
highly tolerated by organs [8]. Metal NPs are good vehicles
for tracers and therapeutic agents and can be easily functionalized. In addition, polymeric NPs are biocompatible and can
serve as active targeting nanocarriers. Despite the many
*Address correspondence to this author at the Bionanotechnology, Kyungwon University, Gyeonggi-do 461-701, South Korea; Tel: +82-31-7508753; Fax: +82-31-750-8819; E-mail: ykyusik@kyungwon.ac.kr
0929-8673/10 $55.00+.00
advantages of NPs, they also have some drawbacks including

the lack of surface properties. In addition, NPs can interact
with host media, substrates and/or other individual species
such as molecules and other particles, all of which could
limit their use in specific applications. However, these drawbacks can be eliminated by functionalizing the NPs with
certain chemical moieties. One of the beneficial consequences of functionalizing NPs is that the desired properties
can be controlled in a predictable manner to fit the specific
applications [9-11]. The processes used to generate, manipulate and deploy functionalized nanoparticles (FNPs) provides
excitingly new possibilities for the development of new multifunctional tools for biomedical and nanotechnological applications. Furthermore, magnetite NPs have received significant attention in diagnostic applications due to their magnetic properties, high surface area and the possibilities of
surface functionalization, which show a great versatility in
specialized fields such as medical diagnosis (MRI - magnetic
resonance imaging), therapy and targeted drug delivery [1217]. Indeed, functionalization has been used to conjugate
drug molecules, polymers and organic groups to NPs. In
addition, functionalization has also been shown to protect
NPs against agglomeration [18, 19] and render them compatible in other phases [20]. Functionalization also improves
the physical, chemical and mechanical properties of NPs,
which are synergetic [21].
In this review, many different types of NP functionalization will be discussed using specific examples. A general
approach by thiol/aminothiol, biomolecules, asymmetric
group, post-polymerization, miscellaneous and their applications will be outlined without attempting to comprehensively
cover all the work that has been done in this field. We will
first discuss the general aspects of functionalizing nanoparticles and will then highlight selected examples where this
2010 Bentham Science Publishers Ltd.
4560 Current Medicinal Chemistry, 2010 Vol. 17, No. 36
type of functionalization was used. Although many reviews

on NPs and surface modification and functionalization of
NPs for biomedical and nanotechnological applications already exist, the present article aims at reviewing the different
classes of functionalization and their synthesis methods,
which are distinguished by the functional groups and specific
application. In addition, we will discuss the use of functionalized NPs as a multifunctional tool in nanobiotechnology
[22-24]. The increasing need for more efficient and less invasive methods to treat diseases is stimulating the development of new technologies in the field of nanotechnology
including NPs functionalized with drugs, biomolecules and
other chemical moieties used for therapy and diagnosis.
Functionalized nanoparticles (FNPs) offer improved transport properties and pharmacokinetic profiles in vivo after
systemic administration; they can penetrate deeper into tissues through fine capillaries and epithelial lining resulting in
more efficient delivery of therapeutic agents to target sites
[25]. Moreover, their dimensions impart remarkable physicochemical properties to the NPs system that are able to
optimize some of the most important properties including
solubility, diffusivity, distribution, release characteristics and
immunogenicity and most importantly the ability to target
the identified tissue with minimal distribution to normal tissues [26, 27]. Thus, FNPs hold promise for overcoming the
failures of traditional therapeutics. According to a recent
survey (Table 2), approximately 26 NPs based medicines
have already been accepted for clinical use and numerous
NPs are under clinical testing [28]. The basic components
and their role in biomedical applications is schematically
illustrated in Fig. (1).
A wide diversity of different methods has been developed for NP functionalization with their specific applications
Subbiah et al.
being the most widely investigated. NPs have been extensively investigated due to their advantageous properties such
as their biodegradability and biocompatibility in physiological systems, natural abundance and suitability for chemical
modification and functionalization of the NPs derived from
various materials. This review provides an update on NPs
functionalization and their specific applications in biomedical science (therapy, diagnosis and sensors). An overview of
the design criteria for functionalization will be briefly discussed, followed by different functionalization groups that
have been specifically used for medicinal applications. The
most appealing aspect of the FNPs systems, namely targeted
delivery, will also be summarized. Finally, future challenges,
perspectives and directions will be discussed.
2. FUNCTIONALIZATION OF NANOPARTICLES
After NPs have been functionalized with chemical and
biomolecules through a covalent bond, the bioactivity of the
synthesized material should be carefully examined for any
undesirable changes in intrinsic activity. The physicochemical properties of the NPs, the size, distribution, surface
charge and nature of the FNPs are likely to determine the in
vivo fate of the delivery of the drug (Fig. 6). It is generally
recognized that 20-200nm particles are suitable for systemic
delivery of therapeutics. Particles larger than this size range
are quickly up taken by the RES and rapidly cleared from the
circulation, whereas particles within this size range can cross
the fenestration in the hepatic sinusoidal endothelium, leading to hepatic accumulation instead of long circulation times
[29]. The targeting ability of NPs for site-specific delivery of
drugs is paramount when the drug is delivered systemically.
Targeted delivery concentrates the drug at the site of action
Fig. (1). General schematic of FNPs, their components, and multifunctional applications in the field of biomedicine.
Nanoparticles
Table 1.
Current Medicinal Chemistry, 2010 Vol. 17, No. 36
List of Abbreviations
APS
Aminopropyl silane
BBB
Blood brain barrier
BSAP
Bovine serum albumin particles
CT
Computed tomography
DACH
Diaminocyclohexane
DEAP-Lys
N-(3-diethylamino) propyl isothiocyanato-L-lysine
DTIC
5-(3, 3-dimethy-1-triazenyl) imidazole-4-carboxamide
EDC
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
EPR
Enhanced permeability & retention effect
FLK
Vascular endothelial growth factor receptor 2
FNPs
Functionalized nanoparticles
HPMA
N-(2-hydroxypropyl) methacrylamide
LHRH
Luteinizing hormone releasing hormone
MPI
Magnetic particle imaging
MPS
(3-methacryloxypropyl) trimethoxysilane
MRI
Magnetic resonance imaging
NPs
Nanoparticles
N-C-F
Nanoparticle-chelating agent-functional group
PASP
Poly (aspartic acid)
PBCA
Poly (butylcyanoacrylate)
PCL
Poly (-caprolactone)
PDLLA
Poly (D,L-lactide)
PE
Poly (ethylenimine)
PEG
Poly (ethylene glycol)
PET
Positron-emission tomography
PGA
Poly (glutamic acid)
PHEO
Poly (hydroxy ethyl oxide)
PHEP-Pal
2-(N-phthalimido) ethyl palmitate
PLA
Poly (lactic acid)
PLGA
Poly (lactic-co-glycolic acid)
PLLA
Poly (L-lactide)
PNIPA
Poly (N-isopropylacrylamide)
PPS
Poly (propylene sulfide)
PSMA
Prostate specific membrane antigen
PVA
Poly (vinyl alcohol)
RES
Reticuloendothelial system
RGD
Arginine-glycine-aspartic acid
scTNF
Single chain tissue necrosis factor
SMCC
Succininamidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate
TDDS
Targeted drug delivery system
THF
Tetrahydrofuran
TOPO
Tri-N-octylphosphine oxide
4561
and potentially reduces any undesired effects at normal tissues. Also, it is essential to design NPs with a controllable
release profile that satisfies the desired application. Better
protection against environmental factors and more tunable
control is achieved if loading is performed by encapsulation
rather than adsorption on to the NPs. Successful combinations of these factors in the design of NPs are likely to lead
to enhanced therapeutic outcomes, while reducing undesired
effects at normal tissues.
Functionalization of the NPs can be defined as the addition of a chemical functional group on their surface in order
to achieve surface modification that enables their self organization and renders them compatible. NPs have mainly been
functionalized with thiols, disulfides, amines, nitriles, carboxylic acids, phosphines and biomolecules [30-35]. The
main goal of functionalizing NPs is to cover their surface
with a molecule that possesses the appropriate chemical
functionality for the desired application. In all cases, functionalization of the particles produces a drastic change in
their surface properties. The surface chemistry of NPs is already an important aspect of their synthesis, since this property can be exploited to control their size and self organization during formation. This can be achieved by complexing
groups that bind on the surfaces during their formation and
complex formation should not promote agglomeration. A
significant amount of research has examined methods of
modifying NPs and it would not be feasible to exhaustively
cover this body of literature in a single review; therefore, this
review will only discuss some representative examples of
NPs functionalization, highlighting the work discussed
above. In addition, we will focus on describing the richness
of such chemistry and potential biomedical applications (Fig.
(1)).
2.1. Methods of Functionalization
There are two strategies for introducing functional groups
to surfaces and NPs. The first method is direct functionalization, where the whole functional ligand is a bi-functional
organic compound. In this approach, one of the functionally
reactive groups is used to attach to the NPs surface (complexing agent) and the second group contains the required
active functionality (NPs surface modifying group). Direct
functionalization is preferred because it only requires a single conjugation step. One limitation of the direct functionalization method is the incompatibility of the functional group
F with the preparation process, for instance the modifying
group may react with the particle surface [10]. Another reason to utilize a step-wise procedure is steric hindrance. An
example of the interference of functional groups with the
particle surface is the back bonding of amino or ammonium
groups to the charged surfaces. In the case of silica particles
covered with 3-aminopropyl groups (from the reaction with
3-aminopropyl-triethoxysilane), the zeta potential and thus
particle agglomeration was controlled by the co-reaction
with 3-(trihydroxysilyl) - propylmethylphosphonate. Back
bonding of the NH2 groups to the particle surface was therefore suppressed by the interaction between the amino and
phosphonate groups [36]. For direct functionalization thiol,
phosphine oxide, phosphonates, carboxylates groups have
commonly been used in the case of chalcogenides, oxide
Subbiah et al.
NPs, and noble metal NPs. The binding strength of the complexing molecule must be high enough to ensure maximum
surface coverage. This is of particular importance, especially
when the complex-functional molecule is grafted in substitution of the complexing agent that was previously used for the
synthesis of the particles. In this sense, it would be best to
utilize polydentate ligands, such as dithiols or oligomeric
phosphines which bind much more strongly to the surface
[37]. Functionalization methods are graphically described in
Fig. (2).
The second method is post-functionalization, which is
generally preferred because this strategy is more versatile
and the nature of the functionalizing moieties may not be
fully compatible with good control over the size and dispersion state of the particles in the solvent used for their synthesis. This describes a bifunctional compound where a bindingchelating group is reacted first and the group of coupling site
can be converted, in a second step, to the final functional
group F. Post-functionalization of the particles requires a
molecule to be grafted on the surface such that it has a structure that can be described as N-C-F (Nanoparticle-Chelating
agent-Functional group). For post-functionalization, silanelike compounds have been generally used. Hydrolysis/condensation reactions lead to the formation of a silane
like coating around the particles with a fraction of the functional group orientated towards the outside of the particle.
This process has been used in many systems, mostly in oxide
systems [38], but it has also been investigated in the case of
chalcogenides [39]. The main advantages of this approach
come from the large number of commercially available silane coupling agents, the chemistry of which is well documented. In addition, the core/shell structure ensures a strong
binding of the functional groups with a high surface coverage. The main problem with this method is that the functional group must have a high affinity to the surfaces of the
particles and cannot exist as isolated clusters. Unavoidable
clusters must be eliminated with special care.
Other functionalization processes have also been used,
including the encapsulation with a polymer that possesses
both the chelating and the functional group. This novel approach has been used for TOPO capped CdSe/ZnS particles,
which consists of retaining the TOPO molecules, and grafting a functionalization molecule in which the complexing
group is a long alkyl chain that interacts with the octyl
groups through hydrophobic interactions [40, 41].
2.2. Class of Functionalization
Thiol/Aminothiol
The thiol conjugation method, which was initially proposed by Brust et al, has been widely used for NPs functionalization [42]. Guerrero et al synthesized three kinds of thiol
FNPs. Initially they synthesized thiol functionalized gold
(Au) clusters through Au-S bonds with dodecanethiol and
octanethiol molecules, named Au-SC12 and Au-SC8 [43],
based on the method of Brust et al. In addition, Au NPs
capped with both octanethiol and thiolated undecanoic acid
molecules, named Au-SC8/SC11COOH, were also fabricated
based on the method of Simard et al synthesis [44]. Finally
water soluble Au NPs capped with tiopronin (Au-ST) were
synthesized based on the method of Templeton et al [45],
Nanoparticles
4563
Fig. (2). Schematic representation of functionalization methods. Direct functionalization, which uses a conjugating agent in order to directly
attach the chemical moiety, and post-functionalization, which uses a binding/chelating agent to attach to the NPs and a secondary functional
group for covalent attachment of the biomolecule of interest.
which utilizes a synthetic thiol containing biomolecule. Thiol

chemistry is one of the most developed functionalization
methods used for the fabrication of functional NPs. Fig. (3)
describes the chemical functionalization reaction of thiols.
Sulfur compounds naturally form strong coordination bonds
with many metals including Ag, Cu, Pt, Hg, Fe, Si, and Au
[46]. Sulfur and organosulfur have a high affinity for metal
surfaces and thus will adsorb spontaneously [47]. Thiol or
disulfide capped NPs can be prepared by either the direct
functionalization method where the metal precursor and the
protective ligand are reacted simultaneously.
Another method based on thiol chemistry is the postfunctionalization method, where the sulfur compounds are
grafted on the surface of presynthesized NPs that are covered
by solvent molecules and are thus replaced by sulfur containing ligands [10, 30, 31, 36, 48-50]. Li et al reported on the
immobilization of trypsin using amine functionalized magnetic NPs [51]. Brousseau et al prepared dimers of Au NPs
by ligand exchange reactions of citrate capped Au NPs with
dithiols [52]. Shen et al covalently conjugated triphenyl
phosphine to thiol group functionalized 5nm Au NPs and
demonstrated their potential application in the electrochemical detection of the anticancer drug Dacarbazine [5-(3, 3dimethy-1-triazenyl) imidazole-4-carboxamide; DTIC].
Likewise, FNPs were used to facilitate the specific interactions between anticancer drugs and DNA or DNA bases [53].
Bio-Functionalization
NPs functionalized with biomolecules have recently attracted great interest because the resulting hybrid materials
have proven to be useful as drug carriers. Small biological
molecules such as amino acids can be anchored to the sur-
face of the NPs, opening the possibility of attaching functional biomolecules to bio FNPs. Sousa et al studied the possibility of employing both aspartic and glutamic acids as
chelating agents for the synthesis of NPs [54]. Tie et al reported a two step synthesis of NPs by directly anchoring
different amino acids such as leucine, arginine, cysteine and
tyrosine to the NPs surface [55]. Viota et al successfully
attached different amino acids to FNPs with the aim of producing biological functional NPs [56]. Wampler et al produced Au NPs functionalized with proteins and investigated
the mechanical properties of the resulting NPs, which could
be used to tune the properties of biomolecular films [57].
Koh et al modified -Fe2O3 NPs with aminopropyltriethoxy
silane and concluded that the functionalized antibody IgG
retained a 50% binding activity [58]. More recently, the use
of N-(2-aminoethyl)-APS (AEAPS) for the surface modification of iron oxide NPs have become a popular method for the
covalent attachment of antibodies such as anti-CD34, as reported by Chen et al [59]. In addition, NPs modified with
molecules such as organosilane, vinyl alcohol/ vinyl amine
co-polymer were used for subsequent conjugation of antibodies, which could then be utilized for targeting specific
biological cells and tissues [60]. Li et al used lipid NPs functionalized with an integrin antagonist (anti-FLK-1 antibody)
to target the monoclonal antibody for antiangiogenesis therapy wherein the NPs were labeled with 90Y for radioimmunotherapy [61]. Dharap et al developed a molecular targeting
camptothecin (anticancer) drug delivery system using BH3
and LHRH peptides functionalized polymeric NPs to treat
ovarian cancer [62]. Missailidis et al developed a targeted
delivery system through the successful functionalization of
aptamer molecules to polymeric NPs to increase the specificity against a C595 monoclonal antibody [63]. In addition,
Subbiah et al.
Fig. (3). Schematic of the thiol group based functionalization.
HPMA NPs were functionalized with Arginine-GlycineAspartic acid (RGD) peptides along with radionucleotides
and drugs to target cell adhesion molecules such as integrins
for applications in cancer treatment [64].
Asymmetric Group
Colloidal NPs with controlled size, shape and composition can be synthesized using state of the art nanomaterials
[65, 66]. Nevertheless only highly symmetric NPs such as
spheres, rods, and more recently tetrapods have been extensively analyzed [67-70]. Nanomaterials of greater complexity can be built with lower symmetry components, offering
the possibility of creating materials with a higher level of
integrated functionality. Asymmetric nanostructures are
more versatile building blocks compared to their symmetric
counterparts [71]. For example, Au NPs were asymmetrically modified with single strand DNA, which can be used as
the building block to prepare more complex structures such
as dimers and trimers [72, 73]. Recent studies have been
demonstrated that asymmetric diblock Au-polymer nanorods
can self-assemble into bundles, tubes, and sheets [74]. Love
et al synthesized Au half-shell structures by evaporating Au
on to an array of silica colloidal particles, which is simply
known as the post-functionalization method [75]. Lu et al
reported that further heat treatment of these structures produced Au-metal oxide asymmetric dimers [76]. Similarly,
Au shell structures were grown on a silica surface to produce
Au cups or caps [77]. The asymmetric structure in the nano
rod system has also been realized using the chemical vapor
deposition technique, which is known as the direct functionalization method [78-80]. Likewise, asymmetric rods can be
synthesized using template directed growth [74, 81]. However, when this approach is used, relatively large particles
are produced. For example, the Au-metal oxide asymmetric
dimers can only be prepared from metal oxide particles
larger than 200nm. The Au-polymer asymmetric nanorods
have diameters around 200nm and lengths over 1m. As a
result, they can only be used to prepare particles with dimensions of m or larger. To synthesize nanometer sized assemblies, smaller asymmetric building blocks are needed. Furthermore, it is desirable to develop a range of methods that
can yield such structures. The structure of the tetrapod is
topologically similar to that of a sp3 hybridized carbon atom.
This kind of structure can serve as a building block to pre-
pare superstructures, especially 3D superstructures, by mimicking the bonding between carbon atoms and organic molecules. Liu et al successfully prepared asymmetrically functionalized Cd/Te tetrapods and nanorods via a site selective
modification method [71]. The properties of the synthesized
products were previously compared with the asymmetric
product produced by Banin and co-workers [82]. Hence
tetrapods or other such materials can be used as building
blocks for asymmetric functionalization. Rajesh et al described a simple asymmetric functionalization technique to
produce Au NPs with reactive ligands localized to a small
region of the Au NPs surface and assembled the particles
together to form dimers [83]. The advantage of this approach
is that the ligands in a spatially limited region of the surface
may be used for further chemistry and the rest of the ligands
can be selected to remain unreactive during any coupling
process [84].
Polymers in Functionalization
Research on the synthesis of colloidal NPs by the topdown or bottom-up methods has recently dramatically increased. The polymer matrix embedded in the NPs plays a
major role in dictating the compatibility of the NPs for applications in harsh environments such as in acidic and alkalic
solutions [85]. Also polymer NPs are widely used in pharmaceuticals application particularly cancer therapy and drug
targeting (see Tables 2, 3, 4). In polymeric nanocomposites
synthesis, NPs or nanofibers have been used as fillers to improve the properties of the nanocomposites [86-88] such as
strength, which is very important in tissue engineering applications. The filler and the polymer linkage is poor when the
nanocomposites are prepared by simple mixing, which produces artificial defects and consequently decreases the mechanical property of the nanocomposites [89-91]. To overcome this problem, an appropriately engineered interphase
will be required, which will also improve the strength,
toughness and compatibility of the composites [92]. The
interfacial interaction of the NPs and the polymer matrix is
an important factor in improving the quality and properties
of the nanocomposites [89, 90]. Nevertheless, functionalization of NPs with polymers requires a surfactant to produce a
strong bond, stabilize the NPs and render the NPs compatible
with the polymer [93]. Zhanhu Guo et al synthesized polymer functionalized alumina NPs using neutral MPS (3-
Nanoparticles
4565
Fig. (4). Covalent attachment of biomolecules such as antibody and antibody fragments using coupling agent EDAC and SMCC respectively.
The label NH2 (A) designates the covalent cross linking reaction and SH (B) designates sulphhydryl-amine coupling reaction respectively.
methacryloxypropyl) trimethoxysilane) in a tetrahydrofuran

(THF) solution where alumina NPs and MPS were used as a
filler and surfactant, respectively [85, 91, 94, 96]. Abboud et
al developed a method using a high temperature reaction at
the silane toluene refluxing point to functionalize NPs with
MPS [97]. Ultimately the polymer functionalization enhanced the mechanical properties of the NPs and no deleterious effects were reported. In addition, this nanocomposite
did not dissolve in acidic and basic medium [85]. Rothenfluh
et al synthesized polymer FNPs using the phage display
technique and were able to use these FNPs to carry a hydrophobic drug [118]. In addition, the bioavailability can be
improved by post-polymerization. 38nm PPS NPs were synthesized and immobilized with a ligand specific for articular
cartilage, which was then covalently grafted to the emulsifier. In addition, post-polymerization using a copolymer such
as pluronic led to a 72 fold increase in targeting to the extracellular compartment of articular cartilage [98-102]. Postpolymerization of the NPs with polymers like PEG produces
the stealth effect, which is an established method to achieve
long-term in vivo circulation and reduce clearance by RES
[103, 104]. The polymerization approach is schematically
illustrated in Fig. (5).
Miscellaneous
Viral NPs with modified chemical groups have been obtained from acidic hot spring in Iceland and can be used in a
variety of harsh conditions such as the acidic environments
found in the body [105]. In addition to the functionalization
methods described above some other methods have also been
examined. Dendritic NPs structures were the first nanomaterials that could be used for precise stoichiometrical functionalization since the stoichiometries were mathematically defined by geometric restrictions [106]. Hainfeld et al reported
the stoichiometrical monofunctionalization of Au NPs [107].
Worden et al reported stoichiometrical functionalization of
Au NPs via solid-phase chemistry and polymerization
method [108, 109].
3. IMPLICATIONS OF FNPS IN BIOMEDICAL
SCIENCES
Nanomedicine and clinical treatments hold promise to
benefit from the considerable investments being made in
nanotechnology research [110]. Nanomedicine depends on
several overlapping molecular technologies and advances in
Fig. (5). Schematic showing the procedure used for FNPs preparation by the post-polymerization method using a surfactant.
other fields including 1) Construction of nanoscale sized

structures for diagnostics, biosensors, and drug delivery, 2)
Ongoing advances in genomics, proteomics and nanoengineered microbes, 3) The creation of molecular machines
to identify and eliminate host pathogens, in tissue engineering and replacing/repairing cells or cellular components in
vivo [111]. Research into the delivery and targeting of therapeutic and diagnostic agents with NPs is at the forefront of
nanomedicine due to the inefficient formulations of oral and
injectable drugs for certain products, which have novel delivery requirements such as optimizing efficacy, minimizing
side effects and improving patient compliance. NPs size in
the formulation can enhance bioavailability, sustained release of drugs and enable more precise targeting to the level
of direct intracellular delivery. Moreover, small size NPs can
bypass the blood brain barrier, pulmonary system and the
tight epithelial junctions of the skin, all of which are vital to
targeted drug delivery [112].
3.1. General Consideration of Nanoparticles Application
In pharmaceutical applications such as drug delivery, the
most important aspect of the NPs or nanocarrier is its stabil-
Subbiah et al.
ity during the course of blood circulation. Drugs must be

stably loaded into the NPs without leakage or catabolism by
enzymes in the blood. NPs must avoid glomerular excretion
by the kidney and uptake by the RES in the liver, spleen and
lung. Since there is a molecular weight threshold for glomerular filtration (42,000-50,000 for water-soluble synthetic
polymers), elimination by this mechanism can be avoided by
increasing the molecular weight of the NPs. Carriers in the
blood circulation may also induce nonspecific complement
activation and opsonization, resulting in the drugs elimination from the blood compartment due to RES recognition. In
this regard, it is crucial to modify the NPs surface with biocompatible materials such as PEG to provide a stealth
characteristic. The second challenge for drug delivery applications is that the NPs carriers must permeate tumor blood
vessel to access the target tissue. One of the most important
advantages of macromolecular carriers is their preferential
accumulation in solid tumors. Such an elevated tumor accumulation is facilitated by microvascular hyper permeability
and impaired lymphatic drainage in tumor tissues known as
the enhanced permeability and retention effect (EPR) (Fig.
(6)). In this case the carriers should be small enough
(<100nm) to allow effective transport from the blood com-
Fig. (6). Programming FNPs for specific tissue delivery using a targeting ligand. Model of cancer cell specific targeting through both passive
(EPR effect) and active tissue targeting, which is shown in the dotted inset image. Cationic charged FNPs are more likely to have an increased affinity to the cell membrane compared to anionic FNPs. Factors affecting FNPs based drug delivery and possible toxicity of FNPs is
also shown along with the example of ROS (Reactive oxygen species) mechanism of cell death.
Nanoparticles
partment into solid tumors. The third challenge is selective

uptake into the target cells. In this regard, an attractive strategy is active targeting, which exploits cell surface receptors
by installing moieties onto the carriers that specifically recognize the target cells. Finally, controlled intracellular trafficking or organelle targeting is important to enhance medicinal effects, such as nuclear targeting in the case of gene
delivery. Carriers ranging from 5 to 100 nm in size are internalized into cells by the endocytotic pathway, where endosomes and encapsulated carriers are separated from the
cell membrane by a process of inward folding. These endosomes have an acidic pH value (5.5) and eventually fuse
with lysosomes, where drugs can be degraded by a host of
lysosomal enzymes [131]. Therefore, careful modulation of
both size and surface properties is required for functionality
and pinpoint targeting, which allow for the maximum medicinal effect to be realized. The role of FNPs in medicine
such as drug delivery by passive and active tissue targeting,
and factors affecting the FNPs therapy and their toxicity is
graphically illustrated in Fig. (6). The application of FNPs in
pharmaceutical sciences will be described henceforth by
considering the above issues. Many NPs based therapeutic
drugs are available in the market as listed in Table 2.
plored with the goal of allowing the NPs to enter (endocytosis) or disrupt the membranes of pathogenic micro organisms
and tumor cells. Polymer-based NPs alone do not have capacity for cell-specific targeting but provide flexible chemistry for the attachment of cell specific targeting agents that
allow for both increased cell uptake and often cell specificity. Many membrane-bound receptors can be used for targeting via receptor mediated endocytosis. NPs with glycosidic
moieties [120-122] and other small molecules such as folate
provide selective targeting to cell types that displays the appropriate receptor protein [123]. Asialoorosomucoid functionalized with poly-lysine to target the asialoglycoprotein
receptor on hepatocytes and NPs functionalized with irontransport protein transferrin [124-128] are the two classic
examples of cell targeting using functionalized NPs. The
success of the targeting strategy is dependent on the conjugation chemistry used for functionalization, the length of the
spacer between the ligand and NPs, the ligand receptor binding strength and the number of targeting ligands per NPs.
Efficient cell-specific targeting always requires careful optimization of the various parameters that affect cell-surface
binding because of nonspecific electrostatic binding to the
surface of non-targeted cells [129].
3.3. Cancer Therapy
3.2. Therapy
Polymeric NPs have been designed to augment drug concentrations in blood or vascularized tissues and aim to reduce
a drugs toxicity and to improve its therapeutic effects [114117]. Rothenfluh et al reported on the development of a
novel NPs based drug delivery system for intra tissue drug
release in articular cartilage, which may prove useful in drug
and biomolecular therapy in diseases such as osteoarthritis
[118, 119]. The interaction of surface charged FNPs with the
endosomal membranes of the cells is schematically shown in
Fig. (6). Different types of NP functionalities have been exTable 2.
4567
Cancer remains one of the worlds most devastating diseases. Although there are more than 10 million new cases
every year [130], the number of deaths due to cancer has
been reduced in the past few years due to the development of
new technological systems, which have been developed
based on a better understanding of tumor biology, improved
diagnostics systems and treatment modalities including surgical intervention, radiation and chemotherapy. Chemotherapeutics often also kill healthy cells and cause toxicity to patients [131]. Developing chemotherapeutics with increased
Representative examples of nanoparticles based therapeutics for Cancer [113, 28]
Company
Drug
Company
Drug
Abraxis
Albumin bound paclitaxel
American pharm partners
Albumin bound paclitaxel
Gilead Sciences
Liposomal daunorubicin
Keroes
Ligand targeted emulsion containing NPs for

cancer
Ortho Biotech
Liposome-PEG doxorubicin
Nanobiotix
Nanobiodrugs for cancer treatment
Skyepharma
Liposomal cytarabine
Introgen therapeutics
NPs to target cancer
Zeneus
Liposomal doxorubicin
Liplasome pharma
Lipid based nanocarrier for targeted delivery
Enzon
PEG-GCSF
Samyang
Bio Alliance
Pharma
Polyglutamate paclitaxel
Amgen
Methoxy-PEG-Poly(D,L-lactide) taxol
Transcave
Liposomal annamycin
Phoenix
HPMA copolymer-DACH platinate
GP-Pharm
Liposomal cisplatin
Acusphere
Nanocrystalline paliperidone palmitate
Inex, Exon
Liposomal fentanyl
Schering-plough
OSI Pharm.,
Liposomal doxorubicin
Cell therapeutics
Polycyclodextrin camptothecin
Supratek Pharma
PEG-camptothecin
Insert therapeutics
Pluronic block-copolymer doxorubicin
Callisto
PEG-L-asparginase
Cell therapeutics
Polyglutamate camptothecin
Access Pharm.,
Liposomal vincristine
Elan entermed
Poly(iso-hexyl-cyanoacrylate)doxorubicin
activities and less toxicity can be achieved by either passively or actively targeting cancer cells. A nano based targeting system reached clinical trials in the mid 1980s then during the 1990s the first product based on polymeric liposome
and polymer protein conjugates were marketed. More recent
studies have focused on creating therapeutics based on the
targeting strategy of NPs and nanocarrier systems that have
been approved for wider use. This can be achieved by conjugating nanocarriers with drugs and ligands that bind to over
expressed antigens or receptors on the target cells. Fig. (6)
illustrates the targeting of tumor cells with functionalized
nanosystem containing therapeutics and the numerous barriers that this technology encounters based on the principle of
EPR [131]. Many research groups have experimented using
liposomes, NPs and other nanomaterials and have suggested
that the most effective threshold size is <200 nm for better
extravasations into tumors [132-135]. Targeting approaches
suffer from several limitations such as the inefficient diffusion of nanosystems to the tumor cells, which might induce
multiple drug resistance and render many potential drugs
inactive. One way to overcome this limitation is functionalization, so that it can actively bind to the specific cells after
extravasations. Ligand functionalization can be used to
achieve active tissue targeting through a variety of conjugation chemistries [134]. It is imperative that the agents bind
with high selectivity to molecules that are uniquely expressed on the cell surface. To maximize specificity, a surface marker should be over expressed on the target cells
where the ligand FNPs may cause receptor mediated internalization to release the drug inside the cells [136]. It is generally known that higher binding affinities increase the targeting efficacy. In addition, multivalent avidity may be used
to improve targeting. Agents such as proteins mainly antibodies and their fragments, nucleic acid, or other receptor
ligands such as peptides, vitamins and carbohydrates can be
used for targeting. Furthermore, it is possible to increase the
binding affinity and selectivity to cell surface targets by engineering proteins that detect a specific conformation of a
drug target receptor. Peer et al used a fusion protein consisting of a scFv antibody fragment to target and deliver small
interfering RNA to lymphocytes where a 10000 fold increased affinity for the target receptor, integrin LFA-1 was
observed [137]. The types of NPs and FNPs, their size and
type of drug that have been used for cancer therapy are listed
in Table 3.
3.4. Drug Delivery
One of the basic goals of pharmacology is delivery of the
right drug, right dose at the right time to the right patient so
as to optimize the therapeutic efficacy of the drug. In this
regard, drug delivery is one of the most important factors in
the field of pharmacology. Nanotechnology may prove vital
to fulfilling the goals of drug delivery. The more traditional
ways of viewing drug delivery is to look at different routes
of drug administration, such as oral, parenteral, transdermal
and inhalational. Throughout the history of medicine, there
has been a need to develop alternative methods of delivering
a drug to a patient. The primary goals of novel drug delivery
approaches would be to provide an easy route of administration, ensure patient compliance, decrease toxicity, improve
bioavailability and achieve precise therapeutic targeting.
Subbiah et al.
Technologies associated with drug delivery are now commonly used to create and extend the potency of the drug. The
discovery of better delivery systems, in conjunction with the
discovery of new pharmacological compounds, will potentially advance disease diagnosis and treatment beyond our
wildest expectation [22]. Nanotechnology now is a crucial
factor in the development of novel drug delivery systems and
it has significantly impacted the field of drug delivery in the
last decade. Nanotechnology is being used to manipulate not
only the size of the drug particles but the physical characteristics and thus the extent and location of drug delivery. NPs
have tremendous applications in therapeutics [28] and transdermal vaccine delivery [180]. Nanotechnologies will again
be examined as they relate specifically to drug delivery. The
application of nanotechnology to the diagnosis and treatment
of cancers is seen as nanotechnologys largest public health
contribution. Nanotechnology shifts the techniques from
microfabrication, such as osmotic pumps, to secondary
nanometer sized constructs (microspheres). Orringer et al
describe targeting brain tumors with NPs through antigen
dependent specific or nonspecific mechanisms [181]. Formulation science has formed a unique bridge with computer
technology for the creation of a controlled-release microchip
capable of infinite modulation [182]. The targeted delivery
can be fulfilled by stimuli induced targeting based on physical properties, such as the magnetic induction between magnetic NPs and a magnet at the site of action and cell or tissue
specific targeting based on a strong affinity between a ligand
and target receptor, such as the RGD peptide to a specific
cellular receptor or mineral affinity of biphosphonates (BPs)
to the mineral phase of bone [183].
3.5. Targeted Drug Delivery System (TDDS)
One of the most promising attributes of NPs is their potential for targeting to specific tissues and their ability to
carry multiple drugs and/or imaging agents. It is possible to
increase the local drug concentration by carrying the drug
within the NPs and releasing it when it is bound to the targets. TDDS would be targetable to individual cellular addresses within specific tissues and organs. Currently, natural,
synthetic polymers and lipids are typically used as drug delivery vectors. While offering great opportunities, designing
tissue seeking NPs is a challenging task that requires overcoming physiological and biochemical barriers [184]. For
intravenously administered NPs, the in vivo fate of NPs is
predominantly determined by their size and surface charge.
NPs size restricted to <200nm and functionalized with polymer to avoid opsonization and subsequent phagocytosis and
to remain in circulation for sufficient time to reach the targeted site. For instance, the BBB restricts the transportation
of even small molecular weight drugs, hydrophilic compounds and charged molecules from circulation to the central
nervous system, likewise bone possesses a membrane that
consists of lining cells, which function as a marrow blood
barrier with pores of approximately 80-100nm [185]. Thus,
identifying targeting ligands and designing the appropriate
NPs are keys for successful delivery of drugs to the site of
action at therapeutic levels for a desired period of time (Fig.
(6)). Polysorbate FNPs are known to result in greater transport of NPs across the BBB [186]. NPs are capable of specifically and locally delivering drugs and other therapeutics
Nanoparticles
Table 3.
4569
NPs and FNPs that have been Used for Cancer Therapy
Nanoparticles
Size (nm)
Drug
Indications
Refs.
PCL
250-300
Tamoxifen
Breast cancer
[138]
Human serum albumin (amino or COOH group)
150-500
Doxorubicin
Antineoplastic
[139]
PBCA
178
Doxorubicin
Daltons lymphoma
[140]
Trimyristin (sterically stabilized)
200
Paclitaxel
Ovarian, lung breast

cancer
[141]
PVA polymeric micelles
Polymer P10(4)
Neuroblastoma, melanoma
[142]
PEG-PASP
50
Doxorubicin
Leukemia
[143]
PLLA-b-PEG (folate targeted)
50-80
Doxorubicin
Solid tumors
[144]
PNIPA-b-PDLLA
60
Paclitaxel
Ovarian, lung breast

cancer
[145]
PEG-PE/egg phosphatidylcholine (lipid conjugated)
100
100
Paclitaxel
Paclitaxel
Various cancer
Various cancer
[146]
[147]
Nucleosome-specific monoclonal Ab functionalized
11
Camptothecin
Various cancer
[148]
PEG-lipid
10-40
Tamoxifen
Lung carcinoma
[149]
Polymer-lipid hybrid NPs
290
Doxorubicin
Solid cancer
[150]
[151]
Poly(2-ethyl-2-oxazoline)-b-PCL
30-80
paclitaxel
Various cancer
Poly (benzyl-L-aspartate)-b-PHEO
37
Doxorubicin
Antineoplastic
[152]
PCL-b-trimethylene carbonate-PEG (serum protein)
96
Ellipticin
Anticancer
[153]
PGA-b-PEG
40
Doxorubicin
Solid cancer
[154]
PDLLA-b-methoxy PEG
30
Paclitaxel
Various cancer
[155]
Pluronics
10-100
10-100
Doxorubicin
Carboplatin
Colon cancer
Colorectal cancer
[156]
[157]
PCL-b-methoxy-PEG
78
<200
Cisplatin
Paclitaxel
Anticancer
Ovarian &breast cancer
[158]
[159]
PLGA-b-PEG
Docetaxel
Prostate cancer
[176]
Au NPs
<50
Gemcitabine
Lung, breast, pancreatic &

bladder cancer
[2]
Silica based NPs
30
Photodynamic therapy
Various cancer
[160]
Au -conjugated cytomegalovirus NPs
<2
phototherapy
Solid tumors
[161]
Anti-HER2 antibody-targeted Au /silicon NPs
60
Nanoshell assisted photo

thermal therapy
Metastatic breast cancer
[162]
Aminosilane-coated iron oxide NPs
3-15
Thermotherapy
Brain tumors
[163]
Starch-coated iron oxide NPs
20-30
Magnetically guided
mitoxantrone
Tumor angiogenesis
[164]
6-PAMAM
<10
Avidin-G6Gd
Intraperitoneal disseminated
tumor
[165]
5- PAMAM
40-100
Methotrexate
Chemotherapeutics
[166]
Methotrexate
Epithelial cancer
[167]
<10
Camptothecin
Colon, ovarian, lung

cancer.
[168]
PEG-PLGA
105
Doxorubicin
Various cancer
[169]
PEG-PCL
50-130
Paclitaxel
Various cancer
[170]
Folic acid-PAMAM dendrimers

Poly (glycerol-succinic acid ) dendrimers
cGRD peptide in PEG-PCL
20-40
Doxorubicin
Various cancer
[171]
Galactose in Poly (L-benzyl L-glutamate)-PEG
104
Paclitaxel
Various cancer
[172]
Glycol chitosan NPs
Doxorubicin
Solid tumors
[173]
Albumin bound-PEG NPs
Doxorubicin,
Various cancers
[174]
mAb 2C5 mAb 2G4
20
Paclitaxel
Various cancers
[175]
Antibody-enzyme-conjucated NPs
Ab-directed enzyme
prodrug
Ovarian cancer
[176]
Biotinylated antibody-conjugated micelles
Daunomycin
Brain tumor
[177]
Anti-PSMA aptamer
168
Docetaxel
Breast, lung cancer
[178]
PHEP-Pal
40-100
Phthalidimide
Anticancer
[179]
- not available.
Subbiah et al.
agents through a novel process known as contact facilitated

drug delivery [187]. The direct transfer of lipids and drug
from the NPs layer to the targeted cell is usually a slow and
inefficient process; however, this can be accelerated by
minimizing the separation between the lipids and NPs surface and increasing the frequency and duration of the lipidsurface interactions. Interestingly, TDDS in the form of
pharmacytes has been recently reported. In this regard, the
NPs were relatively passive and acted as a nanorobot that
was 1-2m in size. Pharmacytes can carry up to 1m of a
pharmaceutical payload and can deliver this payload directly
into the extra cellular fluids or into the cytosol. There are
several potential uses of pharmacytes particularly for the
targeted delivery of cytocidal agents to tumor cell. Another
potential area of application is the control of cell signaling
processes with a functionalized antibody and biochemical
substances [188]. FNPs, targeting ligand, size of the FNPs,
Table 4.
tested drug, target organ and indication for TDDS are shown
in Table 4.
3.6. Gene Delivery and Tissue Engineering
Tissue engineering applications have also trended towards the development and implementation of nanometer
sized components. Tissue engineering typically involves the
fabrication of biological constructs that will restore, maintain
and improve tissue function [214]. One common strategy is
to isolate cells of interest and grown them in culture to form
a three-dimensional (3D) tissue, which can be genetically
modified in vitro before transplantation The resulting cell
tissues can be encapsulated with NPs and functionalized with
growth factors, then transplanted into the body within polymeric 3D matrices, which creates the potential for targeted
tissue development and provides mechanical support for the
Functionalized Nanoparticles for Targeted Drug Delivery

Nanoparticles
Agent
Size (nm)
Drug
Target organ & Indication
Refs.
PLGA
Alendronate
40-60
Estrogen
Bone-osteoporosis
[189]
Poly(DEAP-Lys)-b-PEG -bPLLA block copolymer
poly(lysine)
165
Doxorubicin
pH sensitive tumor targeting
[190]
Protein NPs
Albumin bound
130
Paclitaxel
Tumor cells- breast cancer
[191]
Magnetic NPs
Meso-2,3dimercaptosuccinic acid
8.1
Drugs
Lungs- various diseases
[192]
Magnetic NPs
Luteinizing hormone release

hormone
15
Imaging
Brest cancer cells- cancer diagnosis
[193]
Superparamagnetic NPs
PEG
40-50
Drug & genes
Fibroblasts- cancer
[194]
Au NPs
5-Thiol modified aptamer
32
Scattered light
photo illumination
Brest cancer cells- cancer diagnosis
[195]
PLGA-b-PEG-COOH
PSMA
70-250
Anti cancer
Prostate- cancer
[196]
BSAP
Folate
70
Various drug
Folate receptor- cancer
[197]
PEG or PE hydrogel particles
Transferrin
<100
Oligonucleotide
Brain- gene therapy
[198]
Magnetic NPs
Insulin
20
Drugs & genes
Insulin receptors- cell therapy
[199]
PLLA-PEG NPs
Biotin
100-150
Anti cancer
Cancer cells- cancer therapy
[200]
Polystyrol NPs
Sc-TNF
190
Anti cancer
Cancer cells- cancer therapy
[201]
PLA
Nucleic acid aptamer
250
Anti cancer
Prostate epithelial cells- cancer
[202]
Liposomes
ECM proteins intgrins
100
Raf genes
Melanoma cells- cancer
[203]
PE
RGD peptides
100
siRNA
Tumor vasculature- cancer
[204]
Albumin
Fibrinogen
Radioisotopes
Tumor vasculature- cancer
[205]
PLGA
MP lipid A
357
Dentritic cells
[206]
Liposomes
Folate
110
Doxorubicin
Leukemia cells- cancer
[207]
Liposomes
CD19
Doxorubicin
B-cell lymphoma
[208]
Liposomes
HER2 receptor
110
Doxorubicin
HER2 cells
[209]
mPEG/PLGA
Peptidomimetics
50-300
Various
Brain cells
[210]
Liposomes
Hyaluronic acid
120-170
Doxorubicin
CD44+ melanoma cells
[211]
PLA
Galactose
50-280
Retinoic acid
Hepatocytes
[212]
Viral particles
Von willebrand factor
Cyclin gene
Pancreatic cells- cancer
[213]
- not available.
Nanoparticles
developing tissues [215]. The major obstacles in tissue engineering included a limited half-life and stability of growth
factors proteins in vivo and the degradation of protein and
polymeric matrices during release from the polymer caused
by moisture, temperature, pH, etc., Gene therapy approaches
are now being investigated for tissue regeneration to address
some of the limitations in the current tissue engineering
strategies. Gene therapy can be defined as the treatment of
human diseases by the transfer of genetic materials into specific cells of the patients [216]. The genes of interest can be
cloned into an expression plasmid and used as a DNA complex for tissue regeneration using viral and non-viral gene
delivery vectors. In the age of genetic manipulation and gene
delivery, transfection systems on the nanoscale are being
custom-tailored using a variety of materials for different applications particularly for patients that suffer from lost, deficient or failing tissue and require tissue transplantation. This
technology has been and will be developed from a multidisciplinary perspective (particle mediated gene therapy) and
encompass concepts developed in the fields of gene therapy
and tissue engineering. Delivering DNA with polymeric matrices such as collagen, PLGA and alginate hydrogels was
previously reported [217]. The combination of these fields
involves the functionalization or incorporation of
genes/proteins onto NPs, which can then be implanted or
injected to promote tissue regeneration and treat genetic diseases such as hemophilia, muscular dystrophy, and cystic
fibrosis through replacement of errant genes within the affected cells. In this regard, gene therapies also being developed for cardiovascular, neurological, infectious diseases,
wound healing and cancers by delivering genes to augment
naturally occurring proteins, to alter the expression of existing genes, or to produce cytotoxic proteins or prodrug activating enzymes to kill tumor cells [218]. The list of possible
therapeutic genes and delivery is extremely broad and encompasses a wide array of factors involved in the growth and
differentiation of the various tissues in the body. Makhluf et
al surface modified PVA-Fe3O4 NPs with (3-aminopropyl)
trimethoxysilane through amidation and used this system as
a protein carrier into sperm cells and demonstrated that the
antigenicy of the resulting conjugates was maintained [219].
4571
for the sensitive detection of biomolecules and diseased

cells, etc., Among all the different types of NPs, iron oxide
NPs are recognized as the most promising tool for imaging
and site specific delivery of drugs and other bioactive molecules. Functionalized magnetic NPs will improve tracer response and will make the MPI, a capable in vivo new imaging modality, and has the potential to become a clinically
adopted imaging method. Magnetite NPs, which were first
surface-modified with aminopropylsilane (APS) and conjugated with methotrexate, have been shown to have combined
advantages in their therapeutic functionality to treat tumors,
such their ability to monitor, through magnetic resonance
imaging, real-time drug delivery to the treated tumors, produce a controlled drug release profile, and result in a high
uptake of the conjugate in the tumor cells [224]. Xu et al
reported on the preparation and inclusion of magnetic NPs
into surface modified PEG coated silica NPs as a matrix for
encapsulation of certain reagents, for application for in vivo
diagnosis, analysis, and measurements inside intact biological systems [225]. Yan et al studied the synthesis and characterization of silica functionalized iron oxide NPs for MRI
[226]. Koo et al recently reviewed the literature relating to
brain cancer diagnosis and therapy with nanoplatforms of
polymeric iron oxide NPs based drugs [227]. Based on this
previous research, functionalized iron oxide NPs do not seem
to affect enzyme activity.
4. THE FUTURE PERSPECTIVES
Functionalization of NPs provides a unique bridge from
materials to medicine and back and is becoming indispensable to the discovery and development of innovative therapeutic carriers and diagnostic tools. This approach utilized vari-
3.7. Diagnosis
Over the last decades, tomographic imaging methods
such as Computed Tomography (CT), MRI and PositronEmission Tomography (PET), have become indispensable
tools for the diagnosis of a large number of diseases. While
PET provides high sensitivity in static imaging based on
tracer materials, MRI and CT offers intrinsic tissue contrast
at high spatial resolution and dynamic imaging. Real time
imaging of 3D volumes using MRI remains challenging,
whereas the limitations of CT involve the use of ionizing
radiation. Gleich and Weizenecker presented a new imaging
modality called magnetic particle imaging (MPI), which potentially offers quantitative 3D real-time imaging using magnetic NPs [220-223]. Therefore it could become the modality
of choice for diagnoses requiring fast dynamic information.
In this regard, hybrid organic-inorganic NPs are being used
and are thought to hold promise for use as novel nanocarrier
probes for biological applications such as MRI, MPI, PET,
hyperthermia inducing agent, magnetically controlled media
Fig. (7). 3 in 1 nanosystem can be constructed from metal or polymeric FNPs that contains encapsulated drug, targeting ligand and
diagnostic agent through click chemistry or physical adsorption.
ous types of materials and their functionalization and connects the molecular mechanisms involved in physiology to
drug targets and other biomedical applications such as imaging and tissue engineering. In addition, the fusion of functional groups to NPs allows for the development of multimodality therapeutic strategies to integrate drug targeting,
cancer therapy, diagnostics and tissue engineering. The work
that has been conducted in this field so far has provided a
better understanding of FNPs systems and has advanced the
realization of bringing innovative multifunctional nanocarriers consisting targeting molecules, therapeutics, diagnosing
tool to patients faster. A model of the FNPs 3in 1 nanosystem is shown in Fig. (7). Fabrication of the three in one
FNPs nanosystem for therapy, targeting and imaging, can be
achieved by producing NPs with the appropriate therapeutic,
targeting ligand and imaging agent.
Subbiah et al.
[14]
[15]
[16]
[17]
[18]
[19]
ACKNOWLEDGEMENTS
This work was supported by Kyungwon University research fund in 2010 and Grant No. 10032112 from the Regional Technology Innovation Program of the Ministry of
Knowledge Economy. This work was also supported by
GRRC program of Gyeonggi province [2009-B02, Development biodevice using DNA tile structure].
REFERENCES
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
Drexler, K.E. Nanotechnology: From Feynman to funding. B. Sci.

Technol. Soc., 2004, 24, 21-27.
Priyabrata, M.; Resham, B.; Debabrata, M. Gold nanoparticles
bearing functional anti-cancer drug and anti-angiogenic agent: A
2 in 1 system with potential application in therapeutics. J. Biomed. Nanotech., 2005, 1, 224-228.
Sharma, V.K.; Yngard, R.A.; Lin, Y. Silver nanoparticles: Green
synthesis and their antimicrobial activities. Adv. Colloid Interfac.,
2009, 145, 83-96.
Mahalingam, V.; Onclin, S.; Peter, M.; Ravoo, B.J.; Huskens, J.;
Reinhoudt, D.N. Directed self-assembly of functionalized silica
nanoparticles on molecular printboards through multivalent supramolecular interactions. Langmuir, 2004, 20, 11756-11762.
Chen, T.J.; Cheng, T.H.; Hung, Y.C.; Lin, K.T.; Liu, G.C.; Wang,
Y.M. Targeted Folic acid-PEG nanoparticles for noninvasive imaging of folate receptor by MRI. J. Biomed. Mater. Res. A., 2008, 87,
165-175.
Astete, C.E.; Sabliov, C.M. Synthesis and characterization of
PLGA nanoparticles. J. Biomat. Sci-Polym. E., 2006, 17, 247-289.
Sinha, H.R.; Bansal, K.; Kausik, R.; Kumria, R.; Trehan, A. Poly caprolactone microspheres and nanospheres: an overview. Int. J.
Pharm., 2004, 278, 1-23.
Arshady, R. Microspheres for biomedical applications: preparation
of reactive and labelled microspheres. Biomaterials, 1993, 14, 5-15.
Schulz-Dobrick, M.; Sarathy, K.V.; Jansen, M. Surfactant-free
synthesis and functionalization of gold nanoparticles. J. Am. Chem.
Soc., 2005, 127, 12816-12817.
Neouze, M-A.; Schubert, U. Surface modification and functionalization of metal and metal oxide nanoparticles by organic ligands.
Monatsh. Chem., 2008, 139, 183-195.
Ruckenstein, E.; Li, Z.F. Surface modification and functionalization through the self-assembled monolayer and graft polymerization. Adv. Colloid. Interfac., 2005, 113, 43-63.
Duguet, E.; Vasseur, S.; Mornet, S.; Devoisselle, J.M. Magnetic
nanoparticles and their application in medicine. Nanomedicine,
2006, 1, 157-168.
Arias, J.L.; Ruiz, M.A.; Gallardo, V.; Delgado, A.V. Tegafur loading and release properties of magnetite/poly (alkylcyanoacrylate)
(core/shell) nanoparticles. J. Control. Release, 2008, 125, 50-58.
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
Duran, J.D.G.; Arias, J.L.; Gallardo, V.; Delgado, A.V. Magnetic

colloids as drug vehicles. J. Pharm. Sci., 2008, 97, 2948-2983.
Koo, O.M.; Rubinstein, I.; Onyuksel, H. Role of nanotechnology in
targeted drug delivery and imaging: a concise review. NanomedNanotechnol., 2005, 1, 193-212.
Wang, Y-X.J.; Hussain, S.H.; Krestin, G.P. Superparamagnetic iron
oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur. Radiol., 2001, 11, 2319-2331.
Kluchova, K.; Zboril, R.; Tucek, J.; Pecova, M.; Zajoncova, L.;
Safarik, I.; Mashlan, M.; Markova, I.; Jancik, D.; Sebela, M.; Bartonkova, H.; Bellesi, V.; Novak, P.; Petridis, D. Superparamagnetic
maghemite nanoparticles from solid-state synthesis - their functionalization towards peroral MRI contrast agent and magnetic carrier for trypsin immobilization. Biomaterials, 2009, 30, 2855-2863.
Kickelbick, G.; Schubert, U. Advances in Nanophase Materials and
Nanotechnology, M.I. Baraton, Ed.; American Scientific Publishers: CA, 2003, Vol. Functionalization and Surface Treatment of
nanoparticles, pp. 91-102.
Grancharov, S.G.; Zeng, H.; Sun, S.; Wang, S.X.; OBrien, S.;
Murray, C.B.; Kirtley, J.R.; Held, G.A. Bio-functionalization of
monodisperse magnetic nanoparticles and their use as biomolecular
labels in a magnetic tunnel junction based sensor. J. Phys. Chem.
B., 2005, 109, 13030-13035.
Doty, R.C.; Tshikhudo, T.R.; Brust, M.; Fernig, D.G. Extremely
stable water-soluble Ag nanoparticles. Chem. Mater., 2005, 17,
4630-4635.
Moon, J.H.; Shul, Y.G.; Hong, S.Y.; Choi, Y.S.; Kim, H.T. A study
on UV-curable adhesives for optical pick-up: II. Silane coupling
agent effect. Int. J. Adhes., 2005, 25, 534-542.
Smith, B.; Uhl, K. Drug delivery in the twenty-first century: A new
paradigm. Clin. Pharmacol. Ther., 2009, 85, 451-455.
Cegnar, M.; Kristl, J.; Kos, J. Nanoscale polymer carriers to deliver
chemotherapeutic agents to tumours. Expert Opin. Biol. Ther.,
2005, 5, 1557-1569.
Wang, L.; Wang, L.; Zhu, C.; Wei, X.; Kan, X. Preparation and
application of functionalized nanoparticles of CdS as a fluorescene
probe. Anal. Chim. Acta, 2002, 468, 35-41.
Panyam, J.; Labhasetwar, V. Biodegradable nanoparticles for drug
and gene delivery to cells and tissue. Adv. Drug Deliv. Rev., 2003,
55, 329-347.
Silva, G.A.; Ducheyne, P.; Reis, R.L. Materials in particulate form
for tissue engineering. 1. Basic concepts. J. Tissue Eng. Regen.
Med., 2007, 1, 4-24.
Wagner, V.; Dullaart, A.; Bock, A.K.; Zweck, A. The emerging
nanomedicine landscape. Nat. Biotech., 2006, 24, 1211-1217.
Zhang, L.; Gu, F.X.; Chan, J.M.; Wang, A.Z.; Langer, R.S.; Farokhzad, O.C. Nanoparticles in medicine: Therapeutic applications and
developments. Clin. Pharmacol., 2008, 83, 761-769.
Moghimi, S.M.; Hunter, A.C.; Murray, J.C. Long-circulating and
target-specific nanoparticles: Theory to practice. Pharmacol. Rev.,
2001, 53, 283-318.
Roux, S.; Garcia, B.; Bridot, J-L.; Salome, M.; Marquette, C.;
Lemelle, L.; Gillet, P.; Blum, L.; Perriat, P.; Tillement, O. Synthesis and characterization of dihydrolipoic acid capped gold nanoparticles and functionalization by the electroluminescent luminal.
Langmuir, 2005, 21, 2526-2536.
Zatats, M.; Katz, E.; Baron, R.; Willner, I. Reconstitution of ApoGlucose dehydrogenase on pyrroloquinoline quinine-functionalized
Au nanoparticles yields an electrically contacted biocatalyst. J. Am.
Chem. Soc., 2005, 127, 12400-12406.
Ulman, A. Formation and structure of self-assembled monolayers.
Chem. Rev., 1996, 96, 1533-1554.
Fan, H.; Chen, Z.; Brinker, C.J.; Clawson, J.; Alam, T. Synthesis of
organo-silane functionalized nanocrystal micelles and their selfassembly. J. Am. Chem. Soc., 2005, 127, 13746-13747.
Ramirez, E.; Jansat, S.; Philippot, K.; Lecante, P.; Gomez, M.;
Masdeu-Bulto, A.M.; Chaudret, B. Influence of organic ligands on
the stabilization of palladium nanoparticles. J. Organomet. Chem.,
2004, 689, 4601-4610.
Woehrle, G.H.; Hutchison, J.E. Thiol-functionalized undecagold
clusters by ligand exchange: Synthesis, mechanism, and properties.
Inorg. Chem., 2005, 44, 6149-6158.
Nakamura, M.; Ishimura, K. Synthesis and characterization of
organosilica nanoparticles Prepared from 3-Mercaptopropyl-
Nanoparticles
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
trimethoxysilane as the single silica source. J. Phys. Chem. C.,

2007, 111, 18892-18898.
Kim, S.J.; Bawendi, M.G. Oligomeric ligands for luminescent and
stable nanocrystal quantum dots. J. Am. Chem. Soc., 2003, 125,
14652-14653.
Philipse, A.P.; Nechifor, A-M.; Pathmamanoharan, C. Isotropic and
birefringent dispersions of surface modified silica rods with a
boehmite-needle core. Langmuir, 1994, 10, 4451-4458.
Gerion, D.; Pinaud, F.; Williams, S.C.; Parak, W.J.; Zanchet, D.;
Weiss, S.; Alivisatos, A.P. Synthesis and properties of biocompatible water-soluble silica-coated CdSe/ZnS semiconductor quantum
dots. J. Phys. Chem. B., 2001, 105, 8861-8871.
Dubertret, B.; Skourides, P.; Norris, D.J.; Noireaux, V.; Brivanlou,
A.H.; Libchaber, A. In vivo imaging of quantum dots encapsulated
in phospholipid micelles. Science, 2002, 298, 1759-1762.
Pellegrino, T.; Manna, L.; Kudera, S.; Lied, T.; Koktysh, D.; Rogach, A.L.; Keller, S.; Radler, J.; Natile, G.; Parak, W.J. Hydrophobic nanocrystals coated with an Amphiphilic polymer shell: A
general route to water soluble nanocrystals. Nano Lett., 2004, 4,
703-707.
Brust, M.; Walker, M.; Bethel, D.; Schiffrin, D.J.; Whyman, R.
Synthesis of thiol derivatised gold nanoparticles in a two-phase liquid- liquid system. J. Chem. Soc. Chem. Commun., 1994, 7, 801802.
Guerrero, E.; Munoz-Marquez, M.A.; Fernandez-Pinel, E.; Crespo,
P.; Hernando, A.; Fernandez, A. Electronic structure, magnetic
properties, and microstructural analysis of thiol-functionalized Au
nanoparticles: Role of chemical and structural parameters in the
ferromagnetic behavior. J. Nanopart. Res., 2008, 10, 179-192.
Simard, J.; Briggs, C.; Boal, A.K.; Rotello, V.M. Formation and
pH-controlled assembly of Amphiphilic gold nanoparticles. Chem.
Commun., 2000, 19, 1943-1944.
Templeton, A.C.; Chen, S.; Gross, S.M.; Murray, R.W. Water
soluble, isolable gold clusters protected by tiopronin and coenzyme
A monolayers. Langmuir, 1999, 15, 66-76.
Dong, T-Y.; Wu, H-H.; Lin, M-C. Superlattice of octanethiolprotected copper nanoparticles. Langmuir, 2006, 22, 6754-6756.
Gooding, J.J.; Mearns, F.; Yang, W.; Liu, J. Self-assembled monolayers into the 21st century: Recent advances and applications.
Electroanalysis, 2003, 15, 81-96.
Kisailus, D.; Najarian, M.; Weaver, J.C.; Morse, D.E. Functionalized gold nanoparticles mimic catalytic activity of a polysiloxanesynthesizing enzyme. Adv. Mater., 2005, 17, 1234-1239.
Fleming, M.S.; Walt, D.R. Solubility and exchange studies of alkanethiol monolayers on gold nanoparticle-coated silica microspheres. Langmuir, 2001, 17, 4836-4843.
Price, R.C.; Whetten, R.L. All-aromatic, nanometer-scale, goldcluster thiolate complexes. J. Am. Chem. Soc., 2005, 127, 1375013751.
Li, Y.; Xu, X.; Deng, C.; Yang, P.; Zhang, X. Immobilization of
trypsin on superparamagnetic nanoparticles for rapid and effective
proteolysis. J. Proteom. Res., 2007, 6, 3849-3855.
Brousseau, L.C.; Novak, J.P.; Marinakos, S.M.; Feldheim, D.L.
Assembly of phenylacetylene-bridged gold nanoclusters dimers and
trimers. Adv. Mater., 1999, 11, 447-449.
Shen, Q.; Wang, X.; Fu, D. The amplification effect of functionalized gold nanoparticles on the binding of anticancer drug dacarbazine to DNA and DNA bases. Appl. Surf. Sci., 2008, 255, 577-580.
Sousa, M.H.; Rubin, J.C.; Sobrinho, P.G.; Tourinho, F.A. Biocompatible magnetic fluid precursors based on aspartic and glutamic
acid modified maghemite nanostructures. J. Magn. Magn. Mater.,
2001, 225, 67-72.
Tie, S-L.; Li, Y-Q.; Lee, H-C.; Bae, Y-S.; Lee, C-H. Amino acidcoated nano-sized magnetite particles prepared by two-step transformation. Colloid Surface A., 2006, 273, 75-83.
Viota, J.L.; Arroyo, F.J.; Delgado, A.V.; Horno, J. Electrokinetic
characterization of magnetite nanoparticles functionalized with
amino acids. J. Colloid. Interf. Sci., 2010, 344, 144-149.
Wampler, H.P.; Ivanisevic, A. Nanoindentation of gold nanoparticles functionalized with proteins. Micron, 2009, 40, 444-448.
Koh, I.; Wang, X.; Varughese, B.; Isaacs, L.; Ehrman, S.H.; English, D.S. Magnetic iron oxide nanoparticles for biorecognition:
Evaluation of surface coverage and activity. J. Phys. Chem. B.,
2006, 110, 1553-1558.

[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
4573
Chen, W.; Shen, H.; Li, X.; Jia, N.; Xu, J. Synthesis of immunomagnetic nanoparticles and their application in the separation and
purification od CD34+ hematopoietic stem cells. Appl. Surf. Sci.,
2006, 253,1762-1769.
von Zur Muhlen, C.; von Elverfeldt, D.; Bassler, N.; Neudorfer, I.;
Steitz, B.; Petri-Flink, A.; Hofmann, H.; Bode, C.; Peter, K. Superparamagnetic iron oxide binding and uptake as imaged by magnetic
resonance is mediated by the integrin receptor Mac-1
(CD11b/CD18): implications on imaging of atherosclerotic
plaques. Atherosclerosis, 2007, 193, 102-111.
Li, L.; Wartchow, C.A.; Danthi, S.N.; Shen, Z.; Dechene, N.;
Pease, J.; Choi, S.; Doede, T.; Chu, P.; Ning, S.; Lee, D.Y.; Bednarski, M.D.; Knoz, S.J. A novel antiangiogenesis therapy using an
integrin antagonist or anti-Flk-1 antibody coated 90Y-labeled
nanoparticles. Int. J. Radiat. Oncol. Biol. Phys., 2004, 58, 12151227.
Dharap, S.S.; Qiu, B.; Williams, G.C.; Sinko, P.; Stein, S.; Minko,
T. Molecular targeting of drug delivery systems to ovarian cancer
by BH3 and LHRH peptides. J. Control. Release, 2003, 91, 61-73.
Missailidis, S.; Thomaidou, D.; Borbas, K.E.; Price, M.R. Selection
of aptamers with high affinity and high specificity against C595, an
anti-MUC1 IgG3 monoclonal antibody, for antibody targeting. J.
Immunol. Methods, 2005, 296, 45-62.
Mitra, A.; Mulholland, J.; Nan, A.; McNeill, E.; Ghandehari, H.;
Line, B.R. Targeting tumor angiogenic vasculature using polymerRGD conjugates. J. Control. Release, 2005, 102, 191-201.
Daniel, M-C.; Astruc, D. Gold nanoparticles: Assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology. Chem.
Rev., 2004, 104, 293-346.
Crouch, D.; Norager, S.; OBrien, P.; Park, J.H.; Pickett, N. New
synthetic routes for quantum dots. Phil. Trans. R. Soc. Lond. A.,
2003, 361, 297-310.
Murray, C.B.; Norris, D.J.; Bawendi, M.G. Synthesis and characterization of nearly monodisperse CdE (E=S, Se, Te) semiconductor nanocrystallites. J. Am. Chem. Soc., 1993, 115, 8706-8715.
Peng, X.; Manna, L.; Yang, W.; Wickham, J.; Scher, E.; Kadavanich, A.; Alivisatos, A.P. Shape control of CdSe nanocrystals,
Nature, 2000, 404, 59-61.
Manna, L.; Scher, E.C.; Alivisatos, A.P. Synthesis of soluble and
processable rod-, arrow-, teardrop-, and tetrapod-shaped CdSe
nanocrystals. J. Am. Chem. Soc., 2000, 122, 12700-12706.
Manna, L.; Milliron, D.J.; Meisel, A.; Scher, E.C.; Alivisatos, A.P.
Controlled growth of tetrapod-branched inorganic Nanocrystals.
Nat. Mater., 2003, 2, 382-385.
Liu, H.; Alivisatos, A.P. Preparation of asymmetric nanostructures
through site selective modification of tetrapods. Nano Lett., 2004,
4, 2397-2401.
Alivisatos, A.P.; Johnson, K.P.; Peng, X.; Wilson, T.E.; Loweth,
C.J.; Bruchez, M.P.; Schultz, P.G. Organization of 'nanocrystal
molecules' using DNA. Nature, 1996, 382, 609-611.
Loweth, C.J.; Caldwell, W.B.; Peng, X.; Alivisatos, A.P.; Schultz,
P.G. DNA-based assembly of gold nanocrystals. Angew. Chem. Int.
Edit., 1999, 38, 1808-1812.
Park, S.; Lim, J.H.; Chung, S-W.; Mirkin, C.A. Self-assembly of
mesoscopic metal-polymer amphiphiles. Science, 2004, 303, 348351.
Love, J.C.; Gates, B.D.; Wolfe, D.B.; Paul, K.E.; Whitesides, G.M.
Fabrication and wetting properties of metallic half-shells with submicron diameters. Nano Lett., 2002, 2, 891-894.
Lu, Y.; Xiong, H.; Jiang, X.; Xia, Y.; Prentiss, M.; Whitesides,
G.M. Asymmetric dimers can be formed by dewetting half-shells
of gold deposited on the surfaces of spherical oxide colloids. J. Am.
Chem. Soc., 2003, 125, 12724-12725.
Charnay, C.; Lee, A.; Man, S-Q.; Moran, C.E.; Radloff, C.; Bradley, R.K.; Halas, N.J. Reduced symmetry metallodielectric
nanoparticles: Chemical synthesis and plasmonic properties. J.
Phys. Chem. B., 2003, 107, 7327-7333.
Wu, Y.; Fan, R.; Yang, P. Block-by-Block growth of singlecrystalline Si/SiGe superlattice nanowires. Nano lett., 2002, 2, 8386.
Gudiksen, M.S.; Lauhon, L.J.; Wang, J.; Smith, D.C.; Lieber, C.M.
Growth of nanowire superlattice structures for nanoscale photonics
and electronics. Nature, 2002, 415, 617-620.

[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
Bjork, M.T.; Ohlsson, B.J.; Sass, T.; Persson, A.I.; Thelander, C.;
Magnusson, M.H.; Deppert, K.; Wallenberg, L.R.; Samuelson, L.
One-dimensional steeplechase for electrons realized. Nano Lett.,
2002, 2, 87-89.
Salem, A.K.; Searson, P.C.; Leong, K.W. Multifunctional nanorods
for gene delivery. Nat. Mater., 2003, 2, 668-671.
Mokari, T.; Rothenberg, E.; Popov, I.; Costi, R.; Banin, U. Selective growth of metal tips onto semiconductor quantum rods and
tetrapods. Science, 2004, 304, 1787-1790.
Sardar, R.; Shumaker-parry, J.S. Asymmetrically functionalized
gold nanoparticles organized in one-dimensional chains. Nano
Lett., 2008, 8, 731-736.
Sardar, R.; Heap, T.B.; Shumaker-Parry, J.S. Versatile solid phase
synthesis of gold nanoparticle dimers using an asymmetric functionalization approach. J. Am. Chem. Soc., 2007, 129, 5356-5357.
Guo, Z.; Pereira, T.; Choi, O.; Wang, Y.; Hahn, H.T. Surface functionalized alumina nanoparticle filled polymeric nanocomposites
with enhanced mechanical properties. J. Mater. Chem., 2006, 16,
2800-2808.
Sandi, G.; Kizilel, R.; Carrado, K.A.; Fernandez-saavedra, R.;
Castagnola, N. Effect of the silica precursor on the conductivity of
hectorite-derived polymer nanocomposites. Electrochim. Acta,
2005, 50, 3891-3896.
Huang, W.Y.; Han, C.D. Dispersion characteristics and rheology of
organoclay nanocomposites based on a segmented main-chain liquid-crystalline polymer having pendent pyridyl group. Macromolecules, 2006, 39, 257-267.
Mammeri, F.; Le Bourhis, E.; Rozes, L.; Sanchez, C.J. Mechanical
properties of hybrid organic-inorganic materials. Mater. Chem.,
2005, 15, 3787-3811.
Sanchez, C.; Ribot, F. Design of hybrid organic-inorganic materials
synthesized via sol-gel chemistry. New J. Chem., 1994, 18, 10071047.
Judeinstein, P.; Sanchez, C. Hybrid organic-inorganic materials: a
land of multidisciplinarity. J. Mater. Chem., 1996, 6, 511-525.
Zhang, X.; Simon, L.C. In situ polymerization of hybrid polyethylene-alumina nanocomposites. Macromol. Mater. Eng., 2005,
290,573-583.
Gao, S-L.; Mader, E. Characterization of interphase nanoscale
property variations in glass fibre reinforced polypropylene and epoxy resin composites. Compos. Part A-Appl.S., 2002, 33, 559-576.
Shenhar, R.; Norsten, T.B.; Rotello, V.M. Polymer-mediated
nanoparticle assembly: Structural control and applications. Adv.
Mater., 2005, 17, 657-669.
Kim, D.J.; Kang, P.H.; Nho, Y.C. Characterization of mechanical
properties of Al2O3 dispersed epoxy resin cured by -ray radiation.
J. Appl. Polym. Sci., 2004, 91, 1898-1903.
Ash, B.J.; Siegel, R.W.; Schadler, L.S. Mechanical behavior of
Alumina/Poly(methyl methacrylate) nanocomposites. Macromolecules, 2004, 37, 1358-1369.
Zhang, M.; Singh, R.P. Mechanical reinforcement of unsaturated
polyester by Al2O3 nanoparticles. Mater. Lett., 2005, 58, 408-412.
Abboud, M.; Turner, M.; Duguet, E.; Fontanille, M. PMMA-based
composite materials with reactive ceramic fillers: Part 1-chemical
modification and characterization of ceramic particles. J. Mater.
Chem., 1997, 7, 1527-1532.
Arap, W.; Kolonin, M.G.; Trepel, M.; Lahdenranta, J.; Cardo-vila,
M.; Giordano, R.J.; Mintz, P.J.; Ardelt, P.U.; Yao, V.J.; Vidal,
C.L.; Flamm, C.L.; Valtanen, H.; Weavind, L.M.; Hicks, M.E.;
Pollock, R.E.; Botz, G.H.; Bucana, C.D.; Koivunen, E.; Cahill, D.;
Troncoso, P.; Baggerly, K.A.; Pentz, R.D.; Do, K.A.; Logothetis,
C.J.; Pasqualini, R. Steps toward mapping the human vasculature
by phage display. Nat. Med., 2002, 8, 121-127.
Kolonin, M.G.; Sun, J.; Do, K-A.; Vidal, C.I.; Ji, Y.; Baggerly,
K.A.; Pasqualini, R.; Arap, W. Synchronous selection of homing
peptides for multiple tissues by in vivo phage display. Faseb J.,
2006, 20, 979-981.
Smith, G.P.; Petrenko, V.A. Phage display. Chem. Rev., 1997, 97,
391-410.
Rehor, A.; Hubbell, J.A.; Tirelli, N. Oxidation-sensitive polymeric
nanoparticles. Langmuir, 2005, 21, 411-417.
Rehor, A. Poly(propylene sulfide) nanoparticles as drug carriers.
PhD Thesis, Swiss Federal Institute of Technology: Zurich, 2005.
Subbiah et al.
[103]
[104]
[105]
[106]
[107]
[108]
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
Harris, J.M.; Martin, N.E.; Modi, M. Pegylation: A novel process

for modifying pharmacokinetics. Clin. Pharmacokinet., 2001, 40,
539-551.
Molineux, G. Pegylation: engineering improved pharmaceuticals
for enhanced therapy. Cancer Treat. Rev., 2002, 28, 13-16.
Steinmetz, N.F.; Bize, A.; Findlay, K.C.; Lomonossoff, G.P.; Manchester, M.; Evans, D.J.; Prangishvili, D.P. Site-specific and spatially controlled addressability of a new viral nanobuilding block:
Sulfolobus islandicus rod-shaped virus 2. Adv. Func. Mater., 2008,
21, 3478-3486.
Tomalia, D.A. Birth of a new macromolecular architecture: dendrimers as quantized building blocks for nanoscale synthetic polymer chemistry. Prog. Polym. Sci., 2005, 30, 294-324.
Hainfeld, J.F.; Powell, R.D. New frontiers in gold labeling. J. Histochem. Cytochem., 2000, 48, 471-480.
Worden, J.G.; Shaffer, A.W.; Huo, Q. Controlled functionalization
of gold nanoparticles through a solid phase synthesis approach.
Chem. Commun., 2004, 518-519.
Kruger, C.; Agarwal, S.; Greiner, A. Stoichiometric functionalization of gold nanoparticles in solution through a free radical polymerization approach. J. Am. Chem. Soc., 2008, 130, 2710-2711.
Freitas, R.A. Nanomedicine.; Landes BioScience: Georgetown, TX,
1999. Vol. I.
Emerich, D.F.; Thanos, C.G. The pinpoint promise of nanoparticlebased drug delivery and molecular diagnosis. Biomol. Eng., 2006,
23, 171-184.
Galindo-Rodriguez, S.A.; Allemann, E.; Fessi, H.; Doelker, E.
Polymeric nanoparticles for oral delivery of drugs and vaccines: A
critical evaluation of in vivo studies. Crit. Rev. Ther. Drug, 2005,
22, 419-464.
Emerich, D.F.; Thanos, C.G. The pinpoint promise of nanoparticlebased drug delivery and molecular diagnosis. Biomol. Eng., 2006,
23, 171-184.
Bae, Y.; Nishiyama, N.; Fukushima, S.; Koyama, H.; Yasuhiro, M.;
Kataoka, K. Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: Tumor permeability, controlled subcellular drug
distribution, and enhanced in vivo antitumor efficacy. Bioconjugate
Chem., 2005, 16, 122-130.
Dreher, M.R.; Liu, W.; Michelich, C.R.; Dewhirst, M.W.; Yuan, F.;
Chilkoti, A. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J. Natl. Cancer I., 2006,
98, 335-344.
Duncan, R. The dawning era of polymer therapeutics. Nat. Rev.
Drug Discov., 2003, 2, 347-360.
Shiah, J.J.; Sun, Y.; Peterson, C.M.; Kopecek, J. Biodistribution of
free and N-(2-hydroxypropyl) methacrylamide copolymer-bound
mesochlorin e(6) and adriamycin in nude mice bearing human
ovarian carcinoma OVCAR-3 xenografts. J. Control. Release.,
1999, 61, 145-157.
Rothenfluh, D.A.; Bermudez, H.; Oneil1, C.P.; Hubbell, J.A.
Biofunctional polymer nanoparticles for intra-articular targeting
and retention in cartilage. Nat. Mater., 2008, 7, 248-254.
Wieland, H.A.; Michaelis, M.; Kirschbaum, B.J.; Rudolphi, K.A.
Osteoarthritis - an untreatable disease?. Nat. Rev. Drug. Discov.,
2005, 4, 331-344.
Ferkol, T.; Perales, J.C.; Mularo, F.; Hanson, R.W. Receptormediated gene transfer into macrophages. Proc. Natl. Acad.
Sci.USA., 1996, 93, 101-105.
Zanta, M-A.; Boussif, O.; Adib, A.; Behr, J-P. In vitro gene delivery to hepatocytes with galactosylated polyethylenimine. Bioconjug. Chem., 1997, 8, 839-844.
Bettinger, T.; Remy, J.S.; Erbacher, P. Size reduction of galactosylated PEI/DNA complexes improves lectin mediated gene transfer
into hepatocytes. Bioconjug. Chem., 1999, 10, 558-561.
Leamon, C.P.; Weigl, D.; Hendren, R.W. Folate copolymermediated transfection of cultured cells. Bioconjug. Chem., 1999,
10, 947-957.
Wu, G.Y.; Wu, C.H. Receptor-mediated in vitro gene transformation by a soluble DNA carrier system. J. Biol. Chem., 1987, 262,
4429-4432.
Wu, G.Y.; Wu, C.H. Receptor-mediated gene delivery and expression in vivo. J. Biol. Chem., 1988, 263, 14621-14624.
Nanoparticles
[126]
[127]
[128]
[129]
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144]
[145]
[146]
[147]
Wu, C.H.; Wilson, J.M.; Wu, G.Y. Targeting genes: delivery and
persistent expression of a foreign gene driven by mammalian regulatory elements in vivo. J. Biol. Chem., 1989, 264, 16985-16987.
Wagner, E.; Zenke, M.; Cotten, M.; Beug, H.; Birnstiel, M.L.
Transferrin-polycation conjugates as carriers for DNA uptake into
cells. Proc. Natl Acad. Sci. USA., 1990, 87, 3410-3414.
Zenke, M.; Steinlein, P.; Wagner, E.; Cotton, M.; Beug, H.; Birnstiel, M.L. Receptor-mediated endocytosis of transferrin-polycation
conjugates: an efficient way to introduce DNA into hematopoietic
cells. Proc. Natl Acad. Sci. USA, 1990, 87, 3655-3659.
Schaffer, D.V.; Lauffenburger, D.A. Optimization of cell surface
binding enhances efficiency and specificity of molecular conjugate
gene delivery. J. Biol. Chem., 1998, 273, 28004-28009.
Stewart, B.W.; Kleihues, P. In: World Cancer Report, World
Health Organization Press, Geneva, 2003.
Osada, K.; Christie, R.C.; Kataoka, K. Polymeric micelles from
poly(ethylene glycol)-poly(amino acid) block copolymer for drug
and gene delivery. J. R. Soc. Interfac., 2009, 6, S325-S339.
Couvreur, P.; Vauthier, C. Nanotechnology: Intelligent design to
treat complex disease. Pharm. Res., 2006, 23, 1417-1450.
Yuan, F.; Dellian, M.; Fukumura, D.; Leunig, M.; Berk, D.A.;
Torchilin, V.P.; Jain, R.K. Vascular-permeability in a human tumor
xenograft: Molecular-size dependence and cutoff size. Cancer Res.,
1995, 55, 3752-3756.
Torchilin, V.P. Recent advances with liposomes as pharmaceutical
carriers. Nat. Rev. Drug Discov., 2005, 4, 145-160.
Hobbs, S.K.; Monsky, W.L.; Yuan, F.; Roberts, W.G.; Griffith, L.;
Torchilin, V.L.; Jain, R.K. Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proc. Natl.
Acad. Sci. USA, 1998, 95, 4607-4612.
Peer, D.; Karp, J.M.; Hong, S.; Farokhzad, O.C.; Margalit, R.;
Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol., 2007, 2, 751-760.
Peer, D.; Zhu, P.; Carman, C.V.; Lieberman, J.; Shimaoka, M.
Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1.
Proc. Natl. Acad. Sci. USA, 2007, 104, 4095-4100.
Chawla, J.S.; Amiji, M.M. Biodegradable poly (-caprolactone)
nanoparticles for tumor-targeted delivery of tamoxifen. Int. J.
Pharm., 2002, 249, 127-138.
Dreis, S.; Rothweiler, F.; Michaelis, M.; Cinatl, J.; Kreuter, J.;
Langer, K. Preparation, characterization and maintenance of drug
efficacy of doxorubicin-loaded human serum albumin (HSA)
nanoparticles. Int. J. Pharm., 2007, 341, 207-214.
Reddy, L.H.; Sharma, R.K.; Murthy, R.S.R. Enhanced tumour
uptake of doxorubicin loaded poly (butyl cyanoacrylate) nanoparticles in mice bearing Daltons lymphoma tumour. J. Drug Target,
2004, 12, 443-451.
Lee, M.K.; Lim, S.J.; Kim, C.K. Preparation, characterization and
in vitro cytotoxicity of paclitaxel-loaded sterically stabilized solid
lipid nanoparticles. Biomaterials, 2007, 28, 2137-2146.
Raffaghello, L.; Zuccari, G.; Carosio, R.; Orienti, I.; Montaldo,
P.G. In vitro and in vivo antitumor activity of the novel derivatized
polyvinyl alcohol-based polymer P10(4). Clin. Cancer Res., 2006,
12, 3485-3493.
Yokoyama, M.; Miyauchi, M.; Yamada, N.; Okano, T.; Sakurai,
Y.; Kataoka, K.; Inoue, S. Polymer micelles as novel drug carrier:
Adriamycin-conjugated poly (ethylene glycol)-poly(aspartic acid)
block copolymer. J. Control Release, 1990, 11, 269-278.
Lee, E.S.; Na, K.; Bae, Y.H. Polymeric micelle for tumor pH and
folate-mediated targeting. J. Control Release, 2003, 91, 103-113.
Soga, O.; van Nostrum, C.F.; Fens, M.; Rijcken, C.J.; Schiffelers,
R.M.; Storm, G.; Hennink, W.E. Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery. J. Control. Release,
2005, 103, 341-353.
Wang, J.; Mongayt, D.; Torchilin, V.P. Polymeric micelles for
delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on
poly(ethylene glycol)-lipid conjugate and positively charged lipids.
J. Drug Target, 2005, 13, 73-80.
Gao, Z.; Lukyanov, A.N.; Chakilam, A.R.; Torchilin, V.P. PEGPE/Phosphatidylcholine mixed immunomicelles specifically deliver
encapsulated taxol to tumor cells of different origin and promote
their efficient killing. J. Drug Target, 2003, 11, 87-92.

[148]
[149]
[150]
[151]
[152]
[153]
[154]
[155]
[156]
[157]
[158]
[159]
[160]
[161]
[162]
[163]
[164]
[165]
4575
Mu, L.; Elbayoumi, T.A.; Torchilin, V.P. Mixed micelles made of

poly(ethylene glycol)-phosphatidylethanolamine conjugate and D-tocopheryl polyethylene glycol 1000 succinate as pharmaceutical
nanocarriers for camptothecin. Int. J. Pharm., 2005, 306, 142-149.
Gao, Z.; Lukyanov, A.; Singhal, A.; Torchilin, V. Diacyllipidpolymer micelles as nanocarriers for poorly soluble anticancer
drugs. Nano Lett., 2002, 2, 979-982.
Wong, H.L.; Rauth, A.M.; Bendayan, R.; Wu, X.Y. In vivo evaluation of a new polymerlipid hybrid nanoparticle (PLN) formulation
of doxorubicin in a murine solid tumor model. Eur. J. Pharm.
Biopharm., 2005, 65, 300-308.
Trimaille, T.; Mondon, K.; Gurny, R.; Moller, M. Novel polymeric
micelles for hydrophobic drug delivery based on biodegradable
poly(hexyl-substituted lactides). Int. J. Pharm., 2006, 319, 147154.
Kwon, G.; Naito, M.; Yokoyama, M.; Okano, T.; Sakurai, Y.;
Kataoka, K. Block copolymer micelles for drug delivery: loading
and release of doxorubicin. J. Control Release, 1997, 48, 195-201.
Liu, J.; Zeng, F.; Allen, C. Influence of serum protein on polycarbonate-based copolymer micelles as a delivery system for a hydrophobic anti-cancer agent. J. Control Release, 2005, 103, 481-497.
Nakanishi, T.; Fukushima, S.; Okamoto, K.; Suzuki, M.; Matsumura, Y.; Yokoyama, M.; Okano, T.; Sakurai, Y.; Kataoka, K.
Development of the polymer micelle carrier system for
doxorubicin. J. Control Release, 2001, 74, 295-302.
Uchino, H.; Matsumura, Y.; Negishi, T.; Koizumi, F.; Hayashi, T.;
Honda, T.; Nishiyama, N.; Kataoka, K.; Naito, S.; Kakizoe, T. Cisplatin-incorporating polymeric micelles (NC-6004) can reduce
nephrotoxicity and neurotoxicity of cisplatin in rats. Br. J. Cancer,
2005, 93, 678-687.
Rapoport, N.; Pitt, W.G.; Sun, H.; Nelson, J.L. Drug delivery in
polymeric micelles: From in vitro to in vivo. J. Control Release,
2003, 91, 85-95.
Exner, A.A.; Krupka, T.M.; Scherrer, K.; Teets, J.M. Enhancement
of carboplatin toxicity by pluronic block copolymers. J. Control
Release, 2005, 106, 188-197.
Xu, P.; Van Kirk, E.A.; Li, S.; Murdoch, W.J.; Ren, J.; Hussain,
M.D.; Radosz, M.; Shen, Y. Highly stable core-surface-crosslinked
nanoparticles as cisplatin carriers for cancer chemotherapy. Colloids Surface B., 2006, 48, 50-57.
Shuai, X.; Merdan, T.; Schaper, A.K.; Xi, F.; Kissel, T. Core-crosslinked polymeric micelles as paclitaxel carriers. Bioconjug. Chem.,
2004, 15, 441-448.
Roy, I.; Ohulchanskyy, T.Y.; Pudavar, H.E.; Bergey, E.J.; Oseroff,
A.R.; Morgan, J.; Dougherty, T.J.; Prasad, P.N. Ceramic-based
nanoparticles entrapping water-insoluble photosensitizing anticancer drugs: A novel drug-carrier system for photodynamic therapy.
J. Am. Chem. Soc., 2003, 125, 7860-7865.
Everts, M.; Saini, V.; Leddon, J.L.; Kok, R.J.; Stoff-Khalili, M.;
Preuss, M.A.; Millican, C.L.; Perkins, G.; Brown, J.M.; Bagaria,
H.; Nikles, D.E.; Johnson, D.T.; Zharov, V.P.; Curiel, D.T. Covalently linked Au nanoparticles to a viral vector: potential for combined photothermal and gene cancer therapy. Nano Lett., 2006, 6,
587-591.
Hirsch, L.R.; Stafford, R.J.; Bankson, J.A.; Sershen, S.R.; Rivera,
B.; Price, R.E.; Hazle, J.D.; Halas, N.J.; West, J.L. Nanoshellmediated near-infrared thermal therapy of tumors under magnetic
resonance guidance. Proc. Natl. Acad. Sci. USA, 2003, 100, 1354913554.
Jordan, A.; Scholz, R.; Maier-Hauff, K.; van Landeghem, F.K.H.;
Waldoefner, N.; Teichgraeber, U.; Pinkernelle, J.; Bruhn, H.; Neumann, F.; Thiesen, B.; Deimling, A.V.; Felix, R. The effect of
thermotherapy using magnetic nanoparticles on rat malignant
glioma. J. Neuro Oncol., 2006, 78, 7-14.
Jurgons, R.; Seliger, C.; Hilpert, A.; Trahms, L.; Odenbach, S.;
Alexiou, C. Drug loaded magnetic nanoparticles for cancer therapy.
J. Phys- Condens. Mat., 2006, 18, S2893-S2902.
Kobayashi, H.; Kawamoto, S.; Saga, T.; Sato, N.; Ishimori, T.;
Konishi, J.; Ono, K.; Togashi, K.; Brechbiel, M. Avidin-dendrimer(1B4M-Gd)254 : A tumor-targeting therapeutic agent for gadolinium
neutron capture therapy of intraperitoneal disseminated tumor
which can be monitored by MRI. Bioconjug. Chem., 2001, 12, 587593.

[166]
[167]
[168]
[169]
[170]
[171]
[172]
[173]
[174]
[175]
[176]
[177]
[178]
[179]
[180]
[181]
[182]
[183]
Quintana, A.; Raczka, E.; Piehler, L.; Lee, I.; Myc, A.; Majoros, I.;
Patri, A.; Thomas, T.; Mule, J.; Baker, J. Design and function of a
dendrimer-based therapeutic nanodevice targeted to tumor cells
through the folate receptor. Pharm. Res., 2002, 19, 1310-1316.
Latallo, J.F.; Candido K.A.; Cao, Z.; Nigavekar, S.S.; Majoros, I.J.;
Thomas, T.P.; Balogh, L.P.; Khan, M.K.; Baker, J. Nanoparticles
targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer. Cancer Res., 2005, 65,
5317-5324.
Morgan, M.T.; Nakanishi, Y.; Kroll, D.J.; Griser, A.P.; Carnahan,
M.A.; Wathier, M.; Oberlies, N.H.; Manikumar, G.; Wani, M.C.;
Grinstaff, M.W. Dendrimer-encapsulated camptothecins: Increased
solubility, cellular uptake, and cellular retention affords enhanced
anticancer activity in vitro. Cancer Res., 2006, 66, 11913-11921.
Yoo, H.S.; Park, T.G. Folate receptor targeted biodegradable polymeric doxorubicin micelles. J. Control Release, 2004, 96, 273283.
Park, E.K.; Kim, S.Y.; Lee, S.B.; Lee, Y.M. Folate-conjugated
methoxy poly(ethylene glycol)/poly(-caprolactone) Amphiphilic
block copolymeric micelles for tumor-targeted drug delivery. J.
Control Release, 2005, 109, 158-168.
Nasongkla, N.; Shuai, X.; Ai, H.; Weinberg, B.D.; Pink, J.; Boothman, D.A.; Gao, J.M. cRGD-functionalized polymer micelles for
targeted doxorubicin delivery. Angew. Chem. Int. Edit., 2004, 43,
6323-6327.
Jeong, Y.I.; Seo, S.J.; Park, I.K.; Lee, H.C.; Kang, I.C.; Akaike, T.;
Cho, C.S. Cellular recognition of paclitaxel-loaded polymeric
nanoparticles composed of poly(gamma-benzyl L-glutamate) and
poly(ethylene glycol) diblock copolymer end capped with galactose
moiety. Int. J. Pharm., 2005, 296, 151-161.
Park, J.H.; Kwon, S.; Lee, M.; Chung, H.; Kim, J-H.; Kim, Y-S.;
Park, R-W.; Kim, I-S.; Seo, S.B.; Kwon, I.C.; Jeong, S.Y. Selfassembled nanoparticles based on glycol chitosan bearing hydrophobic moieties as carriers for doxorubicin: In vivo biodistribution
and anti-tumor activity. Biomaterials, 2006, 27, 119-126.
Wosikowski, K.; Biedermann, E.; Rattel, B.; Breiter, N.; Jank, P.;
Loser, R.; Jansen, G.; Peters, G.J. In vitro and in vivo antitumor activity of methotrexate conjugated to human serum albumin in human cancer cells. Clin. Cancer Res., 2003, 9, 1917-1926.
Torchilin, V.P.; Lukyanov, A.N.; Gao, Z.; PapahadjopoulosSternberg, B. Immunomicelles: Targeted pharmaceutical carriers
for poorly soluble drugs. Proc. Natl. Acad. Sci. USA, 2003, 100,
6039-6044.
Fonseca, M.J.; Jagtenberg, J.C.; Haisma, H.J.; Storm, G.
Liposome-mediated targeting of enzymes to cancer cells for sitespecific activation of prodrugs: Comparison with the corresponding
antibody-enzyme conjugate. Pharm. Res., 2003, 20, 423-428.
Schnyder, A.; Krahenbuhl, S.; Drewe, J.; Huwyler, J. Targeting of
daunomycin using biotinylated immunoliposomes: Pharmacokinetics, tissue distribution and in vitro pharmacological effects. J. Drug
Target, 2005, 13, 325-335.
Farokhzad, O.C.; Cheng, J.J.; Teply, B.A.; Sherifi, I.; Jon, S.; Kantoff, P.W.; Richie, J.P.; Langer, R. Targeted nanoparticle-aptamer
bioconjugates for cancer chemotherapy in vivo. Proc. Natl. Acad.
Sci. USA, 2006, 103, 6315-6320.
Kasoju, N.; Bora, D.K.; Bhonde, R.R.; Bora, U. Synthesis and
characterization and application of novel biodegradable selfassembled 2-(N-phthalimido) ethyl-palmitate nanoparticles for
cancer theapy. J. Nanopart. Res., 2010, 12, 801-810.
Lawson, L.B.; Freytag, L.C.; Clements, J.D.; Clements, J.D. Use of
nanocarriers for transdermal vaccine delivery. Clin. Pharmacol.
Ther., 2007, 82, 641-643.
Orringer, D.A.; Koo, Y.E.; Chen, T.; Kopelman, R.; Sagher, O.;
Philbert, M.A. Small solutions for big problems: The application of
nanoparticles to brain tumor diagnosis and therapy. Clin. Pharmacol. Ther., 2009, 85, 531-534.
Prescott, J.H.; Lipka, S.; Baldwin, S.; Sheppard, N.F.; Maloney,
J.M.; Coppeta, J.; Yomtov, B.; Staples, M.A.; Santini, J.T. Chronic,
programmed polypeptide delivery from an implanted, multireservoir microchip device. Nat. Biotechnol., 2006, 24, 437-438.
Thassu, D.; Deleers, M.; Pathak, Y. Nanoparticulate drug delivery
systems. Informa Healthcare: New York, USA, 2007, 24, pp. 129140.
Subbiah et al.
[184]
[185]
[186]
[187]
[188]
[189]
[190]
[191]
[192]
[193]
[194]
[195]
[196]
[197]
[198]
[199]
[200]
[201]
[202]
[203]
[204]
[205]
Vasir, J.K.; Reddy, M.K.; Labhasetwar, V.D. Nanosystems in drug

targeting: Opportunities and challenges. Curr. Nanosci., 2005, 1,
47-64.
Wang, D.; Miller, S.C.; Kopeckova, P.; Kopecek, J. Bone-targeting
macromolecular therapeutics. Adv. Drug. Deliv. Rev., 2005, 57,
1049-1076.
Kreuter, J. Nanoparticulate systems for brain delivery of drugs.
Adv. Drug Deliv. Rev., 2001, 47, 65-81.
Lanza, G.M.; Winter, P.M.; Caruthers, S.D.; Morawski, A.M.;
Schmieder, A.H.; Crowder, K.C.; Wickline, S.A. Magnetic resonance molecular imaging with nanoparticles: From bench to bedside. J. Nucl. Cardiol., 2004, 11, 733-743.
Freitas, R.A. Pharmacytes: An ideal vehicle for targeted drug delivery. J. Nanosci. Nanotech., 2006, 6, 2769-2775.
Choi, S.W.; Kim, J.H. Design of surface modified poly (D, Llactide-co-glycolide) nanoparticles for targeted drug delivery to
bone. J. Control Release, 2007, 122, 24-30.
Oh, K.T.; Oh, Y.T.; Oh, N-M.; Kim, K.; Lee, D.H.; Lee, E.S. A
smart flower-like polymeric micelle for pH-triggered anticancer
drug release. Int. J. Pharm., 2009, 375, 163-169.
Hawkins, M.J.; Soon-Shiong, P.; Desai, N. Protein nanoparticles as
drug carriers in clinical medicine. Adv. Drug Deliv. Rev., 2008, 60,
876-885.
Valois, C.R.A.; Braz, J.M.; Nunes, E.S.; Vinolo, M.A.R.; Lima,
E.C.D.; Curi, R.; Kuebler, W.M.; Azevedo, R.B. The effect of
DMSA-functionalized magnetic nanoparticles on transendothelial
migration of monocytes in the murine lung via 2 integrindependent pathway. Biomaterials, 2010, 31, 366-374.
Zhou, J.; Leuschner, C.; Kumar, C.; Hormes, J.; Soboyejo, W.O. A
TEM study of functionalized nanoparticles targeting breast cancer
cells. Mat. Sci. Eng. C-Bio S., 2006, 26, 1451-1455.
Gupta, A.K.; Curtis, A.S.G. Surface modified superparamagnetic
nanoparticles for drug delivery: Interaction studies with human fibroblasts in culture. J. Mater. Sci-Mater M., 2004, 15, 493-496.
Huang, Y-F.; Lin, Y-W.; Lin, Z-H.; Chang, H-T. Aptamermodified gold nanoparticles for targeting breast cancer cells
through light scattering. J. Nanopart. Res., 2009, 11, 775-783.
Cheng, J.; Teply, B.A.; Sherifi, I.; Sung, J.; Luther, G.; Gu, F.X.;
Levy-Nissenbaum, E.; Radovic-Moreno, A.F.; Langer, R.; Farokhzad, O.C. Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. Biomaterials, 2007, 28, 869876.
Zhang, L.; Hou, S.; Mao, S.; Wei, D.; Song, X.; Lu, Y. Uptake of
folate-conjugated albumin nanoparticles to the SKOV3 cells. Int. J.
Pharm., 2004, 287, 155-162.
Vinogradov, S.V.; Batrakova, E.V.; Kabanov, A.V. Nanogels for
oligonucleotide delivery to the brain. Bioconjug. Chem., 2004, 15,
50-60.
Gupta, A.K.; Berry, C.; Gupta, M.; Curtis, A. Receptor-mediated
targeting of magnetic nanoparticles using insulin as a surface
ligand to prevent endocytosis. IEEE Trans. Nanobioscience, 2003,
2, 255-261.
Patil, Y.B.; Toti, U.S.; Khadir, A.; Ma, L.; Panyam, J. Single-step
surface functionalization of polymeric nanoparticles for targeted
drug delivery. Biomaterials, 2009, 30, 859-866.
Messerschmidt, S.K.E.; Musyanovych, A.; Altvater, M.; Scheurich,
P.; Pfizenmaier, K.; Landfester, K.; Kontermann, R.E. Targeted
lipid-coated nanoparticles: delivery of tumor necrosis factorfunctionalized particles to tumor cells. J. Control Release, 2009,
137, 69-77.
Farokhzad, O.C.; Jon, S.; Khademhosseini, A.; Tran, T.T.; LaVan,
A.; Langer, R. Nanoparticle-Aptamer bioconjugates: A new approach for targeting prostate cancer cells. Cancer Res., 2004, 64,
7668-7672.
Hood, J.D.; Bednarski, M.; Frausto, R.; Guccione, S.; Reiseld,
R.A.; Xiang, R.; Cheresh, D.A. Tumor regression by targeted gene
delivery to the neovasculature. Science, 2002, 28, 2404-2407.
Schiffelers, R.M.; Ansari, A.; Xu, J.; Zhou, Q.; Tang, Q.; Storm,
G.; Molema, G.; Lu, P.Y.; Scaria, P.V.; Woodle, M.C. Cancer
siRNA therapy by tumor selective delivery with ligand-targeted
sterically stabilized nanoparticle. Nucleic Acids Res., 2004, 32,
e149-e150.
Hallahan, D.; Geng, L.; Qu, S.; Scarfone, C.; Giorgio, T.; Donnelly, E.; Gao, X.; Clanton, J. Integrin-mediated targeting of drug
Nanoparticles
[206]
[207]
[208]
[209]
[210]
[211]
[212]
[213]
[214]
[215]
delivery to irradiated tumor blood vessels. Cancer Cell, 2003, 3,

63-74.
Elamanchili, P.; Diwan, M.; Cao, M.; Samuel, J. Characterization
of poly(D,L-lactic-co-glycolic acid) based nanoparticulate system
for enhanced delivery of antigens to dendritic cells. Vaccine, 2004,
22, 2406-2412.
Pan, X.Q.; Zheng, X.; Shi, G.; Wang, H.; Ratnam, M.; Lee, R.J.
Strategy for the treatment of acute myelogenous leukemia based on
folate receptor -targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. Blood, 2002, 100,
594-602.
Lopez de Menezes, D.E.; Pilarski, L.M.; Allen, T.M. In vitro and in
vivo targeting of immunoliposomal doxorubicin to human B-Cell
lymphoma. Cancer Res., 1998, 61, 2592-2601.
Park, J.W.; Hong, K.; Kirpotin, D.B.; Colbern, G.; Shalaby, R.;
Baselga, J.; Shao, Y.; Nielsen, U.B.; Marks, J.D.; Moore, D.; Papahadjopoulos, D.; Benz, C.C. Anti-HER2 immunoliposomes: Enhanced efficacy attributable to targeted delivery. Clin. Cancer Res.,
2002, 8, 1172-1181.
Olivier, J.C. Drug transport to brain with targeted nanoparticles.
NeuroRx, 2005, 2, 108-119.
Eliaz, R.E.; Szoka, F.C. Liposome-encapsulated doxorubicin targeted to CD44: a strategy to kill CD44- overexpressing tumor cells.
Cancer Res., 2001, 61, 2592-2601.
Cho, C.S.; Cho, K.Y.; Park, I.K.; Kim, S.H.; Sasagawa, T.; Uchiyama, M.; Akaike, T. Receptor-mediated delivery of all transretinoic acid to hepatocyte using poly(L-lactic acid) nanoparticles
coated with galactose-carrying polystyrene. J. Control Release,
2001, 77, 7-15.
Gordon, E.M.; Cornelio, G.H.; Lorenzo, C.C.; Levy, J.P.; Reed,
R.A.; Liu, L.; Hall, F.L. First clinical experience using a
pathotropic injectable retroviral vector (Rexin-G) as intervention
for stage IV pancreatic cancer. Int. J. Oncol., 2004, 24, 177-185.
Langer, R.; Vacanti, J.P. Tissue engineering. Science, 1993, 2, 920926.
Putnam, A.; Mooney, D.J. Tissue engineering using synthetic extracellular matrices. Nat. Med., 1996, 2, 824-826.
Received: July 29, 2010
Revised: October 12, 2010
Accepted: October 14, 2010
[216]
[217]
[218]
[219]
[220]
[221]
[222]
[223]
[224]
[225]
[226]
[227]
4577
Mulligan, R.C. The basic science of gene therapy. Science, 1993,

260, 926-932.
Madsen, S-K.; Mooney, D.J. Delivering DNA with polymer matrices: Applications in tissue engineering and gene therapy. Pharm.
Sci. Technol. Today, 2000, 3, 381-384.
Pack, D.W.; Hoffman, A.S.; Pun, S.; Stayton, P.S. Design and
development of polymers for gene delivery. Nat. Rev. Drug
Discov., 2005, 4, 581-593.
Makhluf, S.B-D.; Abu-Mukh, A.; Rubinstein, S.; Breitbart, H.;
Gedanken, A. Modified PVA-Fe3O4 nanoparticles as protein carriers into sperm cells. Small, 2008, 4, 1453-1458.
Ambrose, J. Computerized transverse axial scanning (tomography):
Clinical application. Br. J. Radiol., 1973, 46, 1023-1047.
Lauterbur, P.C. Image formation by induced local interactions:
examples employing nuclear magnetic resonance. Nature, 1973,
242, 190-191.
Chesler, D.A.; Hoop, J.R.B.; Brownell, G.L. Transverse section
imaging of myocardium with 13NH4. J. Nucl. Med., 1973, 14, 623.
Weizenecker, J.; Gleich, B.; Rahmer, J.; Dahnke, H.; Borgert, J.
Three-dimensional real-time in vivo magnetic particle imaging.
Phys. Med. Biol., 2009, 54, L1-L10.
Kohler, N.; Sun, C.; Wang, J.; Zhang, M. Methotrexate-modified
superparamagnetic nanoparticles and their intracellular uptake into
human cancer cells. Langmuir, 2005, 19, 8858-8864.
Xu, H.; Yan, F.; Monson, E.E.; Kopelman, R. Room-temperature
preparation and characterization of poly (ethylene glycol)-coated
silica nanoparticles for biomedical applications. J. Biomed. Mat.
Res., 2003, 66A, 870-879.
Yan, F.; Xu, H.; Anker, J.N.; Kopelman, R.; Ross, B.; Alnawaz, R.;
Reddy, R. Synthesis and characterization of Silica-embedded iron
oxide nanoparticles for magnetic resonance imaging. J. Nanosci.
Nanotech., 2004, 4, 72-76.
Koo, Y.E.L.; Reddy, G.R.; Bhojani, M.; Schneider, R.; Philbert,
M.A.; Rehemtulla, A.; Ross, B.D.; Kopelman, R. Brain cancer diagnosis and therapy with nanoplatforms. Adv. Drug Deliver. Rev.,
2006, 58, 1556-1577.

R Subbiah Et Al - Curr Med Chem

Enviado por

Dados do documento

Título original

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

R Subbiah Et Al - Curr Med Chem

Enviado por

Direitos autorais:

Formatos disponíveis

Current Medicinal Chemistry, 2010, 17, 4559-4577

Nanoparticles: Functionalization and Multifunctional Applications in

advantages of NPs, they also have some drawbacks including

4560 Current Medicinal Chemistry, 2010 Vol. 17, No. 36

type of functionalization was used. Although many reviews

Current Medicinal Chemistry, 2010 Vol. 17, No. 36

Blood brain barrier

Bovine serum albumin particles

N-(3-diethylamino) propyl isothiocyanato-L-lysine

5-(3, 3-dimethy-1-triazenyl) imidazole-4-carboxamide

Enhanced permeability & retention effect

Vascular endothelial growth factor receptor 2

Luteinizing hormone releasing hormone

Magnetic particle imaging

Magnetic resonance imaging

Nanoparticle-chelating agent-functional group

Poly (aspartic acid)

Poly (ethylene glycol)

Poly (glutamic acid)

Poly (hydroxy ethyl oxide)

2-(N-phthalimido) ethyl palmitate

Poly (lactic acid)

Poly (lactic-co-glycolic acid)

Poly (propylene sulfide)

Prostate specific membrane antigen

Poly (vinyl alcohol)

Single chain tissue necrosis factor

Targeted drug delivery system

4562 Current Medicinal Chemistry, 2010 Vol. 17, No. 36

Current Medicinal Chemistry, 2010 Vol. 17, No. 36

which utilizes a synthetic thiol containing biomolecule. Thiol

4564 Current Medicinal Chemistry, 2010 Vol. 17, No. 36

Fig. (3). Schematic of the thiol group based functionalization.

Current Medicinal Chemistry, 2010 Vol. 17, No. 36

methacryloxypropyl) trimethoxysilane) in a tetrahydrofuran

4566 Current Medicinal Chemistry, 2010 Vol. 17, No. 36

other fields including 1) Construction of nanoscale sized

ity during the course of blood circulation. Drugs must be

Current Medicinal Chemistry, 2010 Vol. 17, No. 36

partment into solid tumors. The third challenge is selective

Representative examples of nanoparticles based therapeutics for Cancer [113, 28]

Albumin bound paclitaxel

American pharm partners

Albumin bound paclitaxel

Ligand targeted emulsion containing NPs for

Nanobiodrugs for cancer treatment

NPs to target cancer

Lipid based nanocarrier for targeted delivery

HPMA copolymer-DACH platinate

Nanocrystalline paliperidone palmitate

Pluronic block-copolymer doxorubicin

4568 Current Medicinal Chemistry, 2010 Vol. 17, No. 36

Current Medicinal Chemistry, 2010 Vol. 17, No. 36

Human serum albumin (amino or COOH group)

Trimyristin (sterically stabilized)

Ovarian, lung breast

PVA polymeric micelles

PLLA-b-PEG (folate targeted)

Ovarian, lung breast

PEG-PE/egg phosphatidylcholine (lipid conjugated)

Nucleosome-specific monoclonal Ab functionalized

Polymer-lipid hybrid NPs

PCL-b-trimethylene carbonate-PEG (serum protein)