Use of Core/Shell Structured Nanoparticles For Biomedical Applications
Use of Core/Shell Structured Nanoparticles For Biomedical Applications
Use of Core/Shell Structured Nanoparticles For Biomedical Applications
Received: October 30, 2007; Accepted: November 9, 2007; Revised: November 16, 2007
Abstract: Nanoparticles have found wide spread application in varied fields of engineering. Recently, core/shell
nanostructures have been found to have improved properties when compared to their other alternatives are patented. These
core/shell structures also interest researchers in the field of biomedical engineering and some potential applications have
been identified. The classification of core/shell nanoparticles, the synthesis of these structures and their applications in the
field of biomedical engineering are discussed in this article. The future work points at the possibilities of improvement
and the material that might be preferred for specific applications.
Keywords: Core/shell, nanoparticles, biomedical applications, nanoparticles synthesis.
palladium core/shell structure which are used as catalysts fall under the category of polymer/silica and some of them
[13]. are polycaprolactum/silica, polystyrenemethylmethacrylate/
silica [4,39-47].
2.1.2. Semiconductor Nanoparticles
2.2.2. Inorganic Core and Organic Shell Nanoparticles
These types of nanoparticles have core made of semi-
conductor material, semiconductor alloy or metal oxide with The particles in this class of nanoparticles have a metal,
shell made of semiconductor material, metal oxide or metal oxide or silica core with a polymer of organic material
inorganic material like silica [14]. These structures can be or organic shell. Some of the particles in this category are
binary with a core and shell or a tertiary structure with a core SiO2/PAPBA(Poly(3-aminophenylboronic acid) [48], Ag2S/
and two shells. The most common binary structure that are PVA(Polyvinylalcohol), CuS/PVA, [49,50] Ag2S/PANI(Poly
well known by the name quantum dots are an alloy of group aniline) [51,52], and TiO2/cellulose. The coat of PAPBA
3 and group 5 metals or group 4 and group 6 metals. prevents agglomeration of particles and helps maintain size
CdSe/Cds, CdSe/ZnS, ZnSe/ZnS, CdTe/CdS are the nano- control.SiO2/PAPBA is used in optical devices, sensors and
particles used for fluorescent bioimaging [15]. The shell electrical devices. The PVA or PANI coat prevents oxidation
thickness determines the emission range of these particles. of Ag2S /CuS thus improving stability. Ag2S /CuS are con-
They fall under the category of binary nanoparticles. The ducting polymers [41,53] that are used in electrical industry.
CdSe/CdTe core/shell nanoparticles are stable and have high The addition of cellulose improves the pigment properties of
conductivity. Addition of acceptor ions such as bipyridium to TiO2.Some of these hybrids find application in dentistry as
CdSe/Zns or similar nanoparticles can enhance the fluore- brace material and fillers.
scence properties [15-23]. Mechanical properties can be
improved by adding high performance polyamines and 2.3. Polymeric Core/Shell Nanoparticles
polypyrroles [19,20]. The electronic properties can be These are particles that have a polymeric core and a
enhanced and size tunability of quantum dot nanoparticles polymeric shell and are dispersed in a matrix which can be
depends on the matrix material. Nanoquantum dots can be any material whose property is to be modified. One of the
dispersed in Titania matrix and they have better lumine- materials in this category is Polymethylmethacrylate
scence than the quantum dots in sols. Quantum dots have (PMMA) coated antimony trioxide compounded with Poly-
magnetic property when the core shell structure has Co/Cd or vinylchloride (PVC)/antimony trioxide composites [54]. The
Cd/Co [21,24,25]. There are complex structures such ZnS, interaction between PMMA and the PVC along with
ZnxCd1-xS in PMMA matrix which show variation in lumine- antimony trioxide enhance toughness and strength of PVC.
scence on varying Zn/Cd ratio [26]. There are also tertiary Some of these particles improve the thermal sensitivity of
structures that have magnetic property such as iron oxide/ materials [55,56]. Polystyrene/Poly(N-isopropylacrylamide)
CdSe/ZnSe [18,24]. These are bifunctional having both (P-NIPA) core/shell nanoparticles with silver embedded in
fluorescence and magnetic properties. Thus detailed in vivo the NIPA coat are found to enhance the catalytic activity of
imaging is possible. silver by improving sensitivity. In the field of electronics the
2.1.3. Lanthanide Nanoparticles sensitivity to voltage change is improved by using junctions
such as (poly-(3, 4 dicyanothiophene) PDCTh / (methoxy-5-
These particles core which contains one or more (2’-ethyl-hexyloxy)-1, 4-phenylene vinylene) MEH-PPV
lanthanide group elements surrounded by a shell made of [57,58]. Phase segregated nanoparticles blend of donor
inorganic material like silica or a lanthanide material. (MEH-PPV) and Cyano substituted phenylene vinylene (CN-
Rhabdophane lanthanide phosphate aqueous colloids are one PPV) show enhanced photo induced charge separation. Some
of these categories that show a green luminescence. These of the other composite latexes that find application are
are Ce; Tb doped core particles with an LnPO4-xH2O shell PSt/PVAc, PSt/Ppy and PSt/PBA where PSt is polystyrene
[21,27,28]. These particles can be further coated with silica [59,60]. PVAc is polyvinyl acetate, Ppy is polypyrrole and
to enhance its luminescent properties. These find potential PBA is poly butyl alcohol [61,62].
application in electronics and bioimaging. Other lanthanide
particles include YF3 /Silica, TiO2: Eu phosphors and the 3. SYNTHESIS OF CORE/SHELL NANOPARTICLES
like. The YF3 particles show emission in the range of 400nm The most commonly used technique has been discussed
and TiO2/Eu phosphors show a red emission peak. The and we have tried to generalize the type of particle that can
potential application of these particles is in the field of be synthesized by each of these methods. Though it is not a
bioimaging [29]. rule that is applicable to all cases but it can be applied to
2.2. Organic-Inorganic Hybrid Core/Shell Nanoparticles most cases [63-68].
The core of these particles consists of organic com- 3.1.1. Radical Polymerization
pounds and can be polymers of organic compounds. The The polymerization could be a free radical polymeri-
shell is inorganic and is a metal or silica or silicone. zation or an atom transfer radical polymerization. The
Structures that fall under the category of polymer/metal are process of atom transfer radical polymerization (ATRP) is
polyethylene/silver, polylactide/gold [19,30-38]. These are better than the free radical polymerization as control of
used in joint replacements and due to their high resistance to molecular weight and size of the particle can be achieved.
corrosion and abrasion can be used to improve properties of The coating of polymer on silica nanoparticles is generally
other materials. Many of these nanoparticles manufactured done by ATRP. The surface of the silica particle is modified
36 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sounderya and Zhang
DMAEMA
CuBr
Initiator 2,2-dipyridyl Silicification
RT, water
Fig. (1). Schematic Representation of Procedure (Reprinted with permission from Kang et al. Copyright 2006. Institute of Physics
Publishing).
with a suitable initiator. One of the methods would be to solutions that form micelles. Micelles are formed by mixing
attach a bromine group to the surface of silica and add to aqueous reactant with suitable surfactant. Micelles act as the
solution containing the monomer of the shell polymer. The center for nucleation and epitaxial growth of nanoparticles.
polymerization occurs and is depicted by change in the The molar ratio of the surfactant to water () is the
optical clarity of the solution. This method of attachment of parameter that affects size and morphology of the resultant
bromine group to silica and forming polymer of t-butyl particles. These particles can be further processed to obtain
acrylate has been discussed by lei et al. [69]. Also Kang et core/shell structure by oxidation polymerization as discussed
al. [3] discuss the formation of silica coated gold nanopar- above. Else the surface can be coated with other metals or
ticles by a biomimetic approach through ATRP. silica [79,80]. Carpenter et al. [81] have discussed reverse
3.1.2. Chemical Oxidation Polymerization micelle technique for the synthesis of iron nanoparticles with
a gold shell. Similar method has been proposed for cobalt-
The nanoparticle, if it has suitable groups attached to it platinum core/shell structure by Kumbhar et al. [82].Wang et
allows the monomer which are generally aromatic com- al. [83] discuss iron oxide with gold core but have used
pounds to form adduct. The monomer can be polymerized by ligand exchange reactivity to assemble particles into thin
adding suitable oxidizing agents. Generally metallic particles films. Polymeric particles can also be synthesized if the
are given a coating of poly aromatic compounds by this emulsion of the monomer is thermodynamically stable [84-
method. Most metallic nanoparticles are formed by chemical 87].
reaction and then reduction. This implies there might be
acidic or basic groups attached to the surface that induces 3.4. Mechanochemical Synthesis
modification [70,71]. Such a method has been discussed by The above discussed sub-topics themselves give an idea
Jing et al. [51,52,72] in silver/poly aniline and silver/poly about the process to the readers. This sub-topic in itself
pyrrole and PbS/poly pyrrole core/shell nanocomposite houses varied synthesis techniques of which only two com-
synthesis [73]. monly used ones will be touched upon here. Mechano-
chemical synthesis as the name suggests involves mechanical
3.2. Sol Gel Method
and chemical means of nanoparticle synthesis.
This method of synthesis is used generally for the
3.4.1. Sonochemical Synthesis
synthesis of metal/polymer core metal oxide shell nano-
particles in inorganic matrix that forms a gel, like silica. But The synthesis involves chemical reaction for nanoparticle
some semiconductor nanoparticles have also been synthe- synthesis and sonication to improve the speed of reaction,
sized by this method [74,75]. The steps can be stated in breakdown the particles and to enhance the dispersion of
general as formation of the solution containing the salt of the particles in the solvent. Ultrasonic irradiation of the
metal and silica based compound. The solution is then heat frequency range 20 kHz to 1 MHz has been used in most of
treated and upon gelation, the metal salt is reduced in the sonication methods. Ultrasonic irradiation speeds up the
hydrogen atmosphere to metal nanoparticles. These are then reaction because of the localized cavities that are formed and
subjected to heat in ordinary atmosphere forming an oxide they last only for a short time. Thus, these cavities act as
shell on top of the metal nanoparticles. For polymer core and micro reactors for the reaction to occur and the mechanical
metal oxide shell the polymer nanoparticles can be added to effects to also take place. The mixture of reactants in suitable
metal salt solution and then oxidized. Iron/iron oxide,tin/ solution is subjected to ultrasonic waves and the temperature
tinoxide,copper/copper oxide in silica matrix have been and pH maintained to obtain the nanoparticles dispersed in
synthesized by this method [12,76-78]. There is some refe- silica or in matrix material. The chemical reaction that
rence to synthesis of polypyyrole/iron oxide nanoparticles occurs depends on the shell required as core is synthesized
[35] and Cdse/CdS nanoparticles by this method [19]. separately and added to the reactant mixture. Reduction
reactions are carried out for metallic shells and in situ
3.3. Reverse Micelle Method polymerization for polymeric shells/non-metallic shells [87-
One of the major concerns in the synthesis of nano- 89]. Composites such as iron oxide with gold shell and
particles and in specific core/shell nanoparticles is the iron/cobalt alloy nanoparticles are ones with metallic shell
achievement of control over size and morphology. This can [11] and those such as silica/PAPBA,Ag2S/PVA,CuS/PVA
be obtained by conducting the synthesis in emulsions or in
Use of Core/Shell Structured Nanoparticles for Biomedical Applications Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 37
PMMA PEO
Micelles formation
in a mixture of THF
(a) and H2 O
(b) (c)
50 nm 50 nm
200 nm 200 nm
Fig. (2). Assembly of Titania Hybrid and TEM Pictures (Reprinted with permission from J Wang and AH Yuwono. Copyright 2006.
Engineering research News NUS).
are ones with nonmetallic shell that are synthesized by this 4. BIOMEDICAL APPLICATIONS AND PATENTS
method [11,22,49,90].
Core/Shell Nanoparticles are finding wide spread
3.4.2. Electrodeposition applications in all fields. They are making their way into our
Formation of shell of nanoparticles with charged day to day life. Things such as cabinet and car doors contain
polymers or inorganic material can be carried out by this nanoparticles which improve their durability. At a large scale
method. The electric pulse is varied like a square wave in the industries that make most use of these materials are the
general and it is found that the metal deposits during chemical, electronics, biomedical, civil and mechanical
negative cycle while polymer deposits during positive cycle. Industries. They are used as catalysts, modifiers, fillers, ther-
This gives control over the size of the nanoparticles. The mal and mechanical property enhancers, sensor material due
mode of operation is galvanization hence, the deposition to high sensitivity to slight changes in parameter. The bio-
occurs on one of the electrodes. The matrix material for medical industry is the potential play field today; hence some
nanoparticles can be the electrode or the electrolytic of the possible application will be highlighted. Some of these
medium. Banerjee et al. [7] detail on the synthesis of iron applications are patented and some are still in the research
oxide shell iron in silica nanoparticles. Chipara et al. [35] phase [92]. The diverse branches of the industry where
describe the synthesis of polypyyrole-iron nanoparticles. nanoparticles are being recognized are bioimaging, drug
Both the procedures are almost similar, the only difference delivery, biomarkers and transplants.
being that in the iron oxide shell iron in silica nanoparticles, 4.1. Bioimaging
the electrolytic medium, silica gel, is the matrix for the
nanocomposite while for the PPy-Fe,it doesn’t have a matrix The imaging modalities in which core/shell nanoparticles
material and belongs to the class of nano-nanoparticles.The are used are MRI and luminescence. Magnetic nanoparticles
PPy-Fe can be dispersed in the desired matrix material later iron oxide or cobalt core particles are used to enhance MRI
[30]. images by improving contrast. Core/shell nanoparticles can
enter the cells and they have better spin-lattice relaxation
Some other methods of synthesis include mechanical time. Thus the contrast is better [10,20,35,78,82,93-95].
attrition, colloidal chemical synthesis, layer deposition and These particles are found to be biocompatible, so they seem
the like which are used widely for synthesizing magnetic very promising. The luminescent particles are particles that
nanoparticles. Some copper oxide nanoparticles are synthe- fluoresce by absorbing light over in a wavelength range and
sized by reduction and pulverizing [68,91]. emit in the visible or near-IR range. The nanoparticles with
38 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sounderya and Zhang
Electrooxidative
polymerization
Reference N
electrode N in scCHF3 medium n
Working
500 mA cm-2
electrode
Counter
electrode
scCHF 3
Fig. (3). Electrochemical Synthesis of Nanoparticles (Reprinted with permission from Atobe et al. copyright 2004. The Chemical Society of
Japan).
NHCOCH 3
O O
OH OH
HO HO
NHCOCH3 O
. CH CH CH2OH
NH3 OOC
HO OH HO OH
OH HO O
COO- ‘H N
HOH2C C CH 3
O
H O
OH
OH
HO OH
H3COCHN
OH OH
H3COCHN O
O
H3 COCHN
HO
OH O O
O
OH
HO
‘ H3N
OH OH COO-
HOH2C CH C O
H OH
HO
H3COCHN
Fig. (5). Nanoparticles in Ophthalmic Drug Delivery (Reprinted with permission from Barbu et al. Copyright 2006. Royal Society of
Chemistry).
Encapsulated Drug (Doxorubicin)
Biotin-BSA-Gd-DTPA
Biotin-Anti-CD3
(T-cell target)
Fig. (6). Multifunctional Solid PLGA Nanoparticles Tethered to T cell target and MRI Contrast Enhancer(biotin BSA-Gd-DTPA) and
Encapsulating Immunosuppressive Drug (Doxorubicin)(Reprinted with permission from Fahmy et al.Copyright 2007. American Association
for Pharmaceutical Scientists).
4.4. Replacements, Supports and Engineered Tissues roxyapatite [113] based, collagen based or ceramic based
nanoparticles [114].
Polymeric core shell nanocomposite is the most com-
monly used transplant material. These can be polymer/ 4.5. Miscellaneous Application
polymer or polymer/metal, either ways forming core/shell
Nano-nanoparticles can be used for lipid and protein
structures. They are used in dental braces and in joint
detection by modifying their surface with suitable charged or
replacements [111]. Ultra high molecular weight poly-
specific binding moieties. This is a boon because it reduces
ethylene(UHMWPE)/silver [34] is one such material that’s
size of the testing kits and offers high sensitivity [115-118].
used in joint replacement. The salient features that are
They are used in medical dressing for quicker wound
considered in the choice of these materials for joints are healing. These have the property of absorbing fluids and can
abrasion resistance, high impact strength and resistance to
be medicated that can help in consistent wound healing
corrosion. Biomimetic nanoparticles seem to be better
[119]. There are nanoparticle structures that are used by the
materials for joint replacements [112] as they closely
nutraceutical industry. They are expected to deliver nutrients
resemble the biological structure and behave almost simi-
more efficiently than normal drug capsules [120]. They are
larly. But they are a bit expensive and are still at the research
also used to design filter material for better and efficient
stage. Some nanoparticles are being worked on to be used as separation of components. This application is not restricted
artificial conjunctiva [104,105]. Tissue engineering is also
only to the biological industry [99,119,121,122]. Other
looking up to nanoparticles for design of suitable scaffold for
application that’s common to both biological and the
seeding and proliferation of the cells to develop artificial
chemical industry is that of catalytic activity enhancement
tissues. This shows the salient features of nanoparticles that
[121]. Enzymes immobilized on core/shell nanoparticles or
makes it a preferred choice for different purposes with
catalysts encapsulated suitably into nanoparticles have
suitable modification. Materials used commonly are hyd-
40 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sounderya and Zhang
higher activity than usual [123]. Some find applications a replacements, the material used has to mimic their the
biosensors [14]. biological part they are replacing. For joint replacements
hydroxyapatite base materials seem to hold potential while
5. FUTURE WORK for tissue engineering biopolymer based scaffolds can be
The work discussed above brings forth the green aspects developed.
of the new generation “Smart” materials. The dark side that
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