34 Recent Patents on Biomedical Engineering 2008, 1, 34-42

1874-7647/08 $100.00+.00 © 2008 Bentham Science Publishers Ltd.

Use of Core/Shell Structured Nanoparticles for Biomedical Applications

Nagarajan Sounderya1 and Yong Zhang

1,2

1Division of Bioengineering, Faculty of Engineering, National University of Singapore, Singapore 117574, Singapore,

2Nanoscience and Nanotechnology Initiative, National University of Singapore, Singapore 117576, Singapore

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.

INTRODUCTION

“Small is beautiful”, today we know that small is not only beautiful but also powerful. With the range of applications that nanoparticles find in varied fields of engi-neering and science, nanoparticles seem a promising option when compared to the conventional materials used. Nanoparticles are particles that have at least one dimension in less than 100nm range. They have a high surface to volume ratio and thus mass transfer and heat transfer properties are better than bulk materials. Recently; core/shell nanoparticles are finding widespread application. There is a class of core/shell nanoparticle that has its entire constituent in the nanometer range.Core/shell nanoparticles are nano-structures that have core made of a material coated with another material. They are in the size range of 20nm-200nm. Also, composite structures with these core/shell particles embedded in a matrix material are in use. The necessity to shift to core/shell nanoparticles is the improvement in the properties. Taking into consideration the size of the nanoparticles, the shell material can be chosen such that the agglomeration of particle can be prevented. This implies that the monodispersity of the particles can be improved. The core/shell structure enhances the thermal and chemical stability of the nanoparticles, improves solubility, makes them less cytotoxic and allows conjugation of other mole-cules to these particles. The shell can also prevent the oxida-tion of the core material [1,2]. “When a core nanoparticle is coated with a polymeric layer or an inorganic layer like silica because the polymeric or inorganic layer would endow the hybrid structure with an additional function/property on top of the function/property of the core hence synergistically emerged functions can be envisioned” [3].

2. CLASSIFICATION OF CORE/SHELL NANO-PARTICLES

The properties of the nanomaterials are diverse and cannot be generalized even though the particles under comparison might be made of similar material and com-

*Address correspondence to this author at the Division of Bioengineering,

Faculty of Engineering, Block E3A-04-15, National University of Singapore, 7 Engineering Drive 1, Singapore 117574, Singapore; Tel: +65-

65164871; Fax: +65-68723069; E-mail: biezy@nus.edu.sg

position. This rule is applicable to core/shell nanoparticles and hence, we try to classify them broadly based on the material with which the core and shell of the nanocomposite are made. On these lines we can group the nanoparticles as

2.1. Inorganic Core/Shell Nanoparticles

The core or the shell or both are made of inorganic materials. The inorganic materials in most commercially used and widely synthesized nanoparticles are metals, semiconductors or lanthanides.

2.1.1. Metallic Nanoparticles

The core or the shell should contain metallic component. The core of such structures can be a metal or metal oxide or inorganic like silica while the shell can also be any inorganic material like silica or can be a metal or metal oxide. The most widely used core/shell nancomposites are gold or silver core with silica shell. The gold/silica nanoparticles find application in optical sensing and the thickness of the silica coat alters the optical property of gold nanoparticles.The silica coat makes the gold nanoparticles biocompatible [4,5]. The silver/silica particles can be used in fluorescence imaging and again the region of emission is dependent on the silica coating thickness. The structure can be inversed and silica nanoparticles can form the core and the gold can form the shell. The thickness of the gold coat can be varied and a range of colors can be obtained. These particles find application in fluorescent bioimaging. Metal interaction with the fluorophores increases photo stability, enhances fluore-scence, reduces lifetime. Also fluorescent core/shell nano-particles enhance single particle imaging. Other core/shell nanoparticles that find application in optical bioimaging are copper/copper oxide [6] and these fall into the category of metal/metal oxide nanoparticles. Magnetic imaging for biological applications is the trend of the day and particles that cater to these needs are iron oxide/silica, iron oxide/gold nanocomposite [7-11]. The former is a metal oxide/inorganic nanocomposite while latter is a metal oxide/metal nanocom-posite. The gold coating on iron oxide makes it microchip compatible and the silica coat prevents agglomeration and also enables conjugation. Some other core/shell nanopar-ticles in this category include tin/tin oxide nanoparticles [12] that are used in food processing and humidity sensor, gold/

Use of Core/Shell Structured Nanoparticles for Biomedical Applications Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 35

palladium core/shell structure which are used as catalysts [13].

2.1.2. Semiconductor Nanoparticles

These types of nanoparticles have core made of semi-conductor material, semiconductor alloy or metal oxide with shell made of semiconductor material, metal oxide or inorganic material like silica [14]. These structures can be binary with a core and shell or a tertiary structure with a core and two shells. The most common binary structure that are well known by the name quantum dots are an alloy of group 3 and group 5 metals or group 4 and group 6 metals. CdSe/Cds, CdSe/ZnS, ZnSe/ZnS, CdTe/CdS are the nano-particles used for fluorescent bioimaging [15]. The shell thickness determines the emission range of these particles. They fall under the category of binary nanoparticles. The CdSe/CdTe core/shell nanoparticles are stable and have high conductivity. Addition of acceptor ions such as bipyridium to CdSe/Zns or similar nanoparticles can enhance the fluore-scence properties [15-23]. Mechanical properties can be improved by adding high performance polyamines and polypyrroles [19,20]. The electronic properties can be enhanced and size tunability of quantum dot nanoparticles depends on the matrix material. Nanoquantum dots can be dispersed in Titania matrix and they have better lumine-scence than the quantum dots in sols. Quantum dots have magnetic property when the core shell structure has Co/Cd or Cd/Co [21,24,25]. There are complex structures such ZnS, ZnxCd1-xS in PMMA matrix which show variation in lumine-scence on varying Zn/Cd ratio [26]. There are also tertiary structures that have magnetic property such as iron oxide/ CdSe/ZnSe [18,24]. These are bifunctional having both fluorescence and magnetic properties. Thus detailed in vivo imaging is possible.

2.1.3. Lanthanide Nanoparticles

These particles core which contains one or more lanthanide group elements surrounded by a shell made of inorganic material like silica or a lanthanide material. Rhabdophane lanthanide phosphate aqueous colloids are one of these categories that show a green luminescence. These are Ce; Tb doped core particles with an LnPO4-xH2O shell [21,27,28]. These particles can be further coated with silica to enhance its luminescent properties. These find potential application in electronics and bioimaging. Other lanthanide particles include YF3/Silica, TiO2: Eu phosphors and the like. The YF3 particles show emission in the range of 400nm and TiO2/Eu phosphors show a red emission peak. The potential application of these particles is in the field of bioimaging [29].

2.2. Organic-Inorganic Hybrid Core/Shell Nanoparticles

2.2.1. Organic core and Inorganic Shell Nanoparticles

The core of these particles consists of organic com-pounds and can be polymers of organic compounds. The shell is inorganic and is a metal or silica or silicone. Structures that fall under the category of polymer/metal are polyethylene/silver, polylactide/gold [19,30-38]. These are used in joint replacements and due to their high resistance to corrosion and abrasion can be used to improve properties of other materials. Many of these nanoparticles manufactured

fall under the category of polymer/silica and some of them are polycaprolactum/silica, polystyrenemethylmethacrylate/ silica [4,39-47].

2.2.2. Inorganic Core and Organic Shell Nanoparticles

The particles in this class of nanoparticles have a metal, metal oxide or silica core with a polymer of organic material or organic shell. Some of the particles in this category are SiO2/PAPBA(Poly(3-aminophenylboronic acid) [48], Ag2S/ PVA(Polyvinylalcohol), CuS/PVA, [49,50] Ag2S/PANI(Poly aniline) [51,52], and TiO2/cellulose. The coat of PAPBA prevents agglomeration of particles and helps maintain size control.SiO2/PAPBA is used in optical devices, sensors and electrical devices. The PVA or PANI coat prevents oxidation of Ag2S /CuS thus improving stability. Ag2S /CuS are con-ducting polymers [41,53] that are used in electrical industry. The addition of cellulose improves the pigment properties of TiO2.Some of these hybrids find application in dentistry as brace material and fillers.

2.3. Polymeric Core/Shell Nanoparticles

These are particles that have a polymeric core and a polymeric shell and are dispersed in a matrix which can be any material whose property is to be modified. One of the materials in this category is Polymethylmethacrylate (PMMA) coated antimony trioxide compounded with Poly-vinylchloride (PVC)/antimony trioxide composites [54]. The interaction between PMMA and the PVC along with antimony trioxide enhance toughness and strength of PVC. Some of these particles improve the thermal sensitivity of materials [55,56]. Polystyrene/Poly(N-isopropylacrylamide) (P-NIPA) core/shell nanoparticles with silver embedded in the NIPA coat are found to enhance the catalytic activity of silver by improving sensitivity. In the field of electronics the sensitivity to voltage change is improved by using junctions such as (poly-(3, 4 dicyanothiophene) PDCTh / (methoxy-5-(2’-ethyl-hexyloxy)-1, 4-phenylene vinylene) MEH-PPV [57,58]. Phase segregated nanoparticles blend of donor (MEH-PPV) and Cyano substituted phenylene vinylene (CN-PPV) show enhanced photo induced charge separation. Some of the other composite latexes that find application are PSt/PVAc, PSt/Ppy and PSt/PBA where PSt is polystyrene [59,60]. PVAc is polyvinyl acetate, Ppy is polypyrrole and PBA is poly butyl alcohol [61,62].

3. SYNTHESIS OF CORE/SHELL NANOPARTICLES

The most commonly used technique has been discussed and we have tried to generalize the type of particle that can be synthesized by each of these methods. Though it is not a rule that is applicable to all cases but it can be applied to most cases [63-68].

3.1. Polymerization

3.1.1. Radical Polymerization

The polymerization could be a free radical polymeri-zation or an atom transfer radical polymerization. The process of atom transfer radical polymerization (ATRP) is better than the free radical polymerization as control of molecular weight and size of the particle can be achieved. The coating of polymer on silica nanoparticles is generally 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

with a suitable initiator. One of the methods would be to attach a bromine group to the surface of silica and add to solution containing the monomer of the shell polymer. The polymerization occurs and is depicted by change in the optical clarity of the solution. This method of attachment of bromine group to silica and forming polymer of t-butyl acrylate has been discussed by lei et al. [69]. Also Kang et al. [3] discuss the formation of silica coated gold nanopar-ticles by a biomimetic approach through ATRP.

3.1.2. Chemical Oxidation Polymerization

The nanoparticle, if it has suitable groups attached to it allows the monomer which are generally aromatic com-pounds to form adduct. The monomer can be polymerized by adding suitable oxidizing agents. Generally metallic particles are given a coating of poly aromatic compounds by this method. Most metallic nanoparticles are formed by chemical reaction and then reduction. This implies there might be acidic or basic groups attached to the surface that induces modification [70,71]. Such a method has been discussed by Jing et al. [51,52,72] in silver/poly aniline and silver/poly pyrrole and PbS/poly pyrrole core/shell nanocomposite synthesis [73].

3.2. Sol Gel Method

This method of synthesis is used generally for the synthesis of metal/polymer core metal oxide shell nano-particles in inorganic matrix that forms a gel, like silica. But some semiconductor nanoparticles have also been synthe-sized by this method [74,75]. The steps can be stated in general as formation of the solution containing the salt of the metal and silica based compound. The solution is then heat treated and upon gelation, the metal salt is reduced in hydrogen atmosphere to metal nanoparticles. These are then subjected to heat in ordinary atmosphere forming an oxide shell on top of the metal nanoparticles. For polymer core and metal oxide shell the polymer nanoparticles can be added to metal salt solution and then oxidized. Iron/iron oxide,tin/ tinoxide,copper/copper oxide in silica matrix have been synthesized by this method [12,76-78]. There is some refe-rence to synthesis of polypyyrole/iron oxide nanoparticles [35] and Cdse/CdS nanoparticles by this method [19].

3.3. Reverse Micelle Method

One of the major concerns in the synthesis of nano-particles and in specific core/shell nanoparticles is the achievement of control over size and morphology. This can be obtained by conducting the synthesis in emulsions or in

solutions that form micelles. Micelles are formed by mixing aqueous reactant with suitable surfactant. Micelles act as the center for nucleation and epitaxial growth of nanoparticles. The molar ratio of the surfactant to water ( ) is the parameter that affects size and morphology of the resultant particles. These particles can be further processed to obtain core/shell structure by oxidation polymerization as discussed above. Else the surface can be coated with other metals or silica [79,80]. Carpenter et al. [81] have discussed reverse micelle technique for the synthesis of iron nanoparticles with a gold shell. Similar method has been proposed for cobalt-platinum core/shell structure by Kumbhar et al. [82].Wang et al. [83] discuss iron oxide with gold core but have used ligand exchange reactivity to assemble particles into thin films. Polymeric particles can also be synthesized if the emulsion of the monomer is thermodynamically stable [84-87].

3.4. Mechanochemical Synthesis

The above discussed sub-topics themselves give an idea about the process to the readers. This sub-topic in itself houses varied synthesis techniques of which only two com-monly used ones will be touched upon here. Mechano-chemical synthesis as the name suggests involves mechanical and chemical means of nanoparticle synthesis.

3.4.1. Sonochemical Synthesis

The synthesis involves chemical reaction for nanoparticle synthesis and sonication to improve the speed of reaction, breakdown the particles and to enhance the dispersion of particles in the solvent. Ultrasonic irradiation of the frequency range 20 kHz to 1 MHz has been used in most of the sonication methods. Ultrasonic irradiation speeds up the reaction because of the localized cavities that are formed and they last only for a short time. Thus, these cavities act as micro reactors for the reaction to occur and the mechanical effects to also take place. The mixture of reactants in suitable solution is subjected to ultrasonic waves and the temperature and pH maintained to obtain the nanoparticles dispersed in silica or in matrix material. The chemical reaction that occurs depends on the shell required as core is synthesized separately and added to the reactant mixture. Reduction reactions are carried out for metallic shells and in situ polymerization for polymeric shells/non-metallic shells [87-89]. Composites such as iron oxide with gold shell and iron/cobalt alloy nanoparticles are ones with metallic shell [11] and those such as silica/PAPBA,Ag2S/PVA,CuS/PVA

Fig. (1). Schematic Representation of Procedure (Reprinted with permission from Kang et al. Copyright 2006. Institute of Physics

Publishing).

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Use of Core/Shell Structured Nanoparticles for Biomedical Applications Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 37

are ones with nonmetallic shell that are synthesized by this method [11,22,49,90].

3.4.2. Electrodeposition

Formation of shell of nanoparticles with charged polymers or inorganic material can be carried out by this method. The electric pulse is varied like a square wave in general and it is found that the metal deposits during negative cycle while polymer deposits during positive cycle. This gives control over the size of the nanoparticles. The mode of operation is galvanization hence, the deposition occurs on one of the electrodes. The matrix material for nanoparticles can be the electrode or the electrolytic medium. Banerjee et al. [7] detail on the synthesis of iron oxide shell iron in silica nanoparticles. Chipara et al. [35] describe the synthesis of polypyyrole-iron nanoparticles. Both the procedures are almost similar, the only difference being that in the iron oxide shell iron in silica nanoparticles, the electrolytic medium, silica gel, is the matrix for the nanocomposite while for the PPy-Fe,it doesn’t have a matrix material and belongs to the class of nano-nanoparticles.The PPy-Fe can be dispersed in the desired matrix material later [30].

Some other methods of synthesis include mechanical attrition, colloidal chemical synthesis, layer deposition and the like which are used widely for synthesizing magnetic nanoparticles. Some copper oxide nanoparticles are synthe-sized by reduction and pulverizing [68,91].

4. BIOMEDICAL APPLICATIONS AND PATENTS

Core/Shell Nanoparticles are finding wide spread applications in all fields. They are making their way into our day to day life. Things such as cabinet and car doors contain nanoparticles which improve their durability. At a large scale the industries that make most use of these materials are the chemical, electronics, biomedical, civil and mechanical Industries. They are used as catalysts, modifiers, fillers, ther-mal and mechanical property enhancers, sensor material due to high sensitivity to slight changes in parameter. The bio-medical industry is the potential play field today; hence some of the possible application will be highlighted. Some of these applications are patented and some are still in the research phase [92]. The diverse branches of the industry where nanoparticles are being recognized are bioimaging, drug delivery, biomarkers and transplants.

4.1. Bioimaging

The imaging modalities in which core/shell nanoparticles are used are MRI and luminescence. Magnetic nanoparticles iron oxide or cobalt core particles are used to enhance MRI images by improving contrast. Core/shell nanoparticles can enter the cells and they have better spin-lattice relaxation time. Thus the contrast is better [10,20,35,78,82,93-95]. These particles are found to be biocompatible, so they seem very promising. The luminescent particles are particles that fluoresce by absorbing light over in a wavelength range and emit in the visible or near-IR range. The nanoparticles with

Fig. (2). Assembly of Titania Hybrid and TEM Pictures (Reprinted with permission from J Wang and AH Yuwono. Copyright 2006.

Engineering research News NUS).

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38 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sounderya and Zhang

NIR region emission are still being worked on as the cells do not emit in the same range. Thus signal to noise ratio is high. Though they cannot be easily applied to in-depth live cell imaging, the application is not impossible. Similarly particles that emit in the UV-visible range sometimes have low signal to noise ratio. But the composition and particle size can be varied to get appropriate emission and detection is also a lot easier. The present trend are the up conversion nanoparticles which show anti-stokes emission and these are brighter than down conversion nanoparticles that show stokes emission. The ranges of nanoparticles that are luminescent are semiconductor nanoparticles, lanthanide based nanoparticles, and gold coated silica nanoparticles and the like [18,20, 21,23,27,29,78,96-98]. Multifunctional nanoparticles that have magnetic and luminescent properties can also be synthesized by choosing appropriate core and shell [99]. This helps in obtaining clear 3D images.

4.2. Drug Delivery

Core/Shell structures serve a wide category of drug delivery application. The particles are biocompatible, have the ability to be conjugated to molecules without affecting the core and also can be used to encapsulate drugs [100]. The material of choice decides the multifunctional nature of the particles [21]. They can be structured so that they can be used for imaging and for drug delivery. Drug eluting stents made of nanocomposite material [101,102] are being worked upon to reduce abrasion and also core/shell nanoparticles with antibacterial properties are also being worked upon [103]. The latter seems promising for the manufacture of catheters which shall reduce infections that are caused by catheter contamination. The drugs can be targeted to specific locations by attaching biomolecules such as antibodies to the surface of nanoparticles.This is very useful when it comes to targeting tumor cells. Thermo sensitive and pH sensitive nanoparticles can be used for environment controlled delivery of drug from the particles [71]. Bifunctional nanoparticles with a luminescent core and shell conjugated with a biomolecule/drug that can be used for targeting /drug delivery and imaging. Drug loaded contact lenses are an elucidation of how these materials can be used for encapsulating drugs [104-107].

Fig. (4). Uptake of Nanoparticles by 143B Osteosarcoma Cells. A)

Detection of Texas Red Labeled Nanoparticles, B)Bright Field, C)

Detection of DAPI and D) Overlap of these Three Images (

Reprinted with permission from Azarmi et al. copyright 2006.

Canadian Society for Pharmaceutical Sciences).

4.3. Cell Labeling

Nano biomarkers will be more efficient as they can operate at wide pH and temperature ranges. They are small and can penetrate through cells and even if they do not penetrate they can be targeted to specific cells by attaching suitable moieties to the shell surface. The wide color range that these particles display on varying shell thickness and their photo stability are also important characters that make them suitable for marking/cell labeling [108]. Nanocompo-site biomarkers are used for labeling cancer cells [20,109, 110] and tumor cells. There can be multifunctional particles that act not only as markers, but also can be used for cell separation, if the core of the particle has magnetic properties.

Fig. (3). Electrochemical Synthesis of Nanoparticles (Reprinted with permission from Atobe et al. copyright 2004. The Chemical Society of

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Use of Core/Shell Structured Nanoparticles for Biomedical Applications Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 39

4.4. Replacements, Supports and Engineered Tissues

Polymeric core shell nanocomposite is the most com-monly used transplant material. These can be polymer/ polymer or polymer/metal, either ways forming core/shell structures. They are used in dental braces and in joint replacements [111]. Ultra high molecular weight poly-ethylene(UHMWPE)/silver [34] is one such material that’s used in joint replacement. The salient features that are considered in the choice of these materials for joints are abrasion resistance, high impact strength and resistance to corrosion. Biomimetic nanoparticles seem to be better materials for joint replacements [112] as they closely resemble the biological structure and behave almost simi-larly. But they are a bit expensive and are still at the research stage. Some nanoparticles are being worked on to be used as artificial conjunctiva [104,105]. Tissue engineering is also looking up to nanoparticles for design of suitable scaffold for seeding and proliferation of the cells to develop artificial tissues. This shows the salient features of nanoparticles that makes it a preferred choice for different purposes with suitable modification. Materials used commonly are hyd-

roxyapatite [113] based, collagen based or ceramic based nanoparticles [114].

4.5. Miscellaneous Application

Nano-nanoparticles can be used for lipid and protein detection by modifying their surface with suitable charged or specific binding moieties. This is a boon because it reduces size of the testing kits and offers high sensitivity [115-118]. They are used in medical dressing for quicker wound healing. These have the property of absorbing fluids and can be medicated that can help in consistent wound healing [119]. There are nanoparticle structures that are used by the nutraceutical industry. They are expected to deliver nutrients more efficiently than normal drug capsules [120]. They are also used to design filter material for better and efficient separation of components. This application is not restricted only to the biological industry [99,119,121,122]. Other application that’s common to both biological and the chemical industry is that of catalytic activity enhancement [121]. Enzymes immobilized on core/shell nanoparticles or catalysts encapsulated suitably into nanoparticles have

Fig. (5). Nanoparticles in Ophthalmic Drug Delivery (Reprinted with permission from Barbu et al. Copyright 2006. Royal Society of

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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

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40 Recent Patents on Biomedical Engineering, 2008, Vol. 1, No. 1 Sounderya and Zhang

higher activity than usual [123]. Some find applications a biosensors [14].

5. FUTURE WORK

The work discussed above brings forth the green aspects of the new generation “Smart” materials. The dark side that needs to be considered and modification worked upon hasn’t been discussed. The prime concern is the retention of these particles in the body and the harmful effect in the long run. The other concerns are the result reproducibility in vitro and in vivo. We have to see if the particles behave similarly in vitro and in vivo and also if they trigger side reactions in vivo. Infections caused by the nanoparticles in the case of transplants and suitable modifications have to be worked upon. If the particles are conjugated with charged moieties then the concern is the range of shift in pH for which the charge is maintained. The change in charge might be toxic and start adverse reactions or may not produce desired results. The charge on the particle can also affect the ejection route from the system hence the biodistribution can vary. Even for use as biomarkers or as drug carriers it’s essential to determine the concentration below which these materials are not cytotoxic.These are the chemical characteristics that affect toxicity. The physical properties of these materials also affect toxicity. The size of the particles is a parameter that has effect not only on the toxicity and retention but also on the mode of administration. If the particles are too big they cannot be injected into the system. The physical properties and the chemical properties can to some extent be controlled by the synthesis strategy and the modifications that the synthesized particles are subjected to. And biocompatibility of the material used is also an important parameter. Thus, synthesizing particles that are biocom-patible and are cytotoxic only at very high concentrations is being aimed at. This makes biomimetic synthesis methods more preferable and in material selection biopolymers seem to be promising. Further work on improving core/shell nanoparticles might help us see, in use, in future, medication that multi-task: functions of imaging, therapeutics and specific cell targeting.

The materials discussed above gives an overview of the options that one can choose from. And the choice is very much determined by the application of the particles. The applications decide the type and the size of the particles which affect particle properties. For imaging applications heavy metal nanoparticles might offer a good fluorescence but cytotoxicity is a parameter one needs to consider. The lanthanide based upconversion particles seems to be a better option and needs to be worked upon. Similarly instead of coating the shell with silica some biopolymers have been tried and we still need to prove that the latter are better when it comes to biocompatibility than the former. For drug delivery application it is preferred that the outer shell is a polymer so that antibodies or targeting agents can be attached. The basic criteria for the shell are the availability of functional groups for modification. Functionality of the particles can be increased by using a core that has luminescent properties and encapsulating drug between the core and shell. The core can be quantum dots and the shell can be a thermo-sensitive or pH-sensitive polymer, thus drug release can be controlled. As for tissue engineering and

replacements, the material used has to mimic their the biological part they are replacing. For joint replacements hydroxyapatite base materials seem to hold potential while for tissue engineering biopolymer based scaffolds can be developed.

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