Emerging Trends In Drug Delivery Systems Biology Essay

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Any chemical substance used in treatment, cure, prevention or diagnosis of disease is termed as a drug. Drugs contain the pharmaceutical compound along with other stabilizing compounds which when administered give a desirable positive effect against the disease. Administrations of drugs follow two methods: Enteral- administered via the digestive tract or the Parenteral- administered via the subcutaneously and intravenously, Pharmacokinetics and Biodistribution helped to study the effect of the drug. Along with its positives, traditional drugs were found to cause adverse effects and their pharmacological effects proved to be less effective. Adverse effects include the conventional drug widely being distributed throughout the body other than the target, toxic levels of drugs due to higher dosage required as body would clear out drugs through the immune system or urinary system and instability of the drug itself to physical parameters. In traditional drug delivery systems, the drug is distributed throughout the body via the blood circulatory system causing reduced effect. At present, 95% of all potential therapeutics have poor pharmacokinetics and biopharmaceutical properties [ ]() and has lead research to drug delivery systems that distribute the active drug to the target site with minimal side effects.

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1.1 Drug Delivery System

One of the major challenges in drug delivery is to release drug at the correct place in the body thereby avoiding potential side effects to non diseased organs. Ideal drug delivery systems are based on providing an overall therapeutic effect than conventional drugs. Firstly, the carrier system would be composed either of natural or synthetic materials which are biodegradable and biocompatible hence they would in turn be non-toxic. Secondly, they would be capable of delivering drugs in any state to specific targets without losing its stability. Thirdly, ability to be manufactured in vast commercial quantities.

Nanotechnology in Drug Delivery System

Nanotechnology is the most researched and expanding field for creating of devices of size 1-100 nm with capabilities of functioning at cellular and molecular levels. When nanotechnology is used in the field of medical research it's termed as nanomedicine. According to National Nanotechnology Initiative (NNI)[](),a US government program budget for research and development crossed the 1.5 Billion dollars.

Nanoparticles are of nanometer size (1-100 nm) making them similar in size to many biological molecules like receptors, channels, nucleic acids and can be modified further to achieve a particular physiological effect. Areas in which nanoparticles are being targeted are:

Systems to improve solubility and bioavailability of hydrophilic and hydrophobic drugs - Research has shown 40% of all developmental lead compounds are poorly water soluble and hence difficult to formulate. To tackle this problem size of drug is reduced to nano scale causing increased surface are and increased solubility. Another method is encapsulating the hydrophobic drug into nano scale structures and delivery to the required site.

Systems that enhance circulatory period of drug in the body- Certain nanoparticles have properties which allow them to be retained in the circulatory system for long periods of time due to their structure. They also have increased penetration into cells, membrane and other systems. Nanocarrier(Chiba,Japan) has shown that polymer based, micellar nanoparticles act as stable carrier systems in bloodstream.

Systems that provide a controlled release - Ability to control release of drug over a given timeframe has made nanoparticles a huge success. pSivida (Perth, Australia) have developed delivery systems which can deliver a range of drugs over a defined period, ranging from weeks to months. Drugs are held within the system and released on action.

Systems that can be controlled and monitored from an external source - Implementation of chips into nanoparticles is an increasing research area since they would be able to embed microchips which can be used to control the delivery system using biosensor. The tools of microfabrication, information science and systems biology combined provide a sophisticated drug delivery system able to regulate drug release, attain feedback and transmit updates.

Cancer studies have incorporated nanoparticles since they provide a direct therapeutic effect to the target site. They can be used as probes by conjugating them to peptides, antibodies and nucleic acids to detect cellular movements and molecular changes associated with pathological states. Nanoparticles can be customized to carry large doses of anticancer drugs and penetrate anatomic barriers due to their nano size. They have been engineered to be activated by environmental stimuli like temperature and pH to release the drug compound.

Drug Targeting

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Selective drug delivery to specific physiological sites, organs, tissues, or cells where a drug's pharmacological activities are required is termed as Drug Targeting. Drug targeting may be classified into two general methods: passive and active targeting.

1.3.1 Passive - Targeting Concept

Passive targeting involves the preparation of a drug carrier complex that can avoid the elimination due to body defence mechanisms like metabolism, excretion and opsonisation followed by phagocytosis. The concept of passive targeting occurs due to extensive accumulation and extravasations of nanoparticles into the diseased site. Long systematic circulation time due to vascular permeability of the platform and increased retention accounts for site-specific release. This concept has been widely used for the treatment of cancer related diseases.

Maeda et al. introduced the concept of 'Enhanced Permeability and Retention Effect (EPR) '. Trials showed enhanced retention of drug-carrier complex in tumour as compared to blood prompting passive targeting phenomenon of decreased systemic drug elimination through renal excretion, prolonged circulation, low lymphatic drainage and tumour permeability being the reason for enhanced drug-carrier system effect. For passive targeting to be successful, nanocarriers need to circulate in the blood for extended times so that there would be multiple chances for nanocarriers to pass by the target site. Nanoparticles have short half-live due to natural defence mechanisms of the body. Most nanomedicine systems follow the passive targeting concept and carriers are synthetic polymers, some natural polymers such as albumin, liposomes, micro (or nano) particles, and polymeric micelles. However, delivery of nanomedicine through ERP effect is not a sure guarantee. To enhance intracellular delivery, active targeting approach is being developed.

1.3.2 Active Targeting Concept

Active targeting refers to efforts to increase the delivery of drugs to a target through the use of specific interactions at target sites where a drug's pharmacological activities are required. These interactions include antigen-antibody and ligand-receptor binding. Alternatively, EPR effect also is accounted for. Carriers classified into this methodology include antibodies, liposomes, and thermo-responsive carriers.

Some advantages of active targeting nanocarriers are high concentrations of drug within the carrier delivered to target cell upon ligand interaction with receptor, association of ligand to carrier without disruption of drug components, several ligand molecules can be attached to increase the probability of target binding, high intracellular pressure allows more efficient distribution and since ligand attaches only to the carrier, they extravasate only at the target site thus avoiding side effects. By modifying nanoparticles with ligands and targeting specific cells rather than tissues, studies have shown more therapeutic efficacy.

Since the introduction of liposomes in the early 1960's [](Mamot C, Drummond DC, Hong K, Kirpotin DB, Park JW. Liposomes-based approaches to overcome anticancer drug resistance. Drug Resist Update 2003;6:271-9) and introduction as carriers of proteins and drugs, nanomedicine has made a significant impact on Drug Delivery Systems. As of now more than two dozen nano based drugs are in the market with more undergoing in clinical trials.

Nanoparticles have proved to be the "ideal" drug delivery systems. Ranging from liposomes to MEMS most of the delivery system is discussed below with its advantages, working and few examples.

Nanoscale Systems for drug delivery

2.1 Liposomes for drug delivery

The early 1960s saw the development of liposomes in drug delivery.[] (Mamot C, Drummond DC, Hong K, Kirpotin DB, Park JW. Liposomes-based approaches to overcome anticancer drug resistance. Drug Resist Update 2003;6:271-9) Liposomes are defined as microscopic vesicles formed by phosopholipid membranes covering an aqueous volume completely. Though their size range is from 30 nm to several nanometres, their structure is determined by the lipid composition, surface charge and method of preparation. Sethi et al (2005) describes the various methods involved in liposomes preparation and subsequent liposomal properties affecting drug activity [](Sethi V, Onyuksel H , Rubinstein I. Liposomal vasoactive intestinal peptide, Methods Enzymol 2005;391:377-95).

Their structure resembles the biological cell membranes in which hydrocarbon chains are orientated towards each other with polar groups encapsulating and surrounding the aqueous medium. As Liposomes encapsulate molecules, technological advancements have made them into carrier vehicles to incorporate active agents into compartmentalized systems and both water-soluble and lipid-soluble substances can be incorporated,[] (Gomez-Hens, A., Fernandez-Romero, J.M. (2006). Analytical methods for the control of liposomal delivery systems. Trends Anal Chem 25:167-178.) Thus giving rise to liposomal delivery systems (LDSs). Liposomes containing a single bilayer are called unilamellar vesicles (ULVs) and others are multilamellar vesicles (MLVs).

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Certain features to be considered for choosing a liposome type in LDS are the physicochemical features, effective concentration and toxicity of the substance to be entrapped and those of the ingredients of the liposome, Nature of the medium to which the liposome is dispersed, Additional processes involved during delivery of the liposome and Potential modifications to the features of the liposome on release.[](Gomez-Hens, A., Fernandez-Romero, J.M. (2006). Analytical methods for the control of liposomal delivery systems. Trends Anal Chem 25:167-178.) Studies show liposomes encapsulate molecules and have good biocompatibility, biodegradability, low toxicity, variability of structures and physicochemical behaviors but they come with certain limitations. Stability, Sterilizations, Size Control, Low entrapment coefficient, Irregularities in production of large batches and Half-Life of vesicles being major concern [](A. Sharma, U.S. Sharma, Int. J. Pharm. 154 (1997) 123.)

4 major types of Liposomes have been used as drug delivery systems [](Y. Barenholz, Curr. Opin. Colloid Interface. Sci. 6 (2001) 66.) :

Conventional Liposomes - They have unstable structures (Cholesterol added to stabilize them later), Low carrying capabilities and leak the entrapped material. Still commonly used despite of drawbacks.

Stealth Liposomes (Sterically Stabilized" Liposomes) - PEG, PEGylated liposomes to stabilize and provide extra protection to entrapped substances.

Active Liposomes- Modified Liposomes to provide selective, control release.

Charged Liposomes (Lipoplexes) - Liposomes incorporated with charged phospholipids. Form covalent interactions with macromolecules. Entrapped macromolecules form condensed structure to provide protective and easy internalization. (Gomez-Hens, A., Fernandez-Romero, J.M. (2006). Analytical methods for the control of liposomal delivery systems. Trends Anal Chem 25:167-178.)

LDS are often used for non-water soluble drugs[]( B.A. Klyashchisky, A.J. Owen, J. Drug Target. 5 (1998) 443.), Intracellular delivery where drug has intracellular target and help cross plasma membrane or fuse to target cell[](N. Bergstrand, M.C. Arfvidsson, J.M. Kim, D.H. Thompson,K. Edwards, Biophys Chem. 104 (2003) 361). For long term release of drug using long circulated Stealth Liposomes[](S.L. Yowell, S. Blackwell, Cancer Treat. Rev. Suppl. A (2002) 3.), Site specific targeting of large dose to target site with toxic effect on normal cells [](J.W. Park, C.C. Benz, F.J. Martin, Semin. Oncol. 31 (2004) 196.) And combination with antigenic material like virus or bacteria in vaccine therapy [] (Y. Hattori, S. Kawakami, S. Suzuki, F. Yamashita, M. Hash, Biochem. Biophys. Res. Commun. 317 (2004) 992.) .

Liposome technology is still far from being fully developed as many of the concepts described here are still in preclinical and clinical trials with promising results.

Micelles for drug delivery

Self- assemblies of ampliphiles which form supramolecular core- shell structures in the aqueous environment are called Micelles.[](Tanford C. The hydrophobic effects:formation of micelles and biological membranes 2nd ed. Malabar(Fla):Kreiger Publishing Company ;1991) Micelles are usually spherical, core/shell structure containing a hydrophobic core which acts as a micro-reservoir for the encapsulation of hydrophobic drugs and the hydrophilic shell interfaces the biological media. The versatility of the core/shell structure makes it more useful than other systems. [](Polymeric micelles for drugdelivery -Hamidreza Montazeri Aliabadi & Afsaneh Lavasanifar)Micelles vary between 5 and 50-100 nm and fill gaps between drug carries as individual macromolecules (antibodies) with the size below 5nm. Pharmaceutical micelles range from 10 and 80nm.[] (V.S. Trubetskoy and V.P. Torchilin , Use of polyoxyethylene-lipid conjugates as long-circulating carriers for delivery of therapeutic and diagnostic agents.Adv. Drug Deliv. Rev. 16 (1995), pp. 311-320)

Micellar delivery systems have highly reduced toxicity and are thermodynamically stable due to low monomer concentration in equilibrium with the micelles[](M. Yokoyama , Block copolymers as drug carriers. CRC Crit. Rev. Ther. Drug Carrier Syst. 9 (1992), pp. 213-248). Micellar drug delivery systems can be classified into 4 major classes with similar molecular architecture.

Pluronic micelles - Block polymers contains hydrophilic polyethylene oxide (PEO) and polypropylene oxide (PPO). Pluronics are known to increase transport of drugs across membranes barriers as they have solubilising effects for parenteral drug administration [](V.P. Torchilin and V.S. Trubetskoy, Micellar carriers for therapeutic and diagnostic agents. Farmacevtski Vestnik 48 (1997), pp. 232-233. ). Recent studies also show pluronics inhibit p-glycoprotein, responsible for multi-drug resistance in cancer cells[](E.V. Batrakova, H.Y. Han, V.Y. Alakhov, D.W. Miller and A.V. Kabanov, Effects of Pluronic block copolymers on drug absorption in Caco-2 cell monolayers.Pharm. Res. 15 (1998), pp. 850-855.).

Poly(L-amino acid) micelles (PLAA) -

Previously, PLAA micelles had been studied for their pH-dependent release at tumour sites. Combination of PEO Block Polymer with PLAA is a great new potential for attachment of drug, drug compatible moieties in the micellar core through free functional groups of the amino acid chain. Controlled changes in the structure of the core-forming block lead to better control over the extent of drug loading, release or activation.[](Kazunori Kataoka , Glenn S. Kwon, Masayuki Yokoyama, Teruo Okano and Yasuhisa Sakura,iBlock copolymer micelles as vehicles for drug delivery, Journal of Controlled Release, 24,1993,pp-119-132)

Polyester micelles -

Polyester micelles contain polymers like PEG-poly (lactic acid) (PLA), PEG-poly (lactic-co-glycolic acid)(PLGA) and PEG-poly (caprolactone) that are biocompatible and biodegradable . Lin et all [](Lin WJ, Juang LW, Lin CC. Stability and release performance of a series of pegylated copolymeric micelles.Pharm Res 2003;20:668-73.) says polyester micelles are known to have weaker interactions due to longer chemical structure thereby affecting drug loading and release. Polyester micelles have been successfully been studied for delivery of Doxorubicin. [](Yoo HS,Park TG. Folate receptor targeted biodegradable polymeric doxorubicin micelles. J Control Release 2004,96:273-83)

2.3 Nanoemulsions for drug delivery

Nanoemulsions are emulsions in oil-in-water (o/w) containing droplet diameters ranging from 50 to 1000 nm. The particles exist as water-in-oil (<20% water) and oil- in water (>50% water), the core of the particle was either water or oil. Nanoemulsions have a higher solubilisation capacity and thermodynamic stability than simple micellar solutions. As they contain a lipohilic interior, nanoemulsions are more suitable for the transport of lipophilic compounds than liposomes.

In an O/W, hydrophobic drugs are solubilised mainly in oil droplets and released slowly due to hindered diffusion and reverse behaviour in W/O. Nanoemulsions provide longer oil-water contact area due to the nanosize droplet compared to classical emulsions. [](Nanoemulsion Technology Facilitates Drug Delivery James R. Baker, Jr., MD, Executive Chairman & CEO, NanoBio Corporation, Ann Arbor, Mich.).

Nanoemulsions have higher surface area, free energy, non-toxic and non-irritant features. Some applications include antimicrobial nanoemulsions, production of immune responses by delivery of recombinant proteins or inactivated organisms to mucosal surface; techniques for vaccinating against infectious diseases-using an oil-based emulsion placed in the nose have proved to produce a strong immune response against smallpox and HIV.[]( T. Tadros, P. Izquierdo, J. Esquena and C. Solans, Formation and stability of nano-emulsions, Adv Colloid Interface Sci 108-109 (2004), pp. 303-318.)Formulation of various lipophilic anti-cancer drugs in O/W emulsion is more efficient as the oil phase of the emulsion systems act as solubilizer for the lipophilic compound, thus smaller doses required than an aqueous solution. As lipophilic drugs are incorporated within the innermost oil phase, contact with body fluids and tissues are avoided. Examples of such drugs are diazepam, clarithromycin, and etomidate.[]( Tiwari SB, Amiji MM. Nanoemulsion formulations for tumor-targeted delivery, nanotechnology for cancer therapy. Mansoor M. Amiji, Taylor and Francis Group, editors. 2006. p. 723-39.) In cancer chemotherapy, they are used as vehicles for prolonging the drug release after intramuscular and intra-tumoral injection (W/O systems) and enhancing the transport of anti-cancer drugs via the lymphatic system.[]( Shah P, Bhalodia D, Shelat P. Nanoemulsion: A pharmaceutical review. Syst Rev Pharm 2010;1:24-32)

Although nanoemulsions are widely seen as vehicles for administration of aqueous insoluble drugs, recently they are used as colloidal carriers for targeted delivery of various anticancer drugs.

Nanoparticulate systems for drug delivery

Polymer-based Nanoparticles :

Polymer based nanoparticles contain copolymers so as to increase circulation half life of the drug and inactivation of the MPS. Polymer-based nanoparticles are used as carriers for insoluble drugs, polymeric nanoparticles and hydrophilic drugs.

Commonly used materials include Poly -Lactic acid (PLA) and its copolymers with glycolic acid (PGLA) as they are biocompatible and degradation factors give the ability to control the release time and rate of encapsulated molecules.[](  N. Csaba, L. Gonzalez, A. Sanchez and M.J. Alonso, Design and characterisation of new nanoparticulate polymer blends for drug delivery, J Biomater Sci Polym Ed 15 (2004), pp. 1137-1151)

Apart from the above stated advantages, preparation of polymer based nanoparticles is also simpler. Two classes of preparation include polymerization of monomers- Emulsion polymerization and dispersion polymerization and dispersion of preformed polymers- salting out techniques and nanoprecipation.

Lipid- based Nanoparticles

Solid Lipid Nanoparticles (SLN) combines the positives of polymeric nanoparticles, fat emulsions and liposomes like low cytotoxicity, a solid matrix (fats or waxes) for protection of drugs from external environment, controlled drug release, large scale production, avoidance of organic solvents in preparation, and sterilization by autoclaving. Production is done by either two methods: Hot Homogenization - melted lipids at high temperatures or Cold High-Pressure Homogenization.[]( Dingler A, Gohla S. Production of solid lipid nanoparticles (SLN):scaling up feasibilities. J Microencapsul 2002;19:11- 6)

In spite of these advantages compared to other delivery systems further studies are being done with regard to lipid matrixes, drug loading capacity and effect of drugs with in vitro toxicity. Special emphasis is given to surface modification of SLN particles for site-specific drug delivery. []( Muller RH, Keck CM. Challenges and solutions for the delivery of biotech drugs-a review of drug nanocrystal technology and lipid nanoparticles. J Biotechnol 2004;113:151 - 70.)

Ceramic- based nanoparticles

Ceramic materials, Silica, Alumina and Titania can be introduced to nanoparticles with simpler preparation methods (Sol-gel process), desirable size, shape, porosity and are more biocompatible, with easier surface modifications to different functional groups. They are also inert and can be used to protect absorbed molecules against extreme pH and temperature. In development of cancer based studies Roy et al[] (Roy I, Ohulchanskyy TY, Pudavar HE, Bergey EJ, Oseroff AR, Morgan J, et al. Ceramic-based nanoparticles entrapping water insoluble photosensitizing anticancer drugs: a novel drug-carrier system for photodynamic therapy. J Am Chem Soc 2003;125:7860- 5) used them to carry photosensitizing drugs as they maintained the photodestructive action of the drug using its above properties and could be released through irradiation later.

Albumin nanoparticles

Albumin can be used to attach drugs or proteins as their surfaces contain several amino and carboxylic groups. Like other nanoparticles, albumin has been widely used in the treatment of cancer related diseases and recent developments include creation of the drug Abraxane TM used to treat metastatic breast cancer [](Ferrari M. Cancer nanotechnology: opportunities and challenges. NatRev Cancer 2005;5:161 - 71) with lower toxicity and greater efficacy. Preparation of albumin nanoparticles is done by desolvation/cross-linking techniques to induce albumin nanoparticles cross-linking.

Nanogels

Even though solid nanoparticles have proved to be more advantageous than other Nanoscale systems some drawbacks like low drug loading capacities and organic solvents in complex preparation methods have lead to the introduction of nanogels.

Nanogels are submicron particles sizes of microgels which contain flexible hydrophilic polymers, bio-compatible and high percentage of water. Apart from the large surface area, an interior network is present where drug molecules can be loaded for delivery. They possess a high content of functional groups that can be utilized for crosslinking with additional functional cross linkers, bio-conjugation with cell-targeting agents and biodegradability due to crosslinking of polymers. The nanogels cross-linked with polyester or disulfide linkages were biodegraded in aqueous media or in biocompatible reducing agents like glutathione (naturally present within cells). Upon degradation, encapsulated anticancer drugs such as Dox were released in a controlled manner. [](Atom transfer radical polymerization in inverse miniemulsion: A versatile route toward preparation and functionalization of icrogels/nanogels for targeted drug delivery applications; Jung Kwon Oh a,*, Sidi A. Bencherif b, Krzysztof Matyjaszewski)

Preparation of nanogels is done by copolymerization of hydrophilic monomers in presence of multifunctional cross linkers. For viable therapeutic approach, it's increasingly important to study toxicity, immunogenicity and pharmacokinetics together with drug effects in validated in vivo models. [](Advanced nanogel engineering for drug delivery; Koen Raemdonck, Joseph Demeester and Stefaan De Smedt)

Hydrogels

Hydrogels are cross linked, three dimensional hydrophilic networks that swell. They can protect drugs from hostile environment and by modifying the molecular structure of polymers they can interact with environment (Intelligent hydrogels).These intelligent hydrogels allows release of drugs by external stimuli. Drug delivery systems created with these hydrogels are of 3 major types:

Temperature Responsive Hydrogels

Lower critical solubility temperature (LCST) of the composed polymer in hydrogels is used to control these systems. When temperature is lower than LCST the network tends to swell and shrink as temperature is increased beyond LCST.

The LCST polymers exhibit a hydrophilic-to-hydrophobic transition with increasing temperature. Thus creating a DDS capable of precise delivery. [](Hydrogels in Controlled Drug Delivery Systems Fariba Ganji and Ebrahim Vasheghani-Farahani)

pH Responsive Hydrogels

The side chain groups and crosslinks of polymer's chemical structure are responsible for the response. Movement of water into the polymer network as a result of weak acid/base groups, adsorption and absorption leads to ionization of acid and base groups. Anionic hydrogels donate ions when external pH> internal polymer chains leading to swelling and Cationic hydrogels accept ions when external pH<internal polymer chain leading to swelling. This class of hydrogels have been widely used in drugs for gastric and intestinal applications.

Another system combines the above two classes to have a dual responsive hydrogels. [](Hydrogels in Controlled Drug Delivery Systems Fariba Ganji and Ebrahim Vasheghani-Farahani)

Bio Responsive Hydrogels

An excellent example of such a system is release of insulin in response to blood sugar levels in treatment of insulin-dependent diabetes. Such systems deliver physically entrapped drug molecules within the carrier and no chemical modification required for targeted delivery. [](Peppas NA, Zach Hilt J, Khademhosseini A, Langer R, Hydrogels in biology and medicine: from molecular principles to bionanotechnology, Adv Mater, 18, 1345-1360, 2006)

Dendrimers for Drug Delivery

Dendrimers are artificial macromolecules having ideal drug carrier properties such as well defined globular structure, high penetration through cell membrane, low toxicity, established methods of preparation of dendrimer nano-devices and programmed release of drugs. Dendrimer branching creates high density of functionalities on surface with the core denoted as Generation 0 and each layer between the cascade called generation. [](Cloninger MJ. Biological applications of dendrimers. Curr Opin Chem Biol 2002;6:742 - 8)

Two methods of synthesis of dendrimers are divergent - starting from core to successive generations and convergent - starting from the periphery of final molecule to the core where the dendrimer segments couple [](Cloninger MJ. Biological applications of dendrimers. Curr Opin Chem Biol 2002;6:742 - 8). Drugs are encapsulated in the void spaces of the dendrimers interior by the incubation and dendrimers drug network can be formed. Dendrimers have been investigated for delivery of indomethacin, fluorouracil and antisense oligonucleotides.

Since its introduction to DDS, dendrimers has made a huge promising start but till date production of dendrimer based DDS with low clearance and long plasma half-time in blood has been a step back to developments.

Protein based Platforms

Protein based platforms for drug delivery consists of naturally self-assembled protein subunits or combination of proteins to make a complete system. Like most systems mentioned in the paper biocompatibility, biodegradability and low toxicity make them ideal delivery systems. Some forms of protein based platforms have been mentioned before like liposomes and albumin nanoparticles. Other types of platforms include protein cages, microspheres, films and minirods shall be reviewed.

6.1 Protein Cage:

Protein cage's architectures were derived from viruses. They have structural shells of viruses with nucleic acids removed and contain subunits assembled into nanospheres.

The uniform cage size allows loading of drugs, avoidance of nanoparticles aggregation and protection from enzymatic degradation. Due to their nanosize they remain in the circulation system for longer durations and can be specifically targeted to the site.

Ferritin/Apoferritin :

Ferritin protein cages are used to store iron and avoid toxic build up in the cells. It's a naturally derived cage which can be modified to contain a variety of inorganic cores and due to the ability to change structure under pH influence loading capacity of drugs is better. They also have a porous hydrophobic and hydrophilic channel making it possible for insoluble and soluble drugs to be delivered.

6.1.2 Viral Capsids:

Derived from viruses which are biocompatible, stable and contain modifiable features, hence allowing them to remain in the circulation system for longer duration. Morphology of viral capsid controls the size and shape of materials entrapped inside.

6.1.3 Small Heat Shock Protein(sHsp):

Apart from the common features sHsp survive at high temperatures and pH. Their architecture can be modified through mutagenesis and contain lysine groups on its surfaces for chemical modifications.

Microspheres:

Microspheres consist of hydrophobic proteins (casein) which can encapsulate hydrophobic drugs (progesterone). Emulsification with crosslinking is the common method of preparation where hydrophobic and hydrophilic proteins are cross-linked by glutaraldehyde thereby making drug molecules entrapped in the microsphere. The release rate and loading amount of drugs are kept under control using the ratio between the protein and glutaraldehyde. Swelling of microspheres causes drug release and microspheres have been used to provide sustained drug release for long duration.

Minirods (Minipellets):

Minirods are created using non cross-linked collagen since collagen is widely available, biocompatible, high biodegradability and forms crosslinking and self-aggregation of strong fibres. Minirods protein shape allows effective encapsulation of high molecular-weight drugs and retention time is also increased. A high concentration collagen solution can be used to prepare dense networks to control the retention time of drug molecules. Due to small size Minirods can be injected subcutaneously. [](Protein-based nanomedicine platforms for drug delivery; Maham A, Tang Z, Wu H, Wang J, Lin Y.)

Micro and nano-electromechanical systems (MEMS/NEMS)

MEMS/NEMS based drug delivery systems have been introduced to provide a better means of dosing due to their small size and capabilities of storing and timely release of drugs in a controlled manner. Microreservoirs and Micropumps have been developed using biocompatible materials and programmable microdevices.

Current research has helped integrate active components including battery clocks, reference electrodes and biosensors though polymer based microchips are still being tested. An ideal NEMS/MEMS system would protect the drug until required and allow a continuous or time- specific delivery of the therapeutic agents along with an external control mechanism. An array of sealed reservoirs contains the drugs and biosensors are placed to monitor the reactions. Such systems require surgical implantations in the body in order to be used, whereas polymer based systems require only one surgical procedure due to their biodegradable nature. Furthermore autonomous self-monitoring devices are used to control timing and amount of drug release. [](Application of Micro-and Nano-Electromechanical Devices to Drug Delivery; Mark Staples, Karen Daniel, Michael J.Cima and Robert Langer)

Recent advances have also simplified the control mechanism by using biosensor units which communicate to regulate drug release and send information to external monitors for referencing. Treatment of Diabetics (Type I-II) where control over insulin can be achieved using these intelligent biosensor is an excellent example but there needs to be more trials done before they can be marketed. [](Micro- and nanotechnologies for intelligent and responsive biomaterial based medical systems; Mary Caldoerea-Moore, Nicholas A.Peppas)

Drug Delivery System

Liposomes

Micelles

Pluronic

Poly(L-aminoacid)

Polyester

Nanoemulsions

Nanoparticles

Polymer-based

Lipid-based

Ceramic-based

Albumin-based

Nanogels

Hydrogels

Temperature based

pH based

Bio Responsive

Dendrimers

Protein-based Platform

Protein Cage

Microspheres

Minirods

NEMS/MEMS

Stage of development

Marketed

-

Clinical/Preclinical

Clinical

Preclinical

Preclinical

-

Preclinical

Preclinical

In vitro

Marketed

Preclinical

Marketed

Preclinical

Marketed

Preclinical

Limitations

Examples

Nanoparticles Toxicological Hazards

The use of nanotechnology in creating nanomedicine have clearly been beneficial but the concept of using nanoparticles to reduce toxicity and side effects of drugs have come under the scanner since these carrier systems themselves may impose risks to patients. Studies have shown these levels of hazards were beyond those created by conventional drugs.[](Borm 2002;Nel et al 2006) Buxton et al[](Buxton et al 2003;European Technology Platform on Nanomedicine 2005) criticizes previous studies for having lack of information regarding the following issues:

Nanoparticles have unique surface properties. Nanoparticle surface is the contact layer with the body tissue and also a crucial determinant of the particle response. This unique reactive characteristic may have an impact on the toxicity of the particle itself. Although current tests and procedures using latest techniques may be appropriate to detect many risks, the possibility of missing out on potential risk is very present. Thus calling for additional particle specific assays to be used.

Physico- Chemical characteristics of nanoparticles differ from those seen in micron sized particles, which could result in changed body distribution, passage of blood brain barrier and triggering of blood coagulation pathways. At present there's a gap in the basic understanding of the biological behaviour of nanoparticles in terms of distribution in-vivo both at organ and cellular level.

The effects of combustion derived nanoparticles have been studied and documented with environmentally controlled populations but those present in diseased individuals were not studied. Even though typical pre-clinical screening is done with healthy animals and volunteers the risk of the particles maybe detected at a later stage only.

Buxton et all []() states that though one could argue that some of these effects would be detected during routine testing and post marketing evaluation they would greatly depend on the type of assays used in pre-clinical trials. Even then the toxicity of the whole formulation is usually investigated while those of the nanoparticles itself were not performed. Buxton et al []() calls for more research towards empty non-drug loaded nanoparticles to determine their toxicity. These being more important for nanoparticles which have slow or non- degradable properties as they could accumulate on the target site resulting in chronic inflammatory reactions.

Several studies were performed with different animal species and humans to determine whether nanoparticles have harmful health effects. [](Toxic effects of nanoparticles and nanomaterials: Implications for public health, risk assessment and the public perception of nanotechnology R. D. Handya; B. J. Shawa a School of Biological Sciences, University of Plymouth, Plymouth, UK)

Pulmonary deposition of nanoparticles was observed, whereby the particles, would be deposited throughout the pulmonary system. Oberdörster (2005a, 2005b) clearly shows that mucociliary clearance and phagocytosis are well-documented pulmonary clearance mechanisms for micrometric particles and nano particles can enter the extrapulmonary organs due to their size.

The toxic dose for nanoparticles is expressed in terms of the characteristics of the nanoparticles (number and surface). Nanoparticles have a natural tendency to agglomerate- formation of large particles by grouping (Ostiguy et al., 2006). As nanoparticles used for pharmaceutical applications require unagglomerated particles different post-synthesis strategies to prevent aggregation or stimulate deaggregation were implemented. The nanoparticle surface is modified for by coating the particle with a chemical (Borm, 2003). These surface changes can have a major impact on nanoparticle toxicity or safety.

The current knowledge of the toxic effects of nanoparticles is relatively limited but with the available data it's indicated that some nanoparticles can pass through the different protective barriers, be distributed in the body and accumulate in several organs. Toxic effects have already been documented at the pulmonary, cardiac, reproductive, renal, cutaneous and cellular levels, while nanoparticles can be distributed throughout the body, including the interior of cells. Significant accumulations have been shown in the lungs, brain, liver, spleen and bones. [](Toxic effects of nanoparticles and nanomaterials: Implications for public health, risk assessment and the public perception of nanotechnology R. D. Handya; B. J. Shawa a School of Biological Sciences, University of Plymouth, Plymouth, UK)