ROLE OF NANOTECHNOLOGY IN DRUG DELIVERY

INTRODUCTION: 

At present 95% of all new potential therapeutics have poor pharmacokinetics and biopharmaceutical properties. Therefore, there is a need to develop suitable drug delivery systems that distribute the therapeutically active drug molecule only to the site of action, without affecting healthy organs and tissues. Nanotechnology plays an important role in therapies by lowering doses required for efficiency as well as increasing the therapeutic indices and safety profiles of newer therapeutics. Nanomedicines are delivery systems in the nanometer size range (1-100 nm) containing encapsulated, dispersed, adsorbed or conjugated drugs.      Nanoscale drug delivery systems have the ability to improve the pharmacokinetics and increase biodistribution of therapeutic agents to target organs, which will result in improved efficiency. Drug toxicity is reduced as a consequence of preferential accumulation at target sites and lower concentration in healthy sites. Nanocarriers have the desirable advantage of improving solubility of hydrophobic compounds in aqueous medium to render them suitable for parenteral administration. These delivery systems have shown to increase the stability of a wide variety of therapeutic agents such as small hydrophobic molecules, peptides and oligonucleotides. 

NANODRUG DELIVERY SYSTEMS

LIPOSOMES:

Liposomes are defined as vesicles in which an aqueous volume is entirely surrounded by a phospholipids membrane. Liposome size can vary from 30 nm to several nanometers, and can be uni or multilamellar. Their properties have been extensively investigated and can vary substantially with desired size, lipid composition, surface charge, and method of preparation. Liposomes have to be smaller than the vascular cutoff (380-780 nm) to extravasate and reach solid tumors. Vesicle size also plays a critical role in complement activation. Liposomes are currently investigated for a variety of additional therapeutic agents; anticancer drugs such as paclitaxel, camptothecin, cisplatin; antibiotic such as amikacin, vancomysin, ciprofloxacin; biologics such as antisense oligonucleotides, DNA.

MICELLES:

Micelles are self- assemblies of ampliphiles that form supramolecular core- shell structures in the aqueous environment. Hydrophobic interactions are the predominant driving force in the assembly of the amphiphiles in the aqueous medium when their concentrations exceed the critical micelle concentration.

      Nanosized micellar delivery systems are made up of amphiphilic polymers that consist of a low molecular weight hydrophobic core- forming block. Due to low monomer concentration in equilibrium with the micelles, these micellar delivery systems have reduced toxicity and are more thermodynamically stable. The biodistribution and pharmacokinetics of drugs such as doxorubicin, cisplatin and paclitaxel are altered favorably

Phospholipid micelles:

PEG- conjugated phospholipids such as DSPE-PEG are water soluble and self assemble as Nanosized micelles instead of bilayers. PEGylated phospholipids micelles can also avoid MPS uptake and have been demonstrated to have prolonged circulation times. Therefore, they are described as sterically micelles.

Examples of drugs include paclitaxel, diazepam, and camptothecin.

Pluronic micelles:

Pluronic are block polymers copolymers that consists of hydrophilic polyethylene oxide (PEO) and hydrophobic polypropylene oxide (PPO) blocks arranged in a basic PE0x – PPO y- PEO x structure. The pharmacokinetic profile of pluronic micelles of doxorubicin showed a slower clearance than conventional doxorubicin.

Poly (L-amino acid) micelles:

Poly (L-amino acid) based micelles are investigated for pH dependant release at tumor sites. Poly (L- Histidine) micelles of doxorubicin were investigated at pH 7, pH 6.8, and pH 5 with a release of 32 wt%, 70 wt% and 82wt% respectively.

Polyester micelles:

 Polyester micelles composed of polymers such as PEG- poly (lactic acid) (PLA), PEG- poly(lactic- co- glycolic acid) (PLGA) and PEG- poly(caprolactone) that are biocompatible, biodegradable and FOOD and Drug Administration approved for human use. Polyester micelles for delivery of Paclitaxel and Doxorubicin.

NANOEMULSIONS FOR DRUG DELIVERY: 

Nanoemulsions are dispersions of oil and water where the dispersed phase droplets are in the Nanosized range and stabilized with a surface active film composed of surfactant and co-surfactant. Nanoemulsions are transparent or translucent systems that have dispersed- phase droplet size range of typically 20-200 nm. Nanoemulsions are attractive as pharmaceutical formulations because they form spontaneously, are thermodynamically stable, and optically transparent. The nanosizes of the droplets prevent creaming or sedimentation form occurring on storage and droplet coalescence. A variety of techniques such as density, surface tension measurements, differential scanning caloriemetry and small angle X-ray scattering to characterize the structure of a typical nanoemulsion system. Nanoemulsions provide much longer oil- water contact area due to the nanosize droplet compared to classical emulsions, which facilitates drug release from the dispersed droplets. The biodistribution of Vincristine nanoemulsion to the tumor sites significantly increased. Paclitaxel micro emulsion has been studied for controlled release of paclitaxel, similarly for Acelofenac. Methods to prepare include lab-scale sonication, high energy emulsification and low energy emulsification.

DRUG NANOPARTCLES: 

 Dispersion of drug particles in the nanosize in an aqueous environment is an attractive approach for the delivery of water insoluble drugs. Nanosuspensions of drug particles are commonly produced by two methods. First method involves the breaking down of bigger particles to nanosize using high pressure homogenization of drug suspensions in the presence of surfactants such as Tween 80 and Pluronic F68. The second method involves crystallization building the nanoparticles up from the supersaturated solution state. Mean diameters of drug Nanoparticles are typically 200-400 nm. Drug nanocrystals have been formed for amphotericin B, etopside, camptothecin and paclitaxel.

 SOLID NANOPARTICLES:   

Nanoparticles can further be sub-classified according to their composition mainly polymer based, lipid based, ceramic based materials, albumin nanoparticles and nanogels.   

Polymer based Nanoparticles:

 These nanoparticles are made from copolymers to increase circulation half life and inactivation. Poly lactic acid (PLA), poly glycolic acid (PLGA), poly a- caprolactone and poly methyl methacrylate nanoparticles are most widely studied. Methods involved in the preparation can be broadly into two general classes. The first class involves the polymerization of monomers, second is based on the dispersion of preformed polymers.

 Lipid based Nanoparticles:

Solid lipid nanoparticles are a class of carriers that have advantages such as the use of physiological lipids, avoidance of organic solvents in their preparation, protection of sensitive drugs from the external environmental and controlled release of drugs. SLNs are produced by two different methods: Hot homogenization of melted lipids at elevated temperatures or cold high pressure homogenization process. Example: Doxorubicin SLNs.

Ceramic based Nanoparticles:

  Nanoparticles are made up of ceramic materials such as silica, alumina and titania. Their preparations are simple, similar to the well known sol-gel process and require ambient temperature conditions. The ceramic materials used are biocompatible and their surfaces can be easily modified with different functional groups for ligand attachment. The particles can be prepared to the desired size, shape, porosity are extremely inert. The ceramic nanoparticles are sized at less than 50 nm. Ceramic nanoparticles can protect absorbed or adsorbed molecules against denaturation induced by extreme pH and temperature.

  Albumin Nanoparticles: 

Albumin is a major protein component in serum. Albumin surface possess several amino and carboxylic groups which are available for covalent modification and drug or protein attachment. Albumin nanoparticles can be prepared by a desolvation or cross linking technique, where dissolved albumin in water is desolvated by dropwise addition of ethanol and glutaraldehyde to induce albumin nanoparticles cross linking overtime. Albumin nanoparticles are investigated for DNA delivery

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Nanogels: 

 Nanogels are composed of flexible hydrophilic polymers in the nanosize scale. Upon equilibrium or swelling in water drug can be loaded spontaneously into the nanogels, resulting in the reduction of the solvent volume, leading to gel collapse and formation of dense nanoparticles.

Dendrimers:

Dendrimers are polymeric complexes that comprise a series of well defined branches around an inner core with sizes 1-10 nm and physico chemical properties similar to macromolecules dendritic branching gives rise to semi globular structures and can be functionalized with groups such as carbohydrates, peptides and silicon to form glycodendrimers, peptidedendrimes and silicon based dendrimers respectively. Dendrimers size can influence the extravasations across the endothelium into the surrounding interstitial tissue to reach the target sites.

Dendrimers can be synthesized by either divergent or convergent approaches. In the former approach, the dendrimers is synthesized from the core as the starting point, and each successive generation will be built. The convergent approach of synthesis capitalizes on the symmetrical nature of the dendrimers where synthesis begins at the periphery of the final molecule and stops at the core where dendrimers segment couple. Drugs can be physically encapsulated in the void spaces of the dendrimers interior by the incubation and dendrimers drug network can be formed. Prodrugs can be formed from a linkage of drug to the dendrimers surface. Dendrimers have also been extensively investigated for gene delivery. DNA can be complexed with intact PAMAM dendrimers. Dendrimers have been investigated for delivery of indomethacin, fluorouracil and antisense oligonucleotides.

CURRENT STATUS: 

The current status of various nano drug delivery systems is indicated in table      

CONCLUSION: 

The field of manomedicine has a bright future with the emergence of several promising approaches for delivery of therapeutic agents using the advantageous Nanoscale carriers. However, the cost of these Nanomedicines should be in acceptable low range to be successful in the clinics.    

 REFERENCES: 

1) Nanotechnology in Drug Delivery by Melgardt M. de Villers, Paranong Aramwit, Glen S. Kwon. Pg nos: 581-596

2) Nanoparticulate Drug Delivery Systems by Deepak Thassu, Micheal Deelers, Yaswanth Pathak. Pg nos: 1- 30 

3). Lochmann D, Vogel V, Weyermann J, et al. Physicochemical characterization ofprotamine-phosphorothioate nanoparticles. J Microencapsul 2004; 21:625

4). Muller RH, Dingler T, Schneppe T, Gohla S. In: Wise D, ed. Handbook of Pharmaceutical Controlled Release Technology. New York: Marcel Dekker, 2000:359...