Drug Delivery and Targeting: The aim of this project is encapsulate therapeutic drugs/nucleotides/genes in suitable nanoparticulate carrier system. These nanoparticles could be made from a variety of polymeric/inorganic systems so as to carry the therapeutics load at the site of action in the body and release there in sustained fashion. Targeting ligands could be attached at the nanoparticles surfaces so that they can be targeted at the site of interest. This approach could lead to enhanced therapeutics efficacy and reduced toxic side effects of the drug. At present I am involved in the delivery of DNAs and genes to the brain for treatment of tumors.

Earlier, I successfully devised a polymeric micelles system for ophthalmic delivery of hydrophobic drugs. As is known, ophthalmic drug delivery formulations have limitations of the therapeutic bioavailability of the drugs because these are washed away by the tear dynamics. I have devised a polymeric nanoparticle system, which has overcome most of these limitations. The particles were made having ultrasmall size, mucoadhesive, pH and temperature with appropriate surface hydrophobicity/hydrophilicity so that the particles remain on the corneal surface for a longer period of time and release the drug in a sustainable way and thereby increase the ocular bioavailability of the drugs enormously. Interestingly, the systemic absorption of these particles from ocular route is also very low.

 

 

Magnetic Nanoparticles for Targeting and Diagnostics: This project is based on the synthesis of superparamagnetic iron oxide nanoparticles of a specific shape and narrow size distribution with tailored surface chemistry. In fact, magnetic nanoparticles could be used to attach a targeting ligand on their surface or in their bulk a pharmaceutical drug that could be driven to the target organ using an external magnetic field and released there. These nanoparticles with targeting capacity could be used in highly specialized areas like gene delivery, delivery in brain, tumour targeting, oral vaccine formulations and other areas. The particles are characterized by various physico-chemical techniques like FTIR, 1H-NMR, DLS, TEM, SEM, SQUID, XRD etc. Magnetic nanoparticles surfaces were modified with various proteins, polymers or polysaccharides with an aim to study cell/nanoparticles interaction and to evaluate the phagocytosis and apoptotic effects of particles on various cell types. The current research using surface derivatized iron oxide nanoparticles with high magnetization values is involved in targeting them to the brain in mice and imaging of the tissue using MRI.  To enhance the MRI contrast signal, the hybrid particles would be made using magnetite and gadolinium.

 

 

Gene Delivery to Brain (Non-Viral vectors): This project is involved in the development of viral vectors for delivery of neurotherapeutic proteins and plasmids for neurological diseases. Successful treatment of diseases of brain including brain tumours is very difficult because the delivery of drugs to brain is considerably restricted because of relatively impermeable blood brain barrier (BBB). The BBB, brain's protective barrier, is composed of tightly knit endothelial cells, which line the walls of the blood vessels in the brain. These tightly knit cells create a barrier that not only blocks the entry of various foreign harmful substances but also restricts the entry of many potentially useful therapeutic agents into the brain. To achieve the long blood circulation times in the body, the particles should be made small enough (size less than 50 nm) to pass through BBB with hydrophilic surfaces. Particles with hydrophilic surfaces do not adsorb blood plasma proteins and hence the kupffer cells of the liver would not take them up. I am working on the development of nanoparticles for delivery of proteins and nucleotides to the brain for their systemic and i.v. delivery. In the second part of the research, nanoparticles will be made cell or tissue target specific so that they would only target the cells or tissues of interest, thereby causing minimal toxicity to the neighbouring healthy cells. Tissue and cell-specific drug targeting can be achieved by employing nanoparticle coatings or carrier-drug conjugates that contain a ligand recognized by a receptor on the target cell. Several types of biodegradable/biocompatible/non-toxic nanoparticles have been already made from gelatin, pullulan, poly(lactide-co-glycolide) and thermo-sensitive polymers have been prepared for drug/gene delivery applications.

 

 

Ceramic Nanoparticles: In this project, several kinds of nanoparticles made from non-polymeric materials such as silica, calcium phosphate, calcium carbonate etc. and modified with targeting ligands are under investigation for delivery and targeting purposes.

 

 

Dendrimers: Dendrimers are quite new type of branched polymers that have tree like structures and they can be used to bind DNAs to their outer surfaces. The size of these complexes is in the order of 50-200nm. They are currently under investigation for carrying the therapeutics genes of interest to brain. Since higher concentrations of dendrimers may be toxic, the complex would be modified with suitable polymers and targeting molecules for their safer delivery.

 

 

Viral Vectors: The aim of this project is to develop the viral vectors for brain tumors. Although Herpes Simplex Virus 1716 (HSV1716) has strong therapeutic potential for the treatment of human malignancies, some limitations of its use are anticipated. HSV1716 is able to infect and kill a variety of tumour cells but its permissive range may be restricted to certain cancer types.  For example, HSV1716 infection and lysis of B or T cell lymphomas (leukaemias) has not been tested due to in part to the inherent inability to specifically target and deliver HSV1716 systemically.  It is essential to overcome cell-type and mode of delivery restrictions and increase the efficiency of infection of tumour cells so that HSV1716 can be more widely and effectively applied. To achieve tumour cell type targeting, we intend to modify the tropism of HSV, so that a particular range of cell types can be targeted.  A complex comprising HSV1716 and an agent capable of targeting to a specific cell type will be developed.  The targeting agent will be an antibody, which is capable of specifically binding to a cell surface protein present on a particular cancer cell eg T or B cells, myeloma or breast cancer.  The antibody will be linked to the virus via a viral envelope protein so that it is displayed on the surface of the virus.  Specific antibodies incorporated into the viral envelope will influence the selectivity of the virus by enhancing the efficiency of viral infection.

 

Currently, HSV1716 is administered by direct intratumoural injection.  If administered into the circulation of a patient, not only does the virus have to find the tumour cells but also it has to contend with pre-existing immunological factors eg neutralising antibodies, designed to eliminate the virus (most people have had previous exposure to HSV-1).  Thus, there is an urgent need to develop a delivery system that avoids immunological detection and can specifically target tumour cells.  Our goal is to create a ‘stealth’ virus by encapsulation in a ligand-directed inert matrix.