Ashim K Mitra
Vice Provost Interdisciplinary Research University of Missouri-Kansas City, USA
Ashim K. Mitra received his Ph.D. in Pharmaceutical Chemistry in 1983 from the University of Kansas. He joined the University of Missouri-Kansas City in 1994 as Chairman of Pharmaceutical Sciences. He is also Vice Provost for Interdisciplinary Research, UM Curators? Professor of Pharmacy, Co-Director, Vision Research Center UMKC School of Medicine. He has 30+ years of experience in the field of ocular drug delivery and disposition. He authored and co-authored over 355 refereed articles, 67 book chapters in the area of formulation development and ocular drug delivery, 10 patents, and presented (along with his research group) well over 710+ presentations/abstracts at national and international scientific meetings. This work has attracted over six million dollars in funding from government agencies such (NIH) National Institutes of Health, (DOD) Department of Defense (DOD) and pharmaceutical companies.
My research interest includes ocular delivery system, transporter/receptor specific ligand based delivery to viral reservoir sites particularly the eye and brain. The brain parenchymal cells are protected by highly impermeable capillary cells (blood brain barrier). Similarly, the ocular blood vessels in the retinal choroid (blood retinal barrier) and the anterior segment-aqueous humor (blood-aqueous barrier) are barriers to drug delivery to the eye. Research interest can be categorized into two main areas: delivery and targeting of antiviral agents and development of noninvasive delivery systems for peptides and protein; serves on several National Institutes of Health Study Sections including AIDS and Related Research; editor of a book on "Ophthalmic Drug Delivery Systems" and a journal series on "Advanced Drug Delivery Reviews. In the area of antiviral drug delivery and targeting, work is in progress relative to retinal drug transport, metabolism and targeting of anticytomegalorivus agents like ganciclovir, cidofovir and foscarnet. A new ocular microdialysis technique has been employed for continuous vitreal sampling. Research is also being conducted to improved oral absorption of anti-AIDS agents like cosalane through prodrug modification. The other major research area of interest is the noninvasive delivery of peptides and proteins like calcitonin, insulin, human growth hormone, fibroblast growth factors pulmonary, nasal and buccal routes of delivery are being investigated. Poor mucosal permeability and rapid protease mediated degradation are the two major barriers to protein delivery. Prodrug modification, protease inhibition and various other approaches have been taken to improve protein absorption. Major area of research interest is to develop semi-invasive controlled delivery system for the treatment of posterior segment ocular diseases. Novel tailor-made pentablock (PB) copolymers have been developed and evaluated for the controlled delivery of macromolecules to back of the eye tissues (retina-choroid). PB copolymers were synthesized utilizing various FDA approved biodegradable and biocompatible polymer blocks (polyglycolide, polyethylene glycol, polylactide and polycaprolactone). Various PB copolymers have been optimized with respect to molecular weight and ratios of each block in order to successfully develop a macromolecular (lysozyme, BSA, IgG, and IgG Fab) drug delivery system. A comprehensive drug delivery systems comprising drug-loaded nanoparticles dispersed in thermosensitive gel have been investigated to achieve continuous zero order drug release at the target tissues (retina-choroid). Another major area of research interest is developing topical formulations (eye drops) that enable non-invasive delivery of drugs to back of the eye tissues (retina-choroid) with no/minimal systemic exposure. Drug loaded nanomicellar constructs are prepared with FDA approved polymers for ocular use. Nanomicellar constructs of hydrophobic drugs such as voclosporine, dexamethasone, rapamycin and others are being extensively studied and evaluated as potential drug carrier systems for retinal delivery. Nanomicelles aid to improve drug ocular permeability and deliver therapeutic levels of drug to back of the eye tissues. Research is being extensively conducted to improve posterior ocular drug bioavailability with nanomicelles as vehicles in a patient acceptable route of drug administration i.e. topical drop. This technology is expected to replace the current existing invasive, expensive and patient non-compliant route of drug administration methods (intravitreal and periocular injection, an injection into the eye). Also, this method helps to avoid complications associated with intraocular injections. Research is being conducted to develop nanomicellar formulations for hydrophilic drug molecules (DNA, RNA, protein, peptide) to deliver them to retina-choroid in a patient compliant and non-invasive route, topical drop administration. Recently my laboratory started working on targeted drug delivery to nuclei of cancer cells to overcome drug resistance. Besides gene mutations multidrug resistance proteins (MDR) or efflux pumps are major barriers for absorptions of 70% of drugs. Both MDR proteins and metabolizing enzymes are the major drawback in successful chemotherapy. Most cancer cells overexpress these MDR proteins. Consequently cancer cells receive subtherapeutic concentration of chemotherapeutic agents. It is difficult to eradicate cancer. I am in the process of developing a novel delivery system containing drug loaded nanoclusters conjugated with NLS peptide analogues in inhaler sustained formulation. Our discovery of novel nuclear localization signal (NLS) derived peptides appear to target plasma and nucleopore membranes of cancer cells only. Native NLS peptide sequences penetrate plasma membrane and nuclear envelope of both malignant and non-malignant cells. However our modified NLS sequence will enter specifically to nuclei of cancer cells avoiding non-malignant cells. NLS peptide is a prime facilitator for transport of large cargo into nucleus. To facilitate the process, NLS sequence requires to interact with importin alpha expressed on the nucleopore complex for translocation to nuclear DNA. This adenoviral fiber protein is capable of evading endosomal degradation. Our modifications of NLS peptides have potential to deliver nanocarriers specifically into nuclei of malignant cells. NLS peptides are modified by replacing specific amino acids in the native sequence. This optimized NLS peptides are conjugated to nanoparticles (NP) containing therapeutic agents. This formulation can be delivered via an inhaler device which will be very effective due to local sustained delivery for lung cancer. The drug delivery can provide more efficacious, cost effective, noninvasive and normal cells