Unit: Drug Discovery and Development
Harrison School of Pharmacy
257 Pharmacy Research Building
Auburn, AL 36849
Solid tumors are non-uniform mixtures of tumor cells and stroma (e.g., blood vessels, host tissue, underlying support matrices, and hematological/immunological cells). Most treatment schedules have been developed empirically and do not take into account the spatial and temporal heterogeneities in tumor cell growth and vasculature architecture that exist within tumors. Non-uniformities in the architecture and microenvironment of tumors limit our ability to achieve drug concentrations sufficient to elicit a clinically relevant therapeutic response or may results in regions within a tumor that are unresponsive to a given treatment.
Nanomedicines, i.e., drug-carriers, can be developed rationally to deliver optimal quantities of drug to treat acute (active) disease or prophylactically over prolonged periods to mitigate residual disease. Nanoparticulate drug carriers, such as liposomes, can encapsulate drugs stably and alter their pharmacokinetics (PK) radically compared to free drug. Following administration, sterically stabilized liposomes (SSLs) extravasate and accumulate passively due to defects in the vasculature and lack of functional lymphatics in solid tumors, but their penetration is limited and the kinetics of drug release and intracellular uptake in vivo are not well understood.
A broad goal of my laboratory is to integrate the pathophysiology of a disease state with the known pharmacology of drugs to development optimal delivery systems for existing and novel therapies for cancer, and translate those findings from discovery and preclinical development to clinical use. Specifically, my research interests are in optimizing drug dosing schedules and developing nanomedicines and exploiting such drug carriers for the treatment of primary and metastatic cancer. We have a specific interest in the development and combination of vascular targeting and conventional oncolytic agents to induce immediate tumor regression and/or facilitate long-term tumor dormancy. Our primary aims are to (i) determine the direct anti-tumor effect and ability of novel nanoparticulate drug carriers to limit tumor growth and metastases in vivo, (ii) gain insights into the molecular mechanisms of the antitumor/vascular effects following acute (high-dose) and chronic (low-dose, protracted treatment), (iii) develop a mechanistic understanding of how long-circulating nanoparticulate drug carriers can be used and optimized to enhance conventional antitumor activity while mediating novel antivascular or antiangiogenic effects, (iv) examine the use of existing and novel tumor/vascular molecular targeting moieties, (v) develop mathematical expressions (PK/PD-modeling) to describe drug exposure-response relationships, and use them to predict optimal drug dosing schedules and test new hypotheses, and (vi) determine the effect of tumor microenvironment and acute and chronic concomitant administration of conventional and selective tumor vascular acting agents at high and low doses for the treatment of primary and metastatic disease.
To accomplish these goals we are pursuing two major research projects currently, i) the primary objective is to test hypotheses that alteration in tumor vasculature function or growth using antiangiogenic agents and/or low-dose sustained exposure to chemotherapeutic agents (referred to as metronomic or antiangiogenic dosing), can be used to improve cancer therapy, and ii) exploit differences in tumor microenvironment to modulate the rate and extent of drug-release from drug-carriers. In pursuing this research, pharmacokinetic (PK) and pharmacodynamic (PD) principles are used as tools for the selection of novel therapeutic agents, design of rational drug delivery strategies to improve therapy and elucidation of mechanisms underlying drug action. Passive and actively targeted drug delivery strategies are engineered with maximal drug capacity and various release profiles to achieve optimal exposure at the target site, while limiting systemic toxicity by minimizing delivery to reactive non-target tissues.