Fellowship for Sweta Modi: Mechanism Based Liposome Loading Strategies and Predictive Release Kinetics of Hydrophobic and Hydrophilic Anticancer Agents

Encapsulation of anticancer agents in liposomes can dramatically alter drug distribution because the typical size range for unilamellar liposomes (-50-200 nm) precludes their passage into normal tissues while facilitating their accumulation in tumor tissue by Enhanced permeation and Retention (EPR) effect, exerted by tumors. In this respect, the rate ofdrug release from the formulation is the most important factor governing the drug availability at the target site. However, it is challenging to establish required drug release rate for maximum therapeutic activity. Also there is a need to modulate the drug release based on the tumor type and size in order to provide safe but efficacious concentrations at the tumor site. As a result, it would be highly desirable to design a formulation system with tunable and predictable drug release rate, which can be tailored according to the therapeutic requirement. The main objective of the current project is to develop liposomal formulations for anticancer agents with tunable release characteristics for optimum therapeutic activity. The two drugs selected (AR-67 and Dexamethasone Phosphate) are good model compounds because they represent two types of drugs that are particularly challenging. AR-67 (a novel camptothecin analog) is a highly lipophilic compound with no ionizable groups in its active form while Dexamethasone Phosphate is a highly polar dianion at physiological pH. The problem in the first case is poor loading because of poor solubility and poor retention due to high lipophilicity. The problem in the second case is the hydrophilic, charged character which would appear to preclude both active loading to high concentrations and adequate release ofthe entrapped drug. However, for maximal therapeutic efficacy of a drug, an optimal release rate is desired that is slow enough to avoid immediate drug exposure to healthy tissue while liposomes are in circulation but fast enough to deliver the drug from the vesicles once at the tumor site. We aim to develop liposome formulations of these drugs to get a tunable release rates in vitro and evaluate their performance in vivo. Mechanism based models not only enhance the understanding of the underlying mechanisms but also serve as a powerful predictive tool in modulating loading and release kinetics.