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

The rate of drug release from the formulation is the most important factor governing the drug availability at the target 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 truly enable quality by design in the formulation of liposomal delivery systems by developing comprehensive, mechanism-based mathematical models of drug loading and release kinetics models that take into account not only the therapeutic requirement but the physicochemical properties of the drug, the bilayer membrane, the intraliposomal microenvironment and the local environments that the liposomes may encounter in vivo. The two drugs selected (AR-67 and Dexamethasone Phosphate) are good model compounds because they represent two categories 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 (Dex-P) is amphiphilic, 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 with Dex-P is the hydrophilic, charged character which would appear to preclude both active loading to high concentrations and adequate release of the entrapped drug. For maximal therapeutic efficacy, 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.