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Studies of factors influencing drug efflux rates from liposomes and their impact on antitumor efficacy

The anti-tumor efficacy of liposomal formulations of cell cycle dependent anticancer drugs is dependent on the rates at which the drugs are released from the liposomes. Previous work on liposomal formulations of vincristine has shown increasing efficacy for formulations with progressively slower release rates. This thesis examined methods for increasing drug retention in vitro and in vivo for various antineoplastic agents as well as enhancing the circulation lifetime of the drug delivery system. In Chapter 2 the effects of very high drug-to-lipid (D/L) ratios on vincristine release rates were investigated, and the antitumor efficacy of these formulations characterized in human xenograft tumor models. It is shown that the half-times (T-1/2) for vincristine release from egg sphingomyelin/cholesterol liposomes in vivo can be adjusted from T-1/2 = 6.1 h for a formulation with a D/L of 0.025 (wt/wt) to T1/2 = 117 h (extrapolated) for a formulation with a D/L ratio of 0.6 (wt/wt). The increase in drug retention as the D/L ratio is increased is attributed to the presence of drug precipitates in the liposomes. Variations in the D/L ratio did not affect the circulation lifetimes of the liposomal vincristine formulations. The relationship between drug release rates and antitumor efficacy was evaluated using a MX-1 human mammary tumor model. It was found that the antitumor activity of the liposomal vincristine formulations increased (tumor growth delay 21 d to greater than 60 d respectively) as the D/L ratio was increased from 0.025 to 0.1 (wt/wt) (T-i/2= 6.1 15.6 h respectively) but decreased (tumor growth delay 29 d) at higher D/L ratios (D/L=0.6, wt/wt, Ti/2=117 h). Free vincristine exhibited the lowest activity of all formulations examined. These results demonstrate that varying the D/L ratio provides a powerful method for regulating drug release and allows the