The Role of PH and Ring-opening Hydrolysis Kinetics on Liposomal Release of Topotecan

The use of liposomal delivery systems for the treatment of cancer has been extensively researched because of their passive targeting to the vasculature of solid tumors. While their potential to provide prolonged retention and high drug encapsulation is desirable for anticancer agents, a mechanistic understanding is required to optimize and design liposomal drug delivery systems capable of controllable release tailored to tumor type and patient. Topotecan (TPT) is a topoisomerase I inhibitor that undergoes reversible, pH-sensitive ring-opening hydrolysis. TPT may benefit from liposomal formulation using active loading strategies to generate low intravesicular pH to prolong drug retention and increase drug encapsulation. This paper develops a mathematical model to describe TPT's permeability as a function of pH by accounting for the drug's ionization state, membrane binding, and ring-opening interconversion kinetics. Studies were conducted to determine the acid dissociation constant of TPT's phenolic -OH and interconversion kinetics between TPT's lactone and carboxylate forms. Using the constants determined from these studies and release studies conducted at varying pH, permeability coefficients and membrane binding constants for each species of TPT were determined. Based on this model, three permeable species were observed. Interestingly, the two most permeable species were zwitterionic forms of TPT, and the permeability of the lactone zwitterion was comparable to that of the neutral form of another camptothecin analogue. Furthermore, release was affected by based-catalyzed interconversion kinetics between TPT's lactone and carboxylate forms. At neutral pH, release was rate-limited by formation of the TPT lactone from the ring-opened carboxylate form. Based on these findings, the developed model describing liposomal release of TPT may be used in the future to evaluate and optimize loading and subsequent release of liposomal TPT formulations utilizing active loading strategies.