A novel approach to prepare a liposomal irinotecan formulations that exhibit significant therapeutic activity in vivo

639 Purpose: Liposomal formulations of camptothecins are proving to be of clinical interest for several reasons including the potential of the formulations to protect the active form of the drug. Camptothecins possess an α-hydroxy-δ-lactone ring which undergoes reversible hydrolysis at physiological pH (pH ∼ 7) to an open ring-carboxylate form. The closed α-lactone ring appears to be structurally important for both passive diffusion of drugs into cancer cells and successful interaction with the topoisomerase I target. We have characterized a method for preparing liposomal formulations of irinotecan (CPT-11) that relies on interactions with an encapsulated transition metal. Methods: Liposomes were prepared in various salt solutions containing copper, zinc, manganese, and cobalt. The outside buffers were exchanged in order to create a metal ion gradient and the loading of CPT-11 in response to the encapsulated metal was determined. The role of pH and temperature in defining the loading rates of CPT-11 was assessed. HPLC and fluorescent spectroscopic methods were used to assess the chemical stability of CPT-11 following encapsulation. The therapeutic activity of CPT-11 encapsulated into DSPC/Chol liposomes using this method was determined using a murine LS180 (human colorectal cell line) xenograft model. Results: Using encapsulated unbuffered (pH3.5) transition metal salt solutions, CPT-11 accumulated (incubation temperature 50°C) to levels of 0.2 drug-to-lipid (mol:mol) in liposomes with encapsulated CuSO4 and ZnSO4. The loading efficiencies were >90%. These studies were repeated using an encapsulated buffered (pH7.5) CuSO4 solution. CPT-11 accumulated to levels of 0.2 drug-to-lipid (mol:mol) in liposomes with encapsulated CuSO4. The rate of CPT-11 loading into CuSO4 (pH7.5) containing liposomes was slower when the external pH was reduced to 6.5, however if the incubation temperature was increased to 60°C the rate of loading increased. Formulations exhibiting 0.3 drug-to-lipid ratios could be prepared using this technique and at this ratio the loading efficiency was still >90%. Studies indicated that CPT-11 loading into the liposomes occurred only when CPT-11 was in the closed α-lactone ring form. The resulting liposomal formulation exhibited substantial activity when used to treat mice bearing established LS180 tumours. Conclusion: A stable and therapeutically effective liposomal formulation of CPT-11 was prepared using a method which relied on the presence of an encapsulated transition metal to promote drug uptake.

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