Prolonged exposure to vincristine correlates with improved therapeutic activity. In this work, two methods are used to increase the circulation longevity of liposomal formulations of vincristine. The first involves incorporation of the ganglioside GM1, which acts to increase the circulation longevity of liposomal carriers, while the second approach relies on a modification of the vincristine encapsulation procedure which enhances drug retention. It is shown that these approaches are synergistic and increase the circulation half-life of vincristine from approximately 1 h to greater than 12 h. This results in a dramatic improvement in the therapeutic activity of liposomal vincristine as measured using a murine P388 lymphocytic leukemia model. At doses above 2 mg/kg, the optimized liposomal vincristine formulation cures greater than 50% of mice bearing the P388 tumor, whereas free vincristine results in no cures.
This research was supported by the National Cancer Institute of Canada. N. L. B. is a recipient of an MRC Fellowship. M. B. B. is a B.C. Health Research Foundation Scholar.