SPHINGOMYELIN-CHOLESTEROL LIPOSOMES SIGNIFICANTLY ENHANCE THE PHARMACOKINETIC AND THERAPEUTIC PROPERTIES OF VINCRISTINE IN MURINE AND HUMANTUMOR-MODELS

This study reports on the development of a liposomal formulation of vi ncristine with significantly enhanced stability and biological propert ies. The in vitro and in vivo pharmacokinetic, tumour delivery and eff icacy properties of liposomal vincristine formulations based on sphing omyelin (SM) and cholesterol were compared with liposomes composed of distearoylphosphatidylcholine (DSPC) and cholesterol. SM/cholesterol l iposomes had significantly greater in vitro stability than did similar DSPC/cholesterol liposomes. SM/cholesterol liposomes also had signifi cantly improved biological properties compared with DSPC/cholesterol. Specifically, SM/cholesterol liposomes administered intravenously reta ined 25% of the entrapped vincristine after 72 h in the circulation, c ompared with 5% retention in DSPC/cholesterol liposomes. The improved retention properties of SM/cholesterol liposomes resulted in plasma vi ncristine levels 7-fold higher than in DSPC/cholesterol liposomes. The improved circulation lifetime of vincristine in SM/cholesterol liposo mes correlated with increased vincristine accumulation in peritoneal a scitic murine P388 tumours and in subcutaneous solid A431 human xenogr aft tumours. Increased vincristine delivery to tumours was also accomp anied by increased anti-tumour efficacy. Treatment with SM/cholesterol liposomal formulations of vincristine resulted in greater than 50% cu res in mice bearing ascitic P388 tumours, an activity that could not b e achieved with the DSPC/cholesterol formulation. Similarly, treatment of mice with severe combined immunodeficiency (SCID) bearing solid hu man A431 xenograft rumours with SM/cholesterol vincristine formulation s delayed the time required for 100% increase in tumour mass to >40 da ys, compared with 5 days, 7 days and 14 days for mice receiving no tre atment or treatment with free vincristine or DSPC/cholesterol formulat ions of vincristine respectively.