PHARMACOLOGY OF LIPOSOMAL VINCRISTINE IN MICE BEARING L1210 ASCITIC AND B16 BL6 SOLID TUMORS/

Vincristine pharmacokinetic, tumour uptake and therapeutic characteris tics were investigated here in order to elucidate the processes underl ying the enhanced efficacy observed for vincristine entrapped in small (120 nm) distearoylphosphatidylcholine/cholesterol liposomes. Plasma vincristine levels after intravenous (i.v.) injection are elevated mor e than 100-fold in the liposomal formulation compared with free drug i n tumour-bearing as well as non-tumour-bearing mice over 24 h. Biodist ribution studies demonstrate that the extent and duration of tumour ex posure to vincristine is dramatically improved when the drug is admini stered i.v. in liposomal form. Specifically, 72 h trapezoidal area und er the curve values for liposomal vincristine in the murine L1210 asci tic and B16/BL6 solid tumours are 12.9- to 4.1-fold larger, respective ly, than observed for free drug. Similar to previous results with the L1210 model, increased drug delivery to the B16 tumour results in sign ificant inhibition of tumour growth, whereas no anti-tumour activity i s observed with free vincristine. Comparisons of drug and liposomal li pid accumulation in tumour and muscle tissue indicate that the enhance d efficacy of liposomal vincristine is related predominantly to drug d elivered by liposomes to the tumour site rather than drug released fro m liposomes in the circulation. Consequently, improvements in liposoma l vincristine formulations must focus on factors that increase uptake of liposomes into tumour sites as well as enhance liposomal drug reten tion in the circulation.