ACCUMULATION OF LIPOSOMAL LIPID AND ENCAPSULATED DOXORUBICIN IN MURINE LEWIS-LUNG-CARCINOMA - THE LACK OF BENEFICIAL-EFFECTS BY COATING LIPOSOMES WITH POLY(ETHYLENE GLYCOL)

The efficiency of drug accumulation in tumors was measured after intra venous administration of doxorubicin encapsulated in distearoyl phosph atidylcholine/cholesterol liposomes prepared in the presence or absenc e of 5 mol % polyethylene glycol-modified phosphatidylethanolamine (PE G-PE). These liposomal formulations of doxorubicin were administered a t the maximum tolerated dose in female BDF-1 mice bearing subcutaneous ly established Lewis Lung carcinoma. The parameters used to determine tumor targeting efficiency (T-e) included area under the doxorubicin p lasma (AUC(P)) and tumor (AUC(T)) concentration-time curves. Extended time-course studies evaluating lipid and drug levels in plasma and tum ors during 7 days after administration indicated that the T-e (AUC(T)/ AUC(P)) was greater for liposomes that did not contain PEG-PE. The AUC (P) after administration of free doxorubicin, doxorubicin encapsulated in distearoyl phosphatidylcholine/cholesterol liposomes and doxorubic in encapsulated in distearoyl phosphatidylcholine/cholesterol/PEG-PE-s tabilized liposomes were 0.087 mu mol . ml(-1). h, 50 mu mol . ml(-1). h and 78 mu mol . ml(-1). h, respectively. Maximum drug levels achiev ed in the tumors were similar for both liposomal doxorubicin formulati ons, 140 mu g (250 nmol)/g tumor; however, this level was achieved fas ter when the liposomes did not contain PEG-PE. Maximum levels measured after administration of free drug were less than 5 mu g/g tumor, and these were achieved within 15 min. The results suggest that some of th e benefits associated with the use of PEG-modified liposomes, such as increased blood levels and enhanced circulation lifetime, may be of li ttle advantage in terms of maximizing liposomal drug accumulation in s ites of tumor growth.