TRANSFER OF LIPOSOMAL DRUG CARRIERS FROM THE BLOOD TO THE PERITONEAL-CAVITY OF NORMAL AND ASCITIC TUMOR-BEARING MICE

Previously we have demonstrated that the L1210 antitumor activity of l iposomal doxorubicin increased significantly as the size of the liposo mal carrier was reduced from 1.0 to 0.1 mu m. It is demonstrated herei n that empty and drug-loaded small (0.1-mu m diameter) liposomes accum ulate efficiently into the peritoneal cavity of normal and ascitic L12 10 tumor-bearing animals following i.v. administration. In normal mice injected with 100 nm DSPC/chol liposomal doxorubicin (drug-to-lipid r atio of 0.2; wt/wt) approximately 2.8 mu g drug could be recovered fro m the peritoneal cavity following peritoneal lavage at 24 h. Although this represents only 0.7% of the injected doxorubicin dose, this level of drug is 2 orders of magnitude greater than that achieved following administration of an equivalent dose of free drug (20 mg/kg). The dru g levels achieved within the peritoneal cavity are dependent on the ph ysical characteristics (size, drug-to-lipid ratio and lipid compositio n) of the liposomes employed. Optimal delivery is obtained employing 1 00 nm DSPC/chol liposomal doxorubicin, a vesicle system that is known to retain entrapped drug following i.v. administration and exhibits ex tended circulation lifetimes. Analysis of drug and liposome distributi on within the peritoneal cavity of normal mice indicates that as much as 50% of the measured doxorubicin and liposomal lipid is cell-associa ted. Flow cytometric analysis of the peritoneal cells demonstrated tha t cell-associated doxorubicin resides almost exclusively within reside nt peritoneal macrophages. The increased delivery of doxorubicin to th e peritoneal cavity of normal mice following i.v. administration of sm all (0.1-mu m) liposomal doxorubicin is correlated with a pronounced ( >90%) and prolonged (>14-day) suppression of resident peritoneal cells . Liposomal drug accumulation increased dramatically in animals with a n established L1210 ascitic tumor. More than 5% of the injected dose w as found in the peritoneal cavity of these animals 24 h after treatmen t with DSPC/chol liposomal doxorubicin as compared with a value of 0.0 3% of the injected dose achieved with free drug. It is proposed that a ccumulation of liposomes into the peritoneal cavity of normal and tumo r-bearing mice may serve as a useful model for characterizing factors mediating the transfer of liposomes from the vascular compartment to e xtravascular sites.