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 liposomal doxorubicin increased significantly as the size of the liposomal carrier was reduced from 1.0 to 0.1 micron. It is demonstrated herein that empty and drug-loaded small (0.1-micron diameter) liposomes accumulate efficiently into the peritoneal cavity of normal and ascitic L1210 tumor-bearing animals following i.v. administration. In normal mice injected with 100 nm DSPC/chol liposomal doxorubicin (drug-to-lipid ratio of 0.2; wt/wt) approximately 2.8 micrograms drug could be recovered from 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 drug levels achieved within the peritoneal cavity are dependent on the physical characteristics (size, drug-to-lipid ratio and lipid composition) of the liposomes employed. Optimal delivery is obtained employing 100 nm DSPC/chol liposomal doxorubicin, a vesicle system that is known to retain entrapped drug following i.v. administration and exhibits extended circulation lifetimes. Analysis of drug and liposome distribution within the peritoneal cavity of normal mice indicates that as much as 50% of the measured doxorubicin and liposomal lipid is cell-associated. Flow cytometric analysis of the peritoneal cells demonstrated that cell-associated doxorubicin resides almost exclusively within resident peritoneal macrophages. The increased delivery of doxorubicin to the peritoneal cavity of normal mice following i.v. administration of small (0.1-micron) 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 an established L1210 ascitic tumor. More than 5% of the injected dose was found in the peritoneal cavity of these animals 24 h after treatment with DSPC/chol liposomal doxorubicin as compared with a value of 0.03% of the injected dose achieved with free drug. It is proposed that accumulation of liposomes into the peritoneal cavity of normal and tumor-bearing mice may serve as a useful model for characterizing factors mediating the transfer of liposomes from the vascular compartment to extravascular sites.
Bally
M B
MB
Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada.
Masin
D
D
Nayar
R
R
Cullis
P R
PR
Mayer
L D
LD
D000818:Animals; D001692:Biological Transport; D004317:Doxorubicin / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D004337:Drug Carriers; D005260:Female; D005434:Flow Cytometry; D007275:Injections, Intravenous; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism*; D008081:Liposomes / Q000032:analysis; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D010529:Peritoneal Cavity / Q000166:cytology / Q000502:physiology*; D013997:Time Factors
D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin