title: Accumulation of liposomal lipid and encapsulated doxorubicin in murine Lewis lung carcinoma: the lack of beneficial effects by coating liposomes with poly(ethylene glycol).
abstract: The efficiency of drug accumulation in tumors was measured after intravenous administration of doxorubicin encapsulated in distearoyl phosphatidylcholine/cholesterol liposomes prepared in the presence or absence of 5 mol % polyethylene glycol-modified phosphatidylethanolamine (PEG-PE). These liposomal formulations of doxorubicin were administered at the maximum tolerated dose in female BDF-1 mice bearing subcutaneously established Lewis Lung carcinoma. The parameters used to determine tumor targeting efficiency (T(e)) included area under the doxorubicin plasma (AUC(P)) and tumor (AUC(T)) concentration-time curves. Extended time-course studies evaluating lipid and drug levels in plasma and tumors 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 doxorubicin encapsulated in distearoyl phosphatidylcholine/cholesterol/PEG-PE-stabilized liposomes were 0.087 micromol x ml(-1) x h, 50 micromol x ml(-1) x h and 78 micromol x ml(-1) x h, respectively. Maximum drug levels achieved in the tumors were similar for both liposomal doxorubicin formulations, 140 microg (250 nmol)/g tumor; however, this level was achieved faster when the liposomes did not contain PEG-PE. Maximum levels measured after administration of free drug were less than 5 microg/g tumor, and these were achieved within 15 min. The results suggest that some of the benefits associated with the use of PEG-modified liposomes, such as increased blood levels and enhanced circulation lifetime, may be of little advantage in terms of maximizing liposomal drug accumulation in sites of tumor growth.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Parr
authors.forename: D
authors.initials: D
authors.lastname: Masin
authors.forename: P R
authors.initials: PR
authors.lastname: Cullis
authors.forename: M B
authors.initials: MB
authors.lastname: Bally
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D018827:Carcinoma, Lewis Lung / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004337:Drug Carriers; D005260:Female; D008081:Liposomes; D051379:Mice; D011092:Polyethylene Glycols
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin