Accumulation of Liposomal Lipid and Encapsulated Doxorubicin in Murine Lewis Lung Carcinoma: The Lack of Beneficial Effects by Coating Liposomes with Poly(ethylene glycol)

• Published in: The Journal of pharmacology and experimental therapeutics 1997-03, Vol.280 (3), p.1319-1327
• Main Authors: Parr, M J, Masin, D, Cullis, P R, Bally, M B
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - blood; Antibiotics, Antineoplastic - pharmacokinetics; Carcinoma, Lewis Lung - metabolism; Cell Division - drug effects; Dose-Response Relationship, Drug; Doxorubicin - administration & dosage; Doxorubicin - blood; Doxorubicin - pharmacokinetics; Drug Carriers; Female; Liposomes; Mice; Polyethylene Glycols
• ISSN: 0022-3565; 1521-0103

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 μmol·ml −1 ·h, 50 μmol·ml −1 ·h and 78 μmol·ml −1 ·h, respectively. Maximum drug levels achieved in the tumors were similar for both liposomal doxorubicin formulations, 140 μg (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 μg/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.