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Vol. 280, Issue 3, 1319-1327, 1997
Department of Biochemistry and Molecular Biology, University of
British Columbia, Medical Science Block C, Vancouver, British Columbia,
Canada V6T 1Z3 (M.J.P., P.R.C.) and
Division of Medical Oncology,
Section of Advanced Therapeutics, British Columbia Cancer Agency,
Vancouver, British Columbia, Canada V5Z 4E6 (D.M., M.B.B.)
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
(Te) included area under the doxorubicin plasma
(AUCP) and tumor (AUCT) concentration-time
curves. Extended time-course studies evaluating lipid and drug levels
in plasma and tumors during 7 days after administration indicated that
the Te (AUCT/AUCP) was greater for
liposomes that did not contain PEG-PE. The AUCP 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·ml1·h and
78 µmol·ml1·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.
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