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Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: A possible mechanism and the potential for clinical application
Faculty
Pharmacy
Year:
2012
Type of Publication:
Article
Pages:
176-183
Authors:
Ichihara, Masako, Ishida, Tatsuhiro, Kiwada, Hiroshi, Abu Lila, Amr S, Eldin, Noha Essam
DOI:
10.1016/j.ijpharm.2012.08.030
Journal:
INTERNATIONAL JOURNAL OF PHARMACEUTICS ELSEVIER SCIENCE BV
Volume:
438
Research Area:
Pharmacology \& Pharmacy
ISSN
ISI:000310763700020
Keywords :
ABC phenomenon, Antitumor activity, Apoptosis, Oxaliplatin, PEG-coated cationic liposomes, Sequential administration
Abstract:
We previously developed a PEG-coated cationic liposome that enabled dual targeting delivery of oxaliplatin (l-OHP) to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation consequently elicited potent antitumor efficacy in a murine solid tumor model after 3 sequential injections. However, the probable mechanism(s) for this enhanced antitumor activity has not been fully elucidated. In the present study, therefore, the changes in tumor microenvironment induced by sequential administration of liposomal l-OHP were investigated, with emphasis on its impact to the intratumoral localization of the subsequently injected dose. In addition, the potential for anti-PEG IgM production upon repeated administration of liposomal l-OHP-containing PEGylated lipid was clearly revealed. Two sequential injections of liposomal l-OHP induced superior apoptotic activity in tumor tissue and thus resulted in broader intratumor distribution of the subsequent test dose of PEG-coated cationic liposomes, compared with a single injection of liposomal l-OHP. In addition, it was confirmed that repeated administration of liposomal l-OHP did not induce a significant anti-PEG IgM response, indicating that l-OHP encapsulated in PEG-coated liposomes was efficient in abrogating the ABC phenomenon. These results suggest that sequential treatment strategies with liposomal cytotoxic agents might be superior to mono-treatment strategies in achieving alterations in the tumor microenvironment and maintaining/restoring the pharmacokinetics of the formulation, and, therefore, would result in substantial therapeutic efficacy. (C) 2012 Elsevier B.V. All rights reserved.
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