Oxaliplatin targeting to angiogenic vessels by PEGylated cationic liposomes suppresses the angiogenesis in a dorsal air sac mouse model.
Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum, l-OHP) is a third-generation platinum analogue with proven anti-tumor activity against many tumor cell lines, however it does not show sufficient anti-tumor activity in vivo when used alone. In order to overcome this problem and to achieve an anti-angiogenic therapy with l-OHP, the drug was encapsulated into PEG-coated cationic liposomes, which were designed to target the newly formed vessels, and its anti-angiogenic activity was evaluated in an in vivo mouse dorsal air sac (DAS) assay. For the DAS assay, chambers filled with tumor cells were implanted underneath the dorsal skin. l-OHP encapsulated in PEG-coated cationic liposomes (5 mg/kg mice) was intravenously injected once on day 1, 2, 3 or 4 after chamber implantation. On the fifth day after chamber implantation, animals were sacrificed and tumor-angiogenesis was evaluated. Liposome-encapsulated l-OHP completely suppressed angiogenesis in the skin when it was administered day 3 after chamber implantation. Under similar experimental conditions, neither l-OHP encapsulated in PEG-coated neutral liposomes, nor free l-OHP, nor "empty" (no drug containing) PEG-coated cationic liposomes showed such strong suppressive effect. The present study suggests that the liposomal formulation of l-OHP, which targeted to angiogenic vessels, has a remarkable in vivo anti-angiogenic activity and the formulation may become a promising novel approach to achieve anti-angiogenic therapy.
Abu-Lila
Amr
A
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
Suzuki
Takuya
T
Doi
Yusuke
Y
Ishida
Tatsuhiro
T
Kiwada
Hiroshi
H
D000400:Air Sacs / Q000187:drug effects / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D004912:Erythrocytes / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000077150:Oxaliplatin; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D008081:Liposomes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011092:Polyethylene Glycols