Oxaliplatin encapsulated in PEG-coated cationic liposomes induces significant tumor growth suppression via a dual-targeting approach in a murine solid tumor model.
We recently designed a PEG-coated cationic liposome targeted to angiogenic vessels and showed, in a murine dorsal air sac model, potent anti-angiogenic activity of an oxaliplatin (l-OHP) formulation of this liposome. In the present study, we extended the l-OHP formulation to a murine tumor-xenograft model. Following three injections, l-OHP containing PEG-coated cationic liposomes showed substantial tumor growth suppression and increased survival time of tumor-bearing mice without apparent side effects, compared with other l-OHP containing PEG-coated neutral liposomes and free l-OHP. In vivo imaging showed a preferential tumor accumulation and a broader distribution of PEG-coated cationic liposomes, compared with PEG-coated neutral liposomes. In addition, PEG-coated cationic liposomes delivered larger amounts of l-OHP into the tumor tissue than other l-OHP formulations, correlating with its antitumor efficiency. In vitro studies indicated that PEG-coated cationic liposomes were internalized not only by tumor cells but also by endothelial cells, and consequently its l-OHP formulation displayed higher cytotoxicity towards both cell types as compared with l-OHP containing PEG-coated neutral liposomes. In summary, l-OHP containing PEG-coated cationic liposomes induced significant tumor growth suppression, presumably by delivering encapsulated l-OHP into both tumor endothelial cells and tumor cells. Such dual targeting approach, i.e. vascular-targeting and tumor-targeting with a single liposomal l-OHP formulation, may have great potential for overcoming some major limitations in conventional chemotherapy.
Abu Lila
Amr S
AS
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.
Kizuki
Shinji
S
Doi
Yusuke
Y
Suzuki
Takuya
T
Ishida
Tatsuhiro
T
Kiwada
Hiroshi
H
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D002412:Cations / Q000627:therapeutic use*; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000627:therapeutic use; D004304:Dosage Forms; D004337:Drug Carriers / Q000378:metabolism / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005079:Excipients / Q000378:metabolism / Q000627:therapeutic use; D008081:Liposomes / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000627:therapeutic use; D000077150:Oxaliplatin; D011092:Polyethylene Glycols / Q000737:chemistry / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D002412:Cations; D020099:Coated Materials, Biocompatible; D004304:Dosage Forms; D004337:Drug Carriers; D005079:Excipients; D008081:Liposomes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011092:Polyethylene Glycols