Highly temperature-sensitive liposomes based on a thermosensitive block copolymer for tumor-specific chemotherapy.
Recently, we showed that incorporation of poly[2-(2-ethoxy)ethoxyethyl vinyl ether (EOEOVE)], which exhibits a lower critical solution temperature around 40 degrees C, provides temperature-sensitive properties to stable liposomes. In this study, we applied this thermosensitive polymer for preparation of temperature-sensitive liposomes for tumor-specific chemotherapy with doxorubicin (DOX). We prepared liposomes consisting of PEG-lipid, egg yolk phosphatidylcholine, cholesterol and copoly(EOEOVE-block-octadecyl vinyl ether), which was synthesized as poly(EOEOVE) having anchors for fixation onto liposome membrane. The copolymer-incorporated liposomes were stable and retained DOX in their inside below physiological temperatures. However, they exhibited a significant release of encapsulated DOX above 40 degrees C and released DOX almost completely within 1 min at 45 degrees C. The copolymer-modified liposomes exhibited a long circulating property and biodistribution similar to that of PEG-modified liposomes. The copolymer-modified liposomes loaded with DOX were injected intravenously into tumor-bearing mice. Tumor growth was strongly suppressed when the tumor site was heated to 45 degrees C for 10 min at 6-12 h after injection. However, injection of the liposomes exhibited only slight tumor-suppressive effects as long as mild heating was not applied to the target site. The highly temperature-sensitive properties of the copolymer-incorporated liposomes might contribute to establishment of tumor-selective and effective chemotherapy.
Kono
Kenji
K
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka, Japan. kono@chem.osakafu-u.ac.jp
Ozawa
Toshiaki
T
Yoshida
Tomohide
T
Ozaki
Fuminori
F
Ishizaka
Yukihito
Y
Maruyama
Kazuo
K
Kojima
Chie
C
Harada
Atsushi
A
Aoshima
Sadahito
S
D000818:Animals; D004317:Doxorubicin / Q000627:therapeutic use; D006367:HeLa Cells; D006801:Humans; D008081:Liposomes / Q000138:chemical synthesis / Q000737:chemistry*; D008297:Male; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D013696:Temperature
D008081:Liposomes; D011108:Polymers; D004317:Doxorubicin