Multifunctional liposomes having target specificity, temperature-triggered release, and near-infrared fluorescence imaging for tumor-specific chemotherapy.
We designed functional liposomes with target specificity, temperature-triggered drug release, and near-infrared fluorescence imaging. We prepared the liposomes by triple functionalization of stable pegylated liposomes with thermosensitive poly[2-(2-ethoxy)ethoxyethyl vinyl ether] chains (lower critical solution temperature around 38 °C) with conjugation of antibody trastuzumab (Herceptin, HER), which targets human epidermal growth factor 2, and with incorporation of indocyanine green for near-infrared fluorescence imaging. The liposomes retained DOX in the interior below physiological temperature but released DOX immediately at temperatures higher than 40 °C. The liposomes exhibited excellent ability for association and internalization to target cells overexpressing Her-2, such as SK-OV3 and SB-BR3 cells, and killed these cells when heated at 45 °C for 5 min. When administered intravenously to mice bearing SK-OV3 tumor, the liposomes having HER accumulated in the tumor more efficiently than the liposomes without HER. They stayed there more than 48 h, as judged with near-infrared fluorescence imaging. Furthermore, when the tumor sites of the mice being administered with the DOX-loaded liposomes were heated mildly at 44°C for 10 min at 7h after administration, tumor growth was suppressed strongly thereafter. Treatment with the HER-conjugated liposomes produced more efficient tumor-suppressive effects. Results demonstrate that the synergy of target-specific association, temperature-triggered drug release, and imaging is important for efficient tumor chemotherapy.
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1, Gakuen-cho, Sakai, Osaka 599-8531, Japan. Electronic address: kono@chem.osakafu-u.ac.jp.
Kenji
K
Kono
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1, Gakuen-cho, Sakai, Osaka 599-8531, Japan.
Munenobu
M
Takashima
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1, Gakuen-cho, Sakai, Osaka 599-8531, Japan.
Eiji
E
Yuba
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1, Gakuen-cho, Sakai, Osaka 599-8531, Japan.
Atsushi
A
Harada
R&D Center, Katayama Chemical Industries Co. LTD, 4-1-7 Ina, Minoh, Osaka 562-0015, Japan.
Yoshie
Y
Hiramatsu
R&D Center, Katayama Chemical Industries Co. LTD, 4-1-7 Ina, Minoh, Osaka 562-0015, Japan.
Hiroyuki
H
Kitagawa
R&D Center, Katayama Chemical Industries Co. LTD, 4-1-7 Ina, Minoh, Osaka 562-0015, Japan.
Takayuki
T
Otani
Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
Kazuo
K
Maruyama
Department of Macromolecular Science, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan.
Sadahito
S
Aoshima
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems / Q000379:methods*; D004563:Electrochemistry; D005260:Female; D005453:Fluorescence; D007259:Infrared Rays; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000235:genetics; D013696:Temperature; D000068878:Trastuzumab / Q000008:administration & dosage / Q000627:therapeutic use
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D008081:Liposomes; D010713:Phosphatidylcholines; D011092:Polyethylene Glycols; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
Antibody; Chemotherapy; Doxorubicin; Drug delivery; Liposome; Temperature-sensitive