Multifunctional liposomes having target specificity, temperature-triggered release, and near-infrared fluorescence imaging for tumor-specific chemotherapy

• Published in: Journal of controlled release 2015-10, Vol.216, p.69-77
• Main Authors: Kono, Kenji, Takashima, Munenobu, Yuba, Eiji, Harada, Atsushi, Hiramatsu, Yoshie, Kitagawa, Hiroyuki, Otani, Takayuki, Maruyama, Kazuo, Aoshima, Sadahito
• Format: Article
• Language: English
• Subjects: Animals; Antibody; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Chemotherapy; Delayed-Action Preparations; Doxorubicin; Drug delivery; Drug Delivery Systems - methods; Electrochemistry; Female; Fluorescence; Infrared Rays; Liposome; Liposomes - chemistry; Mice; Neoplasms - drug therapy; Neoplasms - pathology; Phosphatidylcholines - chemistry; Polyethylene Glycols; Receptor, ErbB-2 - drug effects; Receptor, ErbB-2 - genetics; Temperature; Temperature-sensitive; Trastuzumab - administration & dosage; Trastuzumab - therapeutic use
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2015.08.005

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 5min. 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 48h, 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 10min 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. [Display omitted]