College of Pharmacy, Korea University, 2511 Sejongro, Sejong 30019, Republic of Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul 151-742, Republic of Korea.
J Control Release. 2017 Jun 10;255:258-269. doi: 10.1016/j.jconrel.2017.04.039. Epub 2017 Apr 26.
Photo-induced apoptosis-targeted chemotherapy (PIATC) was designed and characterized to propose a new protocol for improved chemotherapy. Intratumoral injection was selected as the mode of administration of the anticancer drug, doxorubicin (DOX). To extend the retention time of DOX at the tumor parenchyma, in-situ gel formation was induced through the sol-gel transition of the Pluronic NPs containing a prodrug of DOX or a photosensitizer. The prodrug (DEVD-S-DOX) was designed to be inactive with a peptide moiety (Aspartic acid-Glutamic acid-Valine-Aspartic acid: DEVD) linked to DOX and to be cleaved into free DOX by caspase-3 expressed with apoptosis. For reactive oxygen species (ROS)-mediated apoptosis, photo-irradiation with methylene blue (MB, photosensitizer) was utilized. The sol-gel transition of the Pluronic NPs containing reactive species, DEVD-S-DOX or MB, was examined by measuring the cloud point and the gel strength in response to temperature change. ROS-mediated apoptosis was observed by measuring the ROS and membrane integrity with induced apoptosis. The in vivo antitumor efficacy of PIATC was measured with a cardiotoxicity assay in tumor-bearing mice.
光诱导凋亡靶向化疗（PIATC）被设计和表征，以提出一种新的化疗改进方案。选择瘤内注射作为抗癌药物阿霉素（DOX）的给药方式。为了延长 DOX 在肿瘤实质中的滞留时间，通过含有 DOX 前药或光敏剂的 Pluronic NPs 的溶胶-凝胶转变来诱导原位凝胶形成。前药（DEVD-S-DOX）设计为无活性，具有与 DOX 连接的肽部分（天冬氨酸-谷氨酸-缬氨酸-天冬氨酸：DEVD），并通过表达凋亡的 caspase-3 切割成游离 DOX。为了进行活性氧（ROS）介导的凋亡，利用亚甲蓝（MB，光敏剂）进行光照射。通过测量浊点和凝胶强度来检查含有反应性物质、DEVD-S-DOX 或 MB 的 Pluronic NPs 的溶胶-凝胶转变，以响应温度变化。通过诱导凋亡测量 ROS 和膜完整性来观察 ROS 介导的凋亡。通过在荷瘤小鼠中的心脏毒性测定测量 PIATC 的体内抗肿瘤功效。
