10.1021/nn504836s.s001 Hung-Chi Yen Hung-Chi Yen Horacio Cabral Horacio Cabral Peng Mi Peng Mi Kazuko Toh Kazuko Toh Yu Matsumoto Yu Matsumoto Xueying Liu Xueying Liu Hiroshi Koori Hiroshi Koori Ahram Kim Ahram Kim Kozo Miyazaki Kozo Miyazaki Yutaka Miura Yutaka Miura Nobuhiro Nishiyama Nobuhiro Nishiyama Kazunori Kataoka Kazunori Kataoka Light-Induced Cytosolic Activation of Reduction-Sensitive Camptothecin-Loaded Polymeric Micelles for Spatiotemporally Controlled <i>in Vivo</i> Chemotherapy American Chemical Society 2014 cytosol spatiotemporal dose CPT drug release vivo antitumor efficacy permeabilization micelle permeabilizing endosomal compartments photosensitizer function nanomedicine tissue confocal laser microscopies rat urothelial carcinoma 2014-11-25 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Light_Induced_Cytosolic_Activation_of_Reduction_Sensitive_Camptothecin_Loaded_Polymeric_Micelles_for_Spatiotemporally_Controlled_i_in_Vivo_i_Chemotherapy/2232214 Nanomedicines capable of smart operation at the targeted site have the potential to achieve the utmost therapeutic benefits. Providing nanomedicines that respond to endogenous stimuli with an additional external trigger may improve the spatiotemporal control of their functions, while avoiding drawbacks from their inherent tissue distribution. Herein, by exploiting the permeabilization of endosomes induced by photosensitizer agents upon light irradiation, we complemented the intracellular action of polymeric micelles incorporating camptothecin (CPT), which can sharply release the loaded drug in response to the reductive conditions of the cytosol, as an effective strategy for precisely controlling the function of these nanomedicines <i>in vivo</i>, while advancing toward a light-activated chemotherapy. These camptothecin-loaded micelles (CPT/m) were stable in the bloodstream, with minimal drug release in extracellular conditions, leading to prolonged blood circulation and high accumulation in xenografts of rat urothelial carcinoma. With the induction of endosomal permeabilization with the clinically approved photosensitizer, Photofrin, the CPT/m escaped from the endocytic vesicles of cancer cells into the cytosol, as confirmed both <i>in vitro</i> and <i>in vivo</i> by real-time confocal laser microscopies, accelerating the drug release from the micelles only in the irradiated tissues. This spatiotemporal switch significantly enhanced the <i>in vivo</i> antitumor efficacy of CPT/m without eliciting any toxicity, even at a dose 10-fold higher than the maximum tolerated dose of free CPT. Our results indicate the potential of reduction-sensitive drug-loaded polymeric micelles for developing safe chemotherapies after activation by remote triggers, such as light, which are capable of permeabilizing endosomal compartments.