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.