title: Light-induced cytosolic activation of reduction-sensitive camptothecin-loaded polymeric micelles for spatiotemporally controlled in vivo chemotherapy.
abstract: 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 in vivo, 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 in vitro and in vivo by real-time confocal laser microscopies, accelerating the drug release from the micelles only in the irradiated tissues. This spatiotemporal switch significantly enhanced the in vivo 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.
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Yen
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.forename: Peng
authors.initials: P
authors.lastname: Mi
authors.forename: Kazuko
authors.initials: K
authors.lastname: Toh
authors.forename: Yu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Xueying
authors.initials: X
authors.lastname: Liu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koori
authors.forename: Ahram
authors.initials: A
authors.lastname: Kim
authors.forename: Kozo
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism*; D008027:Light; D008823:Micelles; D010084:Oxidation-Reduction; D011108:Polymers / Q000737:chemistry*; D051381:Rats
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; D011108:Polymers; D002166:Camptothecin
keywords: Photofrin; camptothecin; glutathione; photochemical internalization; polymeric micelles; reduction-sensitive