title: Intracellularly Acid-Switchable Multifunctional Micelles for Combinational Photo/Chemotherapy of the Drug-Resistant Tumor.
abstract: The intrinsic or acquired drug resistance is the main challenge for cancer chemotherapy today. So far, many nanosized drug delivery systems (NDDS) have been exploited to combat cancer drug resistance. However, the therapy efficacy of current NDDS is severely impaired by the limited tumor penetration of the nanoparticles due to the existence of physiological and pathological barriers in the solid tumor. In this study, we report on the design and fabrication of intracellularly acid-switchable multifunctional micelles for combinational photo- and chemotherapy of the drug-resistant tumor. The micelles were composed of a pH-responsive diblock copolymer, a photosensitizer, and a polymeric prodrug of doxorubicin. The micelle displayed silenced fluorescence and photoactivity during the blood circulation and switched to an active state in weakly acid conditions (i.e., pH ≤ 6.2) in the endocytic vesicles to dramatically induce a 7.5-fold increase of the fluorescence signal for fluorescence imaging. Upon near-infrared (NIR) laser irradiation, the micelle induced notable reactive oxygen species generation to trigger cytosol release of the chemotherapeutics and perform photodynamic therapy (PDT). Moreover, the micelle efficiently converted the NIR light to local heat for enhancing tumor penetration of the anticancer drug, tumor specific photothermal therapy, and photoacoustic (PA) imaging. Furthermore, the micelles could generate amplified magnetic resonance (MR) signal in an acidic microenvironment to perform MR imaging. Collectively, this study presents a robust nanoplatform for multimodal imaging and combinational therapy of the drug-resistant tumor, which might provide an insight for developing polymer-based NDDS for cancer therapy.
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Tingting
authors: T
authors: Wang
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Dangge
authors: D
authors: Wang
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Haijun
authors: H
authors: Yu
authors: Department of Nuclear Medicine, Fudan University Shanghai Cancer Center , Shanghai 200032, China.
authors: Mingwei
authors: M
authors: Wang
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Jianping
authors: J
authors: Liu
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Bing
authors: B
authors: Feng
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Fangyuan
authors: F
authors: Zhou
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Qi
authors: Q
authors: Yin
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Zhiwen
authors: Z
authors: Zhang
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Yongzhuo
authors: Y
authors: Huang
authors: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors: Yaping
authors: Y
authors: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects* / Q000473:pathology; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D064847:Multimodal Imaging; D053758:Nanoparticles / Q000737:chemistry; D061848:Optical Imaging; D061088:Photoacoustic Techniques; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D008823:Micelles; D017319:Photosensitizing Agents; D004317:Doxorubicin
keywords: acid-switchable micelles; combinational therapy; drug resistance; multimodal imaging; tissue penetration