Intracellularly Acid Switchable Multifunctional Micelles for Combinational Photo/Chemotherapy of the Drug Resistant Tumor.
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.
ACS nano