Multifunctional Micelles Dually Responsive to Hypoxia and Singlet Oxygen: Enhanced Photodynamic Therapy via Interactively Triggered Photosensitizer Delivery

Abstract

Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from the limited dose accumulation in tumor. Herein, we report dually hypoxia- and singlet oxygen-responsive polymeric micelles to efficiently utilize the photosensitizer deposited in the disease site and hence facilely improve PDT's antitumor efficacy. Tailored methoxy poly(ethylene glycol)-azobenzene-poly(aspartic acid) copolymer conjugate with imidazole as the side chains was synthesized. The conjugate micelles (189 ± 19 nm) obtained by self-assembly could efficiently load a model photosensitizer, chlorin e6 (Ce6) with a loading of 4.1 ± 0.5% (w/w). The facilitated cellular uptake of micelles was achieved by the triggered azobenzene collapse that provoked poly(ethylene glycol) shedding; rapid Ce6 release was enabled by imidazole oxidation that induced micelle disassembly. In addition, the singlet oxygen-mediated cargo release not only addressed the limited diffusion range and short half-life of singlet oxygen but also decreased the oxygen level, which could in turn enhance internalization and increase the intracellular Ce6 concentration. The hypoxia-induced dePEGylation and singlet oxygen-triggered Ce6 release was demonstrated both in aqueous buffer and in Lewis lung carcinoma (LLC) cells. The cellular uptake study demonstrated that the dually responsive micelles could deliver significantly more Ce6 to the cells, which resulted in a substantially improved cytotoxicity. This concurred well with the superior in vivo antitumor ability of micelles in a LLC tumor-bearing mouse model. This study presented an intriguing nanoplatform to realize interactively triggered photosensitizer delivery and improved antitumor PDT efficacy.

Enhancement of Photodynamic Cancer Therapy by Physical and Chemical Factors

“…Liposomes and micelles are artificially developed vessels for drug and nutrient transport;they have been incorporated as away to deliver photosensitizer drugs in PDT. [35] There are many reasons for this,i ncluding their ability to target and release the drugs at specific locations while maintaining protection of the drugs and their biocompatibility. [36] The encapsulated photosensitizer has ah igher uptake ability because its endocytosis is optimized and eventually it is localized in the organelles.…”

Sensors, Imaging Agents, and Theranostics to Help Understand and Treat Reactive Oxygen Species Related Diseases

“…This enabled the ability to deliver and release the anticancer drug camptothecin and photosensitizer zinc phthalocyanine (ZnPc) for dual therapy (PDT and chemotherapy) of lung cancer, triggered by ROS generated upon light irradiation. Zhao and co‐workers have developed nanoparticles responsive to 1 O 2 , which were able to effectively load Ce6 in buffer solution. The photosensitizer was released in Lewis lung carcinoma (LLC) cells, in an LLC tumor‐bearing mouse model and in its isolated organs upon light irradiation to produce ROS, which was additionally tracked by imaging ( Figure ).…”

“…Fluorescent imaging of the tumor and healthy organs in tumor‐bearing mice with DR (dually responsive), SR (singlet oxygen responsive) micelles and Ce6, and imaging of isolated healthy mouse organs and tumor in vitro (below). Reproduced with permission . Copyright 2018, American Chemical Society.…”

Optimierung photodynamischer Krebstherapien auf der Grundlage physikalisch‐chemischer Faktoren

“…[35] Sie haben die Fähigkeit, Wirkstoffe gezielt an einem vordefinierten Ort abzugeben, gleichzeitig schützen sie die Wirkstoffe und sind biokompatibel. [35] Sie haben die Fähigkeit, Wirkstoffe gezielt an einem vordefinierten Ort abzugeben, gleichzeitig schützen sie die Wirkstoffe und sind biokompatibel.…”