Hypoxia- and singlet oxygen-responsive chemo-photodynamic Micelles featured with glutathione depletion and aldehyde production

Abstract

Triggered drug release from anti-tumor nanomedicine is an efficient approach to address the dilemma of systemic nanocarrier stability and on-demand drug liberation in tumor sites. Combinational drug delivery has been a useful means to enhance antitumor efficacy and reduce adverse effects. We report a multifunctional micelle for dually hypoxia- and singlet oxygen-responsive integration of chemotherapy and photodynamic therapy. The micelles were made of a nitroimidazole (NI)-bearing polymer; doxorubicin (Dox) and chlorin e6 (Ce6) were selected as the model chemodrug and photosensitizer, respectively. The co-delivery micelles displayed a hydrodynamic size of 138.5 ± 3.6 nm with the cargo loading at 2.5 ± 0.2% w/w (Dox) and 1.8 ± 0.3% w/w (Ce6), respectively. Under hypoxia (e.g. tumor microenvironment), the NI moiety was bio-reduced to aminoimidazole, resulting in micelle disassembly, rapid cargo release, and glutathione (GSH) depletion. Upon laser irradiation, the singlet oxygen produced by Ce6 caused the oxidation of NI, leading to micelle collapse, facilitated payload release, and the production of aldehyde end-products. Rapid drug release enabled the fast onset of the therapeutic action. GSH depletion and aldehyde production would provide a supplementary effect to enhance the anti-tumor efficacy of co-delivery micelles. This proof-of-concept was demonstrated in a murine mammary carcinoma cell line (4T1) in vitro as well as in a 4T1 tumor-bearing mouse model in vivo. This study expanded the function of traditional stimuli-responsive nanomedicines by utilizing the multifunctional NI moiety that could realize both triggered release and the amplified anti-tumor effect via the auxiliary action of GSH depletion and aldehyde production.