Light-enhanced hypoxia-responsive and azobenzene cleavage-triggered size-shrinkable micelles for synergistic photodynamic therapy and chemotherapy

Abstract

Hypoxia is an important pathological phenomenon due to uncontrolled cancer cell proliferation and insufficient blood flow, which can be used to design hypoxia-responsive nanocarriers for the intelligent treatment of tumor. However, it is difficult to obtain the response of hypoxia-responsive polymers corresponding to the degree of hypoxia in the tumor sites. Therefore, hypoxia-responsive azobenzene-centered copolymers polyoligo (ethylene glycol) methacrylate-block-poly(ε-caprolactone)-azobenzene-poly(ε-caprolactone)-block-poly oligo (ethylene glycol) (POEGMA-b-PCL-Azo-PCL-b-POEGMA) were synthesized and further self-assembled into spherical micelles. Doxorubicin (DOX) and chlorine e6 (Ce6) were encapsulated inside the micelles. The photodynamic therapy (PDT) of Ce6 could be applied to further amplify the hypoxia condition in the tumor sites through oxygen consumption on laser irradiation (660 nm). Under this condition, the DOX/Ce6-loaded micelles progressively formed spherical micelles with a small size due to the cleavage of azobenzene, thus allowing the controlled release of DOX. The formed smaller micelles could significantly avoid the formation of large aggregates, which is beneficial for clinical application. Moreover, Ce6 would continuously convert oxygen to singlet oxygen (¹O₂), thus showing toxicity to cancer cells. Both in vitro and intracellular studies confirmed that our “all-in-one” micelles showed a superior synergistic effect of photodynamic therapy and chemotherapy.