Intelligent Nanosystem for Light-Activated Synergistic Multimodal Therapy of Drug-Resistant Breast Cancer

Chemotherapy as a primary treatment for breast cancer is limited due to drug resistance in clinical treatment. The rapid proliferation and invasive biological properties of breast cancer, resulting in intratumoral hypoxia and adaptive antioxidation, are common manifestations of drug-resistant breast cancer. Photodynamic therapy is a potential strategy to overcome drug resistance, but its effectiveness is often limited by tumor hypoxia. In order to overcome the problem of tumor hypoxia and improve the effectiveness of photodynamic therapy, a strategy that employs ZIF-90 nanoparticles simultaneously delivering a hypoxia-induced drug (TPZ) and photosensitizer Ce6 labeled antisense nucleic acid (Ce6-G3139) into breast cancer cells was developed. Owing to the pH responsiveness of ZIF-90, TPZ and Ce6-G3139 are able to be efficiently released inside the tumor microenvironment. First, Ce6-G3139 can perform gene therapy, downregulating the expression of antiapoptotic protein BCL-2 and accelerating cell apoptosis. On the other hand, photosensitizer Ce6 can undergo photodynamic therapy (PDT), producing reactive oxygen species that interfere with the apoptosis mechanism of cells. More importantly, although the continuous consumption of oxygen in PDT aggravates the hypoxic environment of the tumor, the hypoxic-induced chemotherapy drug was further activated. Our research results indicate that the designed strategy targeting the hypoxic microenvironment of drug-resistant breast cancer exhibits significant anticancer effects both in vitro and in vivo, favoring the development of a PDT treatment paradigm that is effective against drug resistance under hypoxic conditions.