Affiliation:
1. State Key Laboratory of Pharmaceutical Biotechnology The University of Hong Kong Hong Kong 999077 China
2. Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong 999077 China
3. Dr. Li Dak‐Sum Research Centre The University of Hong Kong Hong Kong 999077 China
Abstract
AbstractConventional photodynamic therapy (PDT) in cancer treatment needs to utilize oxygen to produce reactive oxygen species to eliminate malignant tissues. However, oxygen consumption in tumor microenvironment exacerbates cancer cell hypoxia and may promote vasculature angiogenesis. Since the mammalian target of rapamycin (mTOR) signaling pathway plays a vital role in endothelial cell proliferation and fibrosis, mTOR inhibitor drugs hold the potential to reverse hypoxia‐evoked angiogenesis for improved PDT effect. In this study, a carrier‐free nanodrug formulation composed of Torin 1 as mTORC1/C2 dual inhibitor and Verteporfin as a photosensitizer and Yes‐associated protein inhibitor is developed. These two drug molecules can self‐assemble into stable nanoparticles through π–π stacking and hydrophobic interactions with good long‐term stability. The nanodrugs can prompt synergistic apoptosis, combinational anti‐angiogenesis, and strong immunogenic cell death effects upon near‐infrared light irradiation in vitro. Furthermore, the nanosystem also exhibits improved antitumor effect, anti‐cancer immune response, and distant tumor inhibition through tumor microenvironment remodeling in vivo. In this way, the nanodrugs can reverse PDT‐elicited angiogenesis and promote cancer immunotherapy to eliminate tumor tissues and prevent metastasis. This nanosystem provides insights into integrating mTOR inhibitors and photosensitizers for safe and effective breast cancer treatment in clinical settings.
Funder
National Natural Science Foundation of China