Programmable Therapeutic Nanoscale Covalent Organic Framework for Photodynamic Therapy and Hypoxia-Activated Cascade Chemotherapy

Photodynamic therapy (PDT) is a promising cancer treatment with high temporal and spatial resolution. Under laser irradiation, a photosensitizer converts oxygen into singlet oxygen (1O2) to cause cell death. However, because the hypoxic conditions of solid tumor microenvironment limit the generation of 1O2, clinical PDT only achieves limited cancer treatment effect, and due to the consumption of oxygen in the treatment process, PDT process often leads to a more hypoxic microenvironment. To overcome this problem, several strategies have been developed to improve tumor oxygenation. Among them, PDT combined with hypoxia-activated prodrugs to overcome hypoxic environment has recently been explored as a promising clinical method for cancer treatment. Herein, a multifunctional nanoscale covalent organic framework (COF) platform by crosslinking the photosensitizer tetra(4-hydroxyphenyl)porphine (THPP) and a 1O2 -cleavable thioketal (TK) linker has been synthesized, with a high porphyrin loading capacity, which greatly improves the generation efficiency of reactive oxygen species (ROS) and contributes to PDT. As-synthesized THPPTK -PEG nanoparticles (NPs) possess a high THPP photosensitizer content and mesoporous structure for further loading the hypoxia-responsive prodrug banoxantrone (AQ4N) into the COF with a high-loading content. The surface of the nanocarriers is decorated with a dense PEG layer to enhance their dispersibility in physiological environments and improve its therapeutic performance. Upon a 660 nm irradiation, such a nanoplatform can efficiently produce cytotoxic 1O2 for PDT. Meanwhile, Oxygen consumption could further aggravate the hypoxic environment of tumor, so as to induce the activation of AQ4N for achieving a programmable hypoxia-activated cascade chemotherapy and an enhanced treatment efficacy.This study not only provides a new nanoplatform for photodynamic-chemical synergistic therapy, but also provides important new insights for the design and development of multifunctional supramolecular drug delivery system.Funding Information: This research was supported by the National Natural Science Foundation of China (51933011, 31971296, 52173150, 51973243), the Guangdong Basic and Applied Basic Research Foundation (2021A1515110091), the Seventh Affiliated Hospital of Sun Yat-sen University Research Start-up Fund of Post-doctoral (ZSQYRSFPD0021).Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: Female Balb/c mice (about 4-6 weeks) were provided by the Guangdong Medical Laboratory Animal Center. All surgical interventions and postoperative animal care procedures of our study were approved by the Institutional Animal Care and Use Committee of the Sun Yat-sen University (Guangzhou, China). All animal experiments complied with the Animal Management Regulations of China (1988, revised 2017) and the Guideline on the Humane Treatment of Laboratory Animals of China (MOST 2006). Access Certificate number of animal experiment Department is 2019-001486. Approval number is SYSU-IACUC-2020-B1228.