Programmable therapeutic nanoscale covalent organic framework for photodynamic therapy and hypoxia-activated cascade chemotherapy

Clinical photodynamic therapy (PDT) only has a limited cancer therapeutic effect and typically leads to a more hypoxic milieu owing to the hypoxic conditions of the solid tumor microenvironment that limit the singlet oxygen (1O2), generation. To address this issue, the PDT, in combination with hypoxia-activated prodrugs, has recently been investigated as a possible clinical treatment modality for cancer therapy. By cross-linking the photosensitizer tetra(4-hydroxyphenyl)porphine (THPP) and a 1O2-cleavable thioketal (TK) linker, a multifunctional nanoscale covalent organic framework (COF) platform with a high porphyrin loading capacity was synthesized, which significantly improve the reactive oxygen species (ROS) generation efficiency and contributes to PDT. As-synthesized THPPTK-PEG nanoparticles (NPs) possess a high THPP photosensitizer content and mesoporous structure for further loading of the hypoxia-responsive prodrug banoxantrone (AQ4N) into the COF with a high-loading content. The nano-carriers surfaces are coated with a thick PEG coating to promote their dispersibility in physiological surroundings and therapeutic performance. When exposed to 660 nm radiation, such a nanoplatform can efficiently create cytotoxic 1O2 for PDT. Similarly, oxygen intake may exacerbate the hypoxic environment of the tumor, inducing the activation of AQ4N to achieve hypoxia-activated cascade chemotherapy and increased treatment efficacy. This study provides a new nanoplatform for photodynamic-chemical synergistic therapy and offers critical new insights for designing and developing a multifunctional supramolecular drug delivery system.