Porphy-based drug-delivery nanoparticles for photodynamic therapy and photoactivated cascade chemotherapy

To address the systemic toxicity of the chemotherapeutic drug doxorubicin (DOX) and improve its targeted delivery efficiency for leukemia treatment, this study developed a folic acid (FA) receptor-targeted, photo-responsive nanodrug delivery system. The system was examined for its in vitro and in vivo antitumor performance against the K562 leukemia cell line. The core of this platform is a mesoporous covalent organic framework (COF), THPP_TK, synthesized through the following steps: (1) preparation of a singlet oxygen (¹O₂)-sensitive thioketal (TK) linker; (2) formation of the THPP_TK COF via esterification between TK and 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin (THPP); (3) surface modification of THPP_TK using FA-conjugated polyethylene glycol (FA-PEG), acting as both a reaction terminator and hydrophilic coating; (4) loading of DOX into the COF mesopores to obtain the final nanodrug DOX@THPP_TK-PEG-FA. This system employs a dual photoactivation process: under 660 nm laser irradiation, the THPP component generates ¹O₂ for photodynamic therapy (PDT), while also initiating cleavage of the TK linker to enable controlled release of DOX for chemotherapy (CT). This cascade mechanism strengthens the overall antitumor response. Studies in a Balb/c nude mouse subcutaneous xenograft model using K562 cells confirmed the nanosystem's strong tumor-targeting ability, notable in vitro and in vivo antitumor activity, and reduced DOX-associated systemic toxicity.