Light-programmable, high-drug-loading nanomedicine based on dimeric camptothecin

Efficient nano-encapsulation of highly hydrophobic chemotherapeutic drugs and spatiotemporal control over drug release remain critical challenges for nanomedicine. Herein, we designed light-programmable, high-drug-loading PEG-PLA nanoparticles (hQCC NPs) to co-encapsulate both the photosensitizer (Ce6) and a hypoxia-activatable dimeric camptothecin (CPT) prodrug (hQ-CPT₂) for synergistic antitumor treatment. In particular, quinone-modified hQ-CPT₂ is designed, which can disrupt the strong intermolecular interactions among CPT molecules. As a result, the fast aggregation of CPT during nanoformulation is dramatically inhibited, accounting for an ultra-high drug-loading capacity (46.8%) and drug-loading efficiency (nearly 100%). Under light irradiation, Ce6-mediated photodynamic therapy (PDT) can not only generate reactive oxygen species (ROS) to kill tumor cells, but also aggravate the intratumoral hypoxia level to facilitate CPT release from the hQCC NPs. Thus, Ce6-mediated PDT synergizes with CPT-mediated chemotherapy to enable pronounced antitumor efficacy in 4T1- and MCF-7 mammary xenograft tumor-bearing mice. Meanwhile, the released CPT inhibited PDT-induced upregulation of hypoxia-inducible factor-1α to prevent tumor metastasis. Moreover, because of the spatiotemporally controlled CPT release profile, hQCC NPs induced minimal off-target toxicity in vivo. This study presents a rationally engineered nanoplatform that converts a typically detrimental consequence of PDT, tumor hypoxia, into a therapeutic advantage, offering a promising strategy for programmable combination cancer therapy.