Mannose functionalized small molecule nanodrug self-assembled from amphiphilic prodrug connected by disulfide bonds for synergistic cancer chemotherapy and photodynamic/photothermal therapy.

Compared to conventional nanocarrier-based drug delivery technology, small-molecule-assembled nanomaterials provide various advantages, including higher drug loading efficiency, lower excipient-related toxicity, and a simpler formulation process. Our research constructed a mannonse-modified small-molecule-assembled nanodrug for synergistic photodynamic/chemotherapy against A549 cancer cells. The hydrophobic hypoxic-activated agent tirapazamine (TPZ) and a hydrophilic fluorescence probe Cyanine 3 (Cy3) constitute this amphiphilic prodrug via a glutathione (GSH)-responsive linkage, which could self-assemble into stable nanoparticles (NPs) and encapsulate a newly synthesized photosensitizer (SeBDP). To enhance the tumor targeting capability, we introduced a tumor-targeted nanodrug SeBDP@TPZ-S-S-Cy/Man NPs by co-assembling mannose-modified lipid (DSPE-PEG-Man). The GSH-responsive linkage of TPZ-S-S-Cy can be rapidly cleaved by GSH to release the therapeutic agents and fluorescent molecule. The released SeBDP generate reactive oxygen species (ROS) to specifically kill cancer cells and elevate hypoxia, thereby enhancing the cytotoxicity of TPZ. SeBDP@TPZ-S-S-Cy/Man NPs exhibited high selectivity and efficiency for in vivo combination therapy without adverse effects to normal tissues. Our findings demonstrate that SeBDP@TPZ-S-S-Cy/Man NPs have great potential for enhancing cancer treatment both in vitro and in vivo by combining an oxygen depletion prodrug with a hypoxia-activated antitumor agent. Thus, the GSH-sensitive self-assembled nanodrug from an amphiphilic hypoxia-activated prodrug, could serve as a potential drug carrier in targeted synergistic cancer therapy.