Redox-Responsive Dual Chemophotothermal Therapeutic Nanomedicine for Imaging-Guided Combinational Therapy

Chemotherapy is currently the major therapeutic method against cancer. However, chemo drugs are usually lacking in the specificity towards cancer cells over normal cells. In this study, we prepared a novel multifunctional trimeric prodrug by linking the chemo drug camptothecin (CPT) and the exceptional photostable near infrared (NIR) croconaine dye (CR) via a glutathione (GSH)-sensitive disulfide linker. Compared with CPT, our novel trimeric CR-(SS-CPT)₂ is more hydrophobic and bulky, making it highly effcient to be encapsulated into biocompatible polymeric nanocarrier. The prodrug underwent rapid drug release specifically in cancer cells with high GSH concentration. The hyperthermia produced by CR upon laser irradiation could further accelerate the break of disulfide bond, which makes the release of CPT even more controllable. We further loaded the CR-(SS-CPT)₂ into folate modified lipid-polymer nanoparticles, which demonstrated high in vivo tumor accumulation and retention. The biodistribution of these nanoparticles can be directly monitored in real time via NIR fluorescence and photoacoustic imaging. Under the imaging guided chemo- and photothermal- synergistic therapy, the tumors were completely ablated with no recurrence. The design not only highly enhanced the therapeutic specificity and effeciency of CPT, but also provide a "all in one" nanomedicine for imaging-guided dual modality therapy.