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 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 exceptionally photostable near infrared (NIR) croconaine dye (CR) via a glutathione (GSH)-sensitive disulfide linker. Compared with CPT, our novel trimeric CR-(SS-CPT) is more hydrophobic and bulky, making it highly efficient to be encapsulated into biocompatible polymeric nanocarriers. 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 bonds, which makes the release of CPT even more controllable. We further loaded CR-(SS-CPT) 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 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 efficiency of CPT, but also provided an “all in one” nanomedicine for imaging-guided dual modality therapy.