A targeting nanoplatform for chemo-photothermal synergistic therapy of small-cell lung cancer

Abstract The chemo-photothermal cotherapy has created a breakthrough in cancer treatment, but the precise delivery of drugs to tumor sites and the thermoresistance of tumors remain major challenges in photothermal therapy (PTT). Due to its overexpression in small cell lung cancer (SCLC) and limited normal tissue expression, Somatostatin receptor 2 (SSTR2) is proposed as an ideal target for the precise treatment of SCLC. We first developed a novel anti-SSTR2 monoclonal antibody (MAb), which showed strong and specific affinity toward SSTR2 receptor overexpressed on SCLC cells. Then, a targeting nano-drug delivery system comprising anti-SSTR2 MAb surface-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles co-encapsulating Cypate and gambogic acid (GA) is prepared for achieving specific tumor targeting and chemo-photothermal combination therapy. The formed SGCPNs nanoparticles demonstrated excellent monodispersity, physiological stability, preferable biocompatibility, and resultant efficient photothermal conversion efficacy. Confocal microscopy images showed that SGCPNs were quickly internalized by SSTR2-overexpressing SCLC cells, triggering the release of GA under acidic and near-infrared (NIR) laser irradiation environments, leading to their escape from lysosomes to the cytosol and then diffusion into the nucleus. At the same time, GA molecules can not only decrease the cell survival rate but also inhibit the activity of HSP90 to enhance PTT efficacy. SGCPNs can be precisely delivered to xenograft tumors of SSTR2-positive SCLC in vivo and decrease the undesirable effects on healthy organs. Upon NIR laser irradiation, therapy of SGCPNs showed significant tumor regression. In conclusion, SGCPNs provide a new chemo-photothermal synergistic treatment strategy for targeting SCLC.