Synergistic chemo-photodynamic therapy by "big & small combo nanoparticles" sequential release system

Chemo-photodynamic combination has been manifested great potential for synergistic cancer therapy. Moreover, the synergistic efficacy could be significantly enhanced by well-designed sequential release manner of photosensitizers (PSs). Here we propose a "big & small combo nanoparticles (NP_big&small)" system for double loading PSs methylene blue (MB) and single absorbing chemotherapeutics drug Gemcitabine hydrochloride (GM·HCl). The "grown-in" MB from NP_big&small show two-peak sequential release profile, significantly improve the absorbed chemotherapeutic efficacy of GM·HCl. The corresponding two-peak sequential release profile can be illustrated by related mathematics function. The sequential release property was clearly observed through morphological evolution of NPs both in water and cells by TEM. Furthermore, NP_big&small demonstrate well EPR effect and improved synergistic efficacy from in vitro and in vivo results. Thus, NP_big&small chemo-photodynamic system and the programmable sequential release mechanism provide a promising platform that ensures an enhanced synergistic chemo-photodynamic effect in cancer treatment.