A mitochondrial-targeted prodrug for NIR imaging guided and synergetic NIR photodynamic-chemo cancer therapy

Abstract

Nontoxic prodrugs, especially activated by tumor microenvironment, are urgently required for reducing the side effects of cancer therapy. And combination of chemo-photodynamic therapy prodrugs show effectively synergetic therapeutic efficiency, however, this goal has not been achieved in a single molecule. In this work, we developed a mitochondrial-targeted prodrug <b>PNPS</b> for near infrared (NIR) fluorescence imaging guided and synergetic chemo-photodynamic precise cancer therapy for the first time. <b>PNPS</b> contains a NIR photosensitizer (<b>NPS</b>) and an anticancer drug 5'-deoxy-5-fluorouridine (5'-DFUR). These two parts are linked and caged through a bisboronate group, displaying no fluorescence and very low cytotoxicity. In the presence of H₂O₂, the bisboronate group is broken, resulting in activation of <b>NPS</b> for NIR photodynamic therapy and activation of 5'-DFUR for chemotherapy. The activated <b>NPS</b> can also provide a NIR fluorescence signal for monitoring the release of activated drug. Taking advantage of the high H₂O₂ concentration in cancer cells, <b>PNPS</b> exhibits higher cytotoxicity to cancer cells than normal cells, resulting in lower side effects. In addition, based on its mitochondrial-targeted ability, <b>PNPS</b> exhibits enhanced chemotherapy efficiency compare to free 5'-DFUR. It also demonstrated a remarkably improved and synergistic chemo-photodynamic therapeutic effect for cancer cells. Moreover, <b>PNPS</b> exhibits excellent tumor microenvironment-activated performance when intravenously injected into tumor-bearing nude mice, as demonstrated by <i>in vivo</i> fluorescence imaging. Thus, <b>PNPS</b> is a promising prodrug for cancer therapy based on its tumor microenvironment-activated drug release, synergistic therapeutic effect and "turn-on" NIR imaging guide.