PDT-Driven Highly Efficient Intracellular Delivery and Controlled Release of CO in Combination with Sufficient Singlet Oxygen Production for Synergistic Anticancer Therapy

The precise delivery and controllable release of carbon monoxide (CO) to tumor tissues is an emerging anticancer therapy because CO in a high dose can be detrimental to cell survival and tumor growth. However, CO gas therapy is limited by the gaseous nature of CO that hinders its enrichment and controllable release to tumor tissues. Here, a novel photodynamic therapy (PDT)-driven CO controllable release system (CORM@G3DSP-Ce6) that integrates the photosensitizer chlorin e6 (Ce6) and H2O2-sensitive CO releasing molecule CORM-401 into peptide dendrimer-based nanogels (G3DSP) is described. Upon excitation with near-infrared light, Ce6-mediated photochemical effect not only promotes the efficient cellular internalization of CORM@G3DSP-Ce6, but also triggers the rapid intracellular CO release from CORM-401 by depleting the H2O2 produced during PDT. Importantly, the PDT-driven CO release does not impair the generation capability of singlet oxygen (O-1(2)). As a result, accompanied with the simultaneous generation of large amounts of O-1(2) and CO in cells, the combination of PDT and CO gas therapy offers significant synergistic anticancer effects and superior therapeutic safety both in vitro and in vivo.