Cell membranes targeted unimolecular prodrug for programmatic photodynamic-chemo therapy

Abstract

Photodynamic therapy (PDT) has emerged as one of the most up-and-coming non-invasive therapeutic modalities for cancer therapy in rencent years. However, its therapeutic effect was still hampered by the short life span, limited diffusion distance and ineluctable depletion of singlet oxygen (¹O₂), as well as the hypoxic microenvironment in the tumor tissue. Such problems have limited the application of PDT and appropriate solutions are highly demand. <b>Methods:</b> Herein, a programmatic treatment strategy is proposed for the development of a smart molecular prodrug (<b>D-bpy</b>), which comprise a two-photon photosensitizer and a hypoxia-activated chemotherapeutic prodrug. A rhodamine dye was designed to connect them and track the drug release by the fluorescent signal generated through azo bond cleavage. <b>Results:</b> The prodrug (<b>D-bpy</b>) can stay on the cell membrane and enrich at the tumor site. Upon light irradiation, the therapeutic effect was enhanced by a stepwise treatment: (i) direct generation of ¹O₂ on the cell membrane induced membrane destruction and promoted the <b>D-bpy</b> uptake; (ii) deep tumor hypoxia caused by two-photon PDT process further triggered the activation of the chemotherapy prodrug. Both <i>in vitro</i> and <i>in vivo</i> experiments, <b>D-bpy</b> have exhabited excellent tumor treatment effect. <b>Conclusion:</b> The innovative <b>programmatic</b> treatment strategy provides new strategy for the design of follow-up anticancer drugs.