An ATP-Regulated Ion Transport Nanosystem for Homeostatic Perturbation Therapy and Sensitizing Photodynamic Therapy by Autophagy Inhibition of Tumors

In this article, an adenosine-triphosphate-regulated (ATP-regulated) ion transport nanosystem [SQU@PCN, porphyrinic porous coordination network (PCN) incorporated with squaramide (SQU)] was designed and synthesized for homeostatic perturbation therapy (HPT) and sensitizing photodynamic therapy (PDT) of tumors. It was found that this nanotransporter SQU@PCN easily accumulated in tumor sites while avoiding metabolic clearance and side effects. In response to a high expression of ATP in the tumor, SQU@PCN was decomposed because of the strong coordination of ATP with metal ligand of PCN. Subsequently, incorporated SQU was released and then simultaneously transported chloride ions across membrane of the cell and lysosome along with the chloride ion concentration gradient. On one hand, influx of chloride ions by SQU increased intracellular ion concentration, which disrupted ion homeostasis and further induced tumor cell apoptosis. On the other hand, SQU-medicated coupling transport of H + /Cl - across the lysosomal membrane alkalized the lysosome, resulting in inhibition of autophagy. This SQU-mediated autophagy inhibition would sensitize PCN-based PDT since activated autophagy by traditional PDT would resist and weaken the therapeutic efficacy. In vivo animal test results revealed that combined HPT and sensitized PDT could realize tumor eradication while blocking metastasis, which provided a paradigm for complementary multimodal tumor treatment.