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

Abstract

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.

A Mitochondria‐Driven Metabolic Sensing Nanosystem for Oxygen Availability and Energy Blockade of Cancer

“…This might be attributed to the fact that ATP has a stronger metal coordination ability than porphyrin. [ 50,51 ] Thus, we further explored the drug release behavior of RES@PCN in the presence of ATP. As shown in Figure 1E, less than 20% of RES was released in the group without ATP, avoiding the side effects of RES leakage.…”

“…[ 46–48 ] Moreover, the nature of MOF's coordination assembly also determines the possibility of its being disassembled by coordination substitution with strongly coordinating groups (such as phosphate). [ 49,50 ] This will be benefit for fixed‐point drug release in vivo. This can be exploited to develop stimulus response drug controlled release systems.…”

Chemistry of Advanced Nanomedicines in Cancer Cell Metabolism Regulation

“…Reproduced with permission. [47] Copyright 2019, American Chemical Society. Reproduced with permission.…”

Increased photodynamic therapy sensitization in tumors using a nitric oxide-based nanoplatform with ATP-production blocking capability

“…Tamoxifen (TAM) 25 , metformin (MET) 26 and atovaquone (ATO) 27 have been recently proposed to reduce O 2 consumption in tumor cells and enhanced PDT. However, efficacy of these strategies is affected by resistance mechanisms activated during PDT 28 , 29 . Thus, there is an urgent need to develop an innovative strategy to increase oxygen partial pressure in tumors that also increases sensitivity of cancer cells to phototherapy.…”