Inhibiting PI3K/AKT/mTOR signaling by metal-organic frameworks for overcoming multiple drug resistance in chemoradiotherapy

Angiogenesis in the tumor microenvironment is the main cause for the insensitivity of tumor cells to chemoradiotherapy. Strategies for increasing the sensitivity of tumor cells to conventional therapies using nanoparticles are limited. In this study, we developed rationally designed microenvironment response nanoparticles with physicochemical and biological features to overcome cisplatin resistance by using decomposition product from Zr-metal-organic framework (MOF) to inhibit the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)/vascular endothelial growth factor (VEGF) pathway in chemoradiotherapy. Cisplatin (CDDP) is encapsulated into Zr-MOF and bovine serum albumin (BSA) is modified into the surface of nanoparticles to create CDDP@Zr-MOF-BSA (abbreviated as CDDP@Zr-MOF), which acts as an excellent radiosensitizer and exhibits microenvironment response, preferable tumor accumulation, high-efficiency inhibition of angiogenesis, and obviously reduced efflux on resistant A549 cells. The rate of angiogenesis inhibition in the combined treatment group is 6-fold higher than that in other control groups. Moreover, CDDP@Zr-MOF not only increases the therapeutic effect remarkably, but also regulates the tumor microenvironment and inhibits the expression of a drug-efflux transporter, namely multidrug resistance-associated protein 1 (MRP1), for reversing drug resistance in A549R cells. Thus, CDDP@Zr-MOF causes synergistic cytotoxicity in A549R cells, and high-efficiency eradication of cisplatin-resistant tumor without regrowth by inhibiting angiogenesis in the tumor microenvironment. The microenvironment responsiveness of CDDP@Zr-MOF provides a multipurpose synergistic approach for treating drug-resistant tumors with chemoradiotherapy.