Synergistic therapy of chemotherapeutic drugs and MTH1 inhibitors using a pH-sensitive polymeric delivery system for oral squamous cell carcinoma

MutT homolog 1 (MTH1) is an essential sanitizer of the free nucleotide pool that prevents lethal DNA damage in cancer cells, which has been validated as an anticancer target in recent years. Small molecule TH287 potently and selectively inhibits the MTH1 protein in cells. Here, we developed an effective chemotherapeutic system for oral squamous cell carcinoma (OSCC) based on polymeric nanoparticles that achieve co-delivery of anticancer drug sodium arsenite (NaAsO2) and MTH1 inhibitor TH287. Cationic hyperbranched poly(amine-ester) (HPAE), an amphiphilic and pH-sensitive polymer with a highly branched structure, self-assembled into nanoparticles in aqueous solution. Both NaAsO2 and TH287 could be loaded into HPAE nanoparticles with the help of electrostatic attraction and hydrophobic interaction. The release of NaAsO2 and TH287 from HPAE(NaAsO2 + TH287) nanoparticles was pH-dependent. In vitro evaluation demonstrated that the HPAE(NaAsO2 + TH287) nanoparticles rapidly entered cancer cells and released NaAsO2 and TH287 in response to acidic intracellular environments. In comparison with NaAsO2, TH287, HPAE(NaAsO2) nanoparticles, HPAE(TH287) nanoparticles, and the physical mixture of HPAE(NaAsO2) nanoparticles and TH287, the HPAE(NaAsO2 + TH287) nanoparticles exhibited more effective inhibition of tumor cell proliferation, illustrating the synergistic effect of NaAsO2 and TH287. The experimental results show that TH287 is likely to inhibit MTH1 in tumor cells, rendering them more sensitive to NaAsO2.