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.

中文翻译：

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使用pH敏感的聚合物递送系统对化疗药物和MTH1抑制剂进行协同治疗口腔鳞状细胞癌

MutT同系物1（MTH1）是游离核苷酸库的必需消毒剂，可防止癌细胞中的致死性DNA损伤，近年来已被确认为抗癌靶标。小分子TH287有效和选择性地抑制细胞中的MTH1蛋白。在这里，我们开发了一种基于聚合物纳米粒子的口腔鳞状细胞癌（OSCC）的有效化疗系统，该聚合物纳米粒子可实现抗癌药亚砷酸钠（NaAsO ₂）和MTH1抑制剂TH287的共同递送。阳离子超支化聚（胺酯）（HPAE）是一种具有高度支化结构的两亲且对pH敏感的聚合物，可在水溶液中自组装成纳米颗粒。两种NaAsO ₂TH287和TH287可以借助静电吸引和疏水相互作用被装载到HPAE纳米颗粒中。HPAE（NaAsO ₂ + TH287）纳米颗粒中NaAsO ₂和TH287的释放是pH依赖性的。体外评估表明，HPAE（NaAsO ₂ + TH287）纳米粒子可快速进入癌细胞并响应酸性细胞内环境释放NaAsO ₂和TH287。与NaAsO比较₂，TH287，HPAE（NaAsO ₂）纳米颗粒，HPAE（TH287）纳米颗粒，和HPAE的物理混合物（NaAsO ₂）纳米颗粒和TH287，所述HPAE（NaAsO ₂+ TH287）纳米粒子表现出对肿瘤细胞增殖的更有效抑制，说明了NaAsO ₂和TH287的协同作用。实验结果表明，TH287可能抑制肿瘤细胞中的MTH1，使其对NaAsO ₂更敏感。