Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, People's Republic of China.
Biomater Sci. 2017 Sep 26;5(10):2068-2078. doi: 10.1039/c7bm00395a.
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 (NaAsO) 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 NaAsO and TH287 could be loaded into HPAE nanoparticles with the help of electrostatic attraction and hydrophobic interaction. The release of NaAsO and TH287 from HPAE(NaAsO + TH287) nanoparticles was pH-dependent. In vitro evaluation demonstrated that the HPAE(NaAsO + TH287) nanoparticles rapidly entered cancer cells and released NaAsO and TH287 in response to acidic intracellular environments. In comparison with NaAsO, TH287, HPAE(NaAsO) nanoparticles, HPAE(TH287) nanoparticles, and the physical mixture of HPAE(NaAsO) nanoparticles and TH287, the HPAE(NaAsO + TH287) nanoparticles exhibited more effective inhibition of tumor cell proliferation, illustrating the synergistic effect of NaAsO and TH287. The experimental results show that TH287 is likely to inhibit MTH1 in tumor cells, rendering them more sensitive to NaAsO.
MutT 同源物 1（MTH1）是游离核苷酸池的必需净化剂，可防止癌细胞中的致命 DNA 损伤，近年来已被验证为抗癌靶标。小分子 TH287 可有效且选择性地抑制细胞中的 MTH1 蛋白。在这里，我们基于聚合纳米颗粒开发了一种有效的口腔鳞状细胞癌（OSCC）化疗系统，该系统可实现抗癌药物亚砷酸钠（NaAsO）和 MTH1 抑制剂 TH287 的共递药。阳离子超支化聚（胺-酯）（HPAE）是一种具有高度支化结构的两亲性和 pH 敏感聚合物，在水溶液中自组装成纳米颗粒。在静电吸引和疏水相互作用的帮助下，NaAsO 和 TH287 都可以负载到 HPAE 纳米颗粒中。HPAE（NaAsO + TH287）纳米颗粒中 NaAsO 和 TH287 的释放与 pH 有关。体外评价表明，HPAE（NaAsO + TH287）纳米颗粒迅速进入癌细胞，并在响应酸性细胞内环境时释放出 NaAsO 和 TH287。与 NaAsO、TH287、HPAE（NaAsO）纳米颗粒、HPAE（TH287）纳米颗粒和 HPAE（NaAsO）纳米颗粒与 TH287 的物理混合物相比，HPAE（NaAsO + TH287）纳米颗粒对肿瘤细胞增殖的抑制作用更有效，说明 NaAsO 和 TH287 具有协同作用。实验结果表明，TH287 可能会抑制肿瘤细胞中的 MTH1，使它们对 NaAsO 更敏感。
