金属-有机骨架化合物与癌细胞及其微环境作用机制研究

Little evidence exists that nanomaterials themselves might possess intrinsic anticancer properties. The use of porous solids for biomedical applications requires a biologically friendly composition, which raises concerns for the potential cytotoxicity or unknown biological activity of metal-organic frameworks (MOFs), a new born family of hybrid materials, in vivo. Until now, the available toxicity information dealing with MOFs or coordination polymers are very scarce. Information about mechanisms of apoptosis induced by MOFs is largely lacking. In particular, little is known about the interactions of MOFs with the tumour microenvironment. And the antiangiogenic properties, inhibition of MMPs, and destabilization of filamentous actin of MOFs remain almost completely unknown as far as we know, in comparison of the intensive studies about their synthesis, characterization and possible applications. We found that Cu-MOF (or MOF-199, HKUST-1) possesses an intrinsic enzyme mimicking activity similar to that found in natural trypsin to bovine serum albumin (BSA) and casein (Scientific Reports, 2014). We also found that Fe-MIL-101 shows higher cytotoxic activity than oxaliplatin towards selected HUVEC and SKOV3 cell lines, lower cytotoxic activity for normal BABL-3T3 cells under identical conditions (Scientific Reports, , 2016, 6,26126). Surprisingly, Fe-MIL-101 exerts stronger antiangiogenic effect on HUVEC cells than SU5416, a potent synthetic inhibitor of the tyrosine kinase activity of VEGFR1/2 (CN201610299834.6; US:201715589162:A).. Thus, in this proposed project, we will investigate the inhibitory effects of some MOFs such as Fe、Cu、Zn、Sn-MOF on human ovarian cancer SKOV3, cervical cancer Hela, lung cancer A549, breast cancer MCF-7, and HT-29 human colon cancer cells lines growth and the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). Moreover, the possible roles of MOFs in inhibition of MMPs, and destabilization of filamentous actin will also studied. This project is aimed to explain the mechanism associated with the antitumor and antiangiogenic activity of these MOFs and provide information for developing a new class of anti-angiogenic agents that will simultaneously inhibit the function of multiple growth factors. These findings could open a new avenue of using MOFs as potential therapeutics in angiogenesis-dependent diseases, including cancers.

金属-有机骨架化合物（MOFs）在生物医学方面的研究目前主要集中在药物载体及检测等方面，关于其细胞毒性尤其是自身抗癌活性的研究还非常有限，尚未见MOFs与肿瘤微环境作用机制，尤其是MOFs的抗血管生成、抑制基质金属蛋白酶MMPs及其与纤维型肌动蛋白F-actin作用的任何报道。为此，本项目拟在前期Fe-MIL-101对人卵巢癌细胞有选择性毒性且抑制其血管生成等研究基础上，进一步研究Fe、Cu、Zn、Sn-MOF等MOFs材料对人卵巢癌、血管内皮细胞、肺癌、宫颈癌、乳癌、结肠癌细胞株和正常细胞BABL-3T3细胞株的增殖、迁移和血管生成的影响。拟揭示MOFs与血管生成调控的重要靶向蛋白如血管内皮生长因子受体VEGFR1/2、MMPs和F-actin等的作用机制。为探索MOFs与肿瘤微环境作用机制及其在生物医药中的潜在应用尤其是开发选择性抑制癌细胞而对正常细胞低毒的MOFs提供重要信息。

项目主要围绕MOFs材料的细胞毒性以及与肿瘤微环境作用机制研究开展，为MOFs在生物医药中的潜在应用尤其是开发选择性抑制癌细胞而对正常细胞低毒的MOFs提供重要信息。合成了ZIF-8(Zn)、UiO-66(Zr)、MIL-53(Al)、Cu-MOF、FJU-21(Cu)以及 ZIF-67(Co)材料并进行结构确认，通过MTT法以及体外血管模型研究材料对人卵巢癌细胞SKOV3的毒性及抑制血管生成的效果。发现Cu-MOF能明显抑制SKOV3增殖。进一步研究了Cu-MOF对人非小细胞肺癌细胞A549、人卵巢癌细胞SKOV3、人脐静脉内皮细胞HUVEC以及小鼠胚胎成纤细胞BABL-3T3的毒性，发现其对SKOV3具有选择性抑制作用，对正常小鼠细胞的毒性较低，且效果比抗肿瘤药物（奥沙利铂和青蒿琥酯）强3倍。Cu-MOF能损伤细胞线粒体功能，将细胞阻滞在G2/M期，诱导细胞凋亡；同时Cu-MOF通过调控肌动蛋白相关基因（ACTA2、ACTN3、FSCN2和SCIN）和有丝分裂纺锤体调节基因（PLK1和TPX2）表达，破坏肌动蛋白纤维丝以及促进微管蛋白聚合，从而触发细胞有丝分裂灾难。将材料拓展到其他含Cu纳米材料（CQDs/ Cu2O、磁性CuFe2O4、Cu2O/SBA-3、Cu2O/MoS2以及Cu NPs），CQDS /Cu2O通过下调金属基质蛋白酶MMP-2/9、细胞骨架蛋白F-actin以及血管内皮生长因子受体VEGFR2的表达，影响肿瘤细胞迁移和血管生成；其他材料也表现出良好的抗肿瘤和抑制肿瘤细胞迁移的效果。拓展了MOFs材料以及其他纳米材料在生物医药领域的应用，为抗肿瘤提供新的方法和途径。.项目还拓展性的研究了含Cu纳米材料在模拟蛋白酶中的应用，将模拟蛋白酶的性能从弱碱性拓展到中性，不断提高材料对底物的亲和力和催化能力，同时具有良好的重复利用效率，开发了一系列纳米模拟酶材料。.发表6篇论文，授权发明专利3件（其中1件为美国专利），项目组所在团队主办国际学术会议2次。培养硕士研究生4名，项目组成员2人晋升副高级职称，1人入选“兴滇人才-青年人才”。完成了预期目标。

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