分会

第四十一分会：纳米生物效应与纳米药物化学

摘要

金属有机框架结构纳米晶体由于生长易于调控、生物相容性好等优点，其生物医学应用备受关注。其中，沸石咪唑酯骨架结构（ZIFs, Zeolitic Imidazolate Frameworks）具备孔隙结构且在酸性条件下发生解体，适用于向细胞中递送蛋白质等生物大分子。在葡萄糖氧化酶(GOx, Glucose Oxidase)介导的肿瘤饥饿治疗中，其递送效率是关键。但是，葡萄糖并非细胞中唯一的营养源，且葡萄糖需转化为乳酸后才可以参与细胞的供能过程。这意味着GOx清除细胞内葡萄糖的条件下，细胞仍可通过摄取周围环境中的乳酸为自身供能，从而免于“饿死”。因此，同时抑制肿瘤细胞的乳酸摄取对于提高饥饿治疗的效果具有重要意义。本研究中在以ZIF-8为载体向细胞中递送GOx的基础上，同时向细胞中递送单羧酸酸转运蛋白的抑制剂，α-氰基-4-羟基肉桂酸（CHC, α-Cyano-4-hydroxycinnamic acid）,以同时清除细胞内的葡萄糖和乳酸。 研究中发现，CHC对于ZIF-8本身形貌的改变影响比较大，且过量的CHC 掺入ZIF-8中会导致形成的晶体发生聚集。通过调控2-甲基咪唑与锌离子的比例可以重新调整ZIF-8晶体的尺寸在170 nm 左右。而且，在CHC@ZIF-8中掺入GOx, 其尺寸略有增加。通过体外实验证明,所合成的ZIF-8纳米颗粒显示出较好的生物相容性；CHC@ZIF-8可以有效抑制细胞对乳酸的摄取；体内和体外的实验均证明GOx/CHC@ZIF-8对肿瘤细胞的生长抑制效果明显优于GOx@ZIF-8和CHC@ZIF-8。对其机制的研究表明，乳酸的摄取被抑制之后，细胞的氧化呼吸速率减慢，从而提高了GOx的催化活性，加快对葡萄糖的清除并且产生更多的ROS。 Metal organic framework (MOF) was of great interest in biomedical applications for its controllable crystal growth and satisfactory biocompatibility. Zeolitic Imidazolate Frameworks (ZIFs), a MOF of pore structure and could disassembly under acidic condition, was suitable for intra-cellular delivery of macromolecules. Efficient delivery of glucose oxidase (GOx) is essential for the GOx based starvation therapy. However, glucose was not the only fuel for cell survive and glucose feeds the TCA circle via circulating lactate. It means that cancer cells can still survive for the availability of lactate from the adjacent tissue. So, the simultaneous inhibition of glucose and lactate in cancer cells is of great significance in cancer starvation therapy. In this study, inhibitor of monocarboxylate transporter 1, α-Cyano-4-hydroxycinnamic acid (CHC), was simultaneously delivered with GOx by ZIF-8 to delete glucose and lactate in cancer cells. It was observed that CHC can significantly influence the size of ZIF-8 and cause aggregation of nano crystals. We tuned the size of nano crystals to around 170 nm by adjusting the ratio between Zn2+ and 2-Methylimidazole. When GOx was doped into CHC@ZIF-8, the morphology didn’t change significantly. According to in vitro study, CHC@ZIF-8 can successfully inhibit the availability of lactate; GOx@ZIF-8 can efficientluy deplete the intracellular glucose and starve cells to death; both the in vitro and in vivo experiments proved that the GOx/CHC@ZIF-8 is prior to either GOx@ZIF-8 or CHC@ZIF-8 in starving cells to death. The improved starvation therapy is that due to the improved catalytic activity of GOx by inhibiting he lactate-fueled respiration, which accelerated the glucose depletion and ROS genereation.

关键词

沸石咪唑酯骨架结构;葡萄糖氧化酶;葡萄糖;α-氰基-4-羟基肉桂酸;乳酸

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