分會(huì)

第四十一分會(huì)：納米生物效應(yīng)與納米藥物化學(xué)

摘要

金屬有機(jī)框架結(jié)構(gòu)納米晶體由于生長(zhǎng)易于調(diào)控、生物相容性好等優(yōu)點(diǎn)，其生物醫(yī)學(xué)應(yīng)用備受關(guān)注。其中，沸石咪唑酯骨架結(jié)構(gòu)（ZIFs, Zeolitic Imidazolate Frameworks）具備孔隙結(jié)構(gòu)且在酸性條件下發(fā)生解體，適用于向細(xì)胞中遞送蛋白質(zhì)等生物大分子。在葡萄糖氧化酶(GOx, Glucose Oxidase)介導(dǎo)的腫瘤饑餓治療中，其遞送效率是關(guān)鍵。但是，葡萄糖并非細(xì)胞中唯一的營(yíng)養(yǎng)源，且葡萄糖需轉(zhuǎn)化為乳酸后才可以參與細(xì)胞的供能過(guò)程。這意味著GOx清除細(xì)胞內(nèi)葡萄糖的條件下，細(xì)胞仍可通過(guò)攝取周?chē)h(huán)境中的乳酸為自身供能，從而免于“餓死”。因此，同時(shí)抑制腫瘤細(xì)胞的乳酸攝取對(duì)于提高饑餓治療的效果具有重要意義。本研究中在以ZIF-8為載體向細(xì)胞中遞送GOx的基礎(chǔ)上，同時(shí)向細(xì)胞中遞送單羧酸酸轉(zhuǎn)運(yùn)蛋白的抑制劑，α-氰基-4-羥基肉桂酸（CHC, α-Cyano-4-hydroxycinnamic acid）,以同時(shí)清除細(xì)胞內(nèi)的葡萄糖和乳酸。 研究中發(fā)現(xiàn)，CHC對(duì)于ZIF-8本身形貌的改變影響比較大，且過(guò)量的CHC 摻入ZIF-8中會(huì)導(dǎo)致形成的晶體發(fā)生聚集。通過(guò)調(diào)控2-甲基咪唑與鋅離子的比例可以重新調(diào)整ZIF-8晶體的尺寸在170 nm 左右。而且，在CHC@ZIF-8中摻入GOx, 其尺寸略有增加。通過(guò)體外實(shí)驗(yàn)證明,所合成的ZIF-8納米顆粒顯示出較好的生物相容性；CHC@ZIF-8可以有效抑制細(xì)胞對(duì)乳酸的攝??；體內(nèi)和體外的實(shí)驗(yàn)均證明GOx/CHC@ZIF-8對(duì)腫瘤細(xì)胞的生長(zhǎng)抑制效果明顯優(yōu)于GOx@ZIF-8和CHC@ZIF-8。對(duì)其機(jī)制的研究表明，乳酸的攝取被抑制之后，細(xì)胞的氧化呼吸速率減慢，從而提高了GOx的催化活性，加快對(duì)葡萄糖的清除并且產(chǎn)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.

關(guān)鍵詞

沸石咪唑酯骨架結(jié)構(gòu);葡萄糖氧化酶;葡萄糖;α-氰基-4-羥基肉桂酸;乳酸

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