Surface-Functionalization of Zr-Fumarate MOF for Selective Cytotoxicity and Immune System Compatibility in Nanoscale Drug Delivery
Surface-Functionalization of Zr-Fumarate MOF for Selective Cytotoxicity and Immune System Compatibility in Nanoscale Drug Delivery
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DOI：
10.1021/acsami.8b11652
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发表时间：
2018-09-19
影响因子：
9.5
通讯作者：
Forgan, Ross S.
中科院分区：
文献类型：
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作者：
Lazaro, Isabel Abanades;Haddad, Salame;Forgan, Ross S.
金属-有机框架（mof）是一种由金属离子或簇连接有机配体到多孔材料中的网络结构，作为纳米级药物输送装置正在被积极研究，因为它们提供了高载货量的可调结构，可以很容易地进一步功能化，以实现靶向和增强生理稳定性。Zr优异的生物相容性意味着其mof是迄今为止研究最多的mof之一，特别是原型对苯二甲酸锆UiO-66。相比之下，富马酸酯（Zr-fum）连接的等孔类似物很少受到关注，尽管内源性连接物是克雷布斯循环的一部分。在此，我们报道了Zr-fum在药物传递方面的全面研究。减少颗粒大小被证明可以增加癌细胞的摄取，同时减少巨噬细胞的内化，巨噬细胞是清除血液中异物的免疫系统细胞。Zr-fum在合成过程中，通过配位调制和合成后，与药物二氯乙酸（DCA）的缺陷负载以及表面修饰相兼容。dca负载的聚乙二醇化Zr-fum对HeLa和MCF-7癌细胞显示出选择性的体外细胞毒性，这可能是由于与未包被的前体相比，它增强了小泡介导的内吞作用，并且对HEK293肾细胞、J774巨噬细胞和人外周血淋巴细胞具有良好的耐受性。与UiO-66相比，Zr-fum更有效地将药物模拟钙黄蛋白转运到HeLa细胞中，并且负载dca的聚peg化Zr-fum比类似的UiO-66样品更有效地降低HeLa和MCF-7细胞的增殖。免疫系统反应的体外检测表明，Zr-fum样品诱导的活性氧比UiO-66类似物少，可能是由于连接物是内源性的，并且不激活C3和C4补体级联途径，这表明Zr-fum可以避免吞噬激活。结果表明，Zr-fum是一种有吸引力的纳米级药物递送替代UiO-66，并且广泛的体外实验可用于在早期动物研究之前为药物递送系统的设计提供极大的信息。
Metal-organic frameworks (MOFs), network structures wherein metal ions or clusters link organic ligands into porous materials, are being actively researched as nanoscale drug delivery devices as they offer tunable structures with high cargo loading that can easily be further functionalized for targeting and enhanced physiological stability. The excellent biocompatibility of Zr has meant that its MOFs are among the most studied to date, in particular the archetypal Zr terephthalate UiO-66. In contrast, the isoreticular analog linked by fumarate (Zr-fum) has received little attention, despite the endogenous linker being part of the Krebs cycle. Herein, we report a comprehensive study of Zr-fum in the context of drug delivery. Reducing particle size is shown to increase uptake by cancer cells while reducing internalization by macrophages, immune system cells that remove foreign objects from the bloodstream. Zr-fum is compatible with defect loading of the drug dichloroacetate (DCA) as well as surface modification during synthesis, through coordination modulation and postsynthetically. DCA-loaded, PEGylated Zr-fum shows selective in vitro cytotoxicity toward HeLa and MCF-7 cancer cells, likely as a consequence of its enhanced caveolae-mediated endocytosis compared to uncoated precursors, and it is well tolerated by HEK293 kidney cells, J774 macrophages, and human peripheral blood lymphocytes. Compared to UiO-66, Zr-fum is more efficient at transporting the drug mimic calcein into HeLa cells, and DCA-loaded, PEGylated Zr-fum is more effective at reducing HeLa and MCF-7 cell proliferation than the analogous UiO-66 sample. In vitro examination of immune system response shows that Zr-fum samples induce less reactive oxygen species than UiO-66 analogs, possibly as a consequence of the linker being endogenous, and do not activate the C3 and C4 complement cascade pathways, suggesting that Zr-fum can avoid phagocytic activation. The results show that Zr-fum is an attractive alternative to UiO-66 for nanoscale drug delivery, and that a wide range of in vitro experiments is available to greatly inform the design of drug delivery systems prior to early stage animal studies.