Dual ATP and pH responsive ZIF-90 nanosystem with favorable biocompatibility and facile post-modification improves therapeutic outcomes of triple negative breast cancer in vivo
Dual ATP and pH responsive ZIF-90 nanosystem with favorable biocompatibility and facile post-modification improves therapeutic outcomes of triple negative breast cancer in vivo
复制标题
双 ATP 和 pH 响应型 ZIF-90 纳米系统具有良好的生物相容性和易于后修饰，可改善三阴性乳腺癌的体内治疗效果
DOI：
10.1016/j.biomaterials.2019.01.001
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发表时间：
2019-03-01
期刊：
影响因子：
14
通讯作者：
Wu, Aiguo
中科院分区：
文献类型：
--
作者：
Jiang, Zhenqi;Wang, Yinjie;Wu, Aiguo
沸石咪唑骨架（ZIFs）具有良好的生物相容性、pH响应性降解结构和高载药量等独特性能，成为生物医学领域的一个重要纳米体系。与ZIF-8在肿瘤诊断和治疗中日益受到关注相比，ZIF-90的生物学应用，特别是其体内治疗效果和相关毒性的研究有限。在这里，我们通过快速自组装过程合成纳米ZIF-90，合成的纳米ZIF-90约为75 nm，具有负zeta电位，与纳米ZIF-8相比，提供更好的线粒体靶向性，细胞生物相容性和体内存活率。为了进一步探索ZIF-90在癌症治疗中的适用性，使用简单的后修饰将Y-1受体配体[Asn（6），Pro（34）]-NPY（AP）缀合在阿霉素（DOX）包封的纳米ZIF-90的表面上。AP-ZIF-90显著减少生理pH水平下的过早DOX释放，并触发肿瘤细胞内更有效和更快的DOX释放，对高三磷酸腺苷（ATP）和低pH条件具有双重响应。组合DOX的靶向递送和双重响应释放显著提高了AP-ZIF-90@DOX在MDA-MB-231荷瘤小鼠中的治疗功效，并且在40天的治疗中导致80%的存活率。在给定剂量下，纳米ZIF-90在体内具有良好的生物相容性，对肝肾功能的副作用极小。因此，纳米ZIF-90与Y-1受体配体结合具有良好的生物相容性和双重响应性，可以用作靶向三阴性乳腺癌体内治疗的有希望的纳米系统。
Zeolitic imidazole frameworks (ZIFs) are becoming a notable nanosystem in biomedicine field, due to their unique properties of favorable biocompatibility, pH-responsive degradable structure and high drug loading. Compared with the increasing attention on ZIF-8 in cancer diagnosis and treatment, there is limited research about the bio-application of ZIF-90, especially its in vivo therapeutic efficacy and related toxicity. Here, we synthesize nano ZIF-90 through a fast self-assembling process, and the synthesized nano ZIF-90 is about 75 nm with a negative zeta potential, providing better mitochondria targetability, cell biocompatibility and in vivo survival rate comparing to nano ZIF-8. To further explore the applicability of ZIF-90 in cancer treatment, a facile post-modification is used to conjugate Y-1 receptor ligand [Asn(6), Pro(34)]-NPY (AP) on the surface of doxorubicin (DOX)-encapsulated nano ZIF-90. AP-ZIF-90 significantly reduces premature DOX release at physiological pH level, and triggers more effective and faster DOX release inside the tumor cells with dual responsive to high adenosine triphosphate (ATP) and low pH condition. Combining targeted delivery and dual responsive release of DOX significantly improves the therapeutic efficacy of AP-ZIF-90@DOX in MDA-MB-231 tumor bearing mouse, and results in 80% survival rate over 40 days of treatment. At the given dosage, nano ZIF-90 is with excellent biocompatibility in vivo, inducing minimal side effect on the liver and renal functions. Therefore, nano ZIF-90 combines with Y-1 receptor ligand with favorable biocompatibility and dual responsiveness can be used as a promising nanosystem for targeted triple negative breast cancer treatment in vivo.