非金属-有机配位键用于pH响应和肿瘤靶向药物传递的研究

pH-Responsive systems have attracted the interest of a broad range of researchers in recent years. The forces that give rise to pH responses are limited to the formation or destruction of chemical interactions, such as electrostatic interactions, hydrophobic effects, and hydrogen bond, covalent bond et al. Based on metal-organic coordination bond for pH-responsive drug delivery system, the idea of this project is based on non-metal-organic coordination bond for pH-responsive drug delivery system, in which polyvinyl alcohol (PVA) and functional PVA (fPVA) were chosen as the carriers and grafted PEG-Folic acid (FA) with FA targeting moiety. Bortezomib (BTZ) as the first-in-class proteasome inhibitor was chosen as a model drug. By loading anticancer drugs through the coordination bond interaction between boron and fPVA, we designed and synthesized a novel pH-responsive prodrug polymer FA-PEG-g-fPVA-BTZ for targeting ovarian cancer,and then the prodrug polymer self-assembled into nanoparticles by means of hydrophobic interaction of anticancer drugs. we expected to study the mechanism of the nanoparticles' targeted therapeutic effct on ovarian cancer. Furthermore, we expected to demonstrate active by targeting combination and inhibition of the nanoparticles targeting inhibition test on the ovarian cancer SKOV3 cell in vitro. Simultaneously, we expected to investigate in vivo metabolic process and anticancer effect of the nanoparticles and elucidate the application of the nanoparticles on active targeting chemotherapy for ovarian cancer based on in vivo tests and the ovarian cancer animal model in mice. Therefore, we can provide theoretical guidance and experimental basis for establishment of a new high-efficiency ovarian cancer chemotherapy targeting drug delivery system.

pH-响应性药物传递系统是近年来人们研究的热点，主要利用化学键（包括静电作用力、疏水力、氢键、共价键等）的形成与破坏构筑pH响应性药物释放系统。在对金属-有机配位键的pH响应性释放体系研究的基础上，本项目是基于非金属-有机配位键的pH响应性释放体系，以聚乙烯醇（PVA）和官能化PVA（fPVA）为载体，嫁接PEG化靶分子叶酸(FA)，以硼替佐米为模型药物，通过硼酸和邻二醇/胺的配位来装配药物，设计并合成用于卵巢癌靶向化疗的新型pH响应性前药聚合物"FA-PEG-g-fPVA-BTZ"，通过药物的疏水作用自组装成纳米颗粒，研究其在卵巢癌靶向化疗中的作用机制。通过对卵巢癌SKOV3细胞体外靶向抑制试验证实其主动靶向结合和抑制作用；通过在体试验和小鼠卵巢癌荷瘤模型，观察其体内代谢过程和主动靶向治疗卵巢癌的应用价值，为构建新型高效低毒的卵巢癌化疗药物靶向输送系统提供理论指导和实验依据。

pH响应性药物传递系统是近年来人们研究的热点，主要利用化学键（包括静电作用力、疏水力、氢键、共价键等）的形成与破坏构筑pH响应性药物释放系统。在对金属-有机配位键的pH响应性释放体系研究的基础上，构建了三种基于非金属-有机配位键的药物递送体系，它们分别为基于姜黄素和硼酸配位作用构建氧化响应型纳米粒用于肺癌的治疗，pH响应性脱落PEG的三苯基膦-槲皮素自组装隐形纳米粒用于线粒体靶向肿瘤的治疗和基于非金属-有机配位键构建了前药聚合物纳米粒体系。第一个体系首先合成了一种具有高度生物相容性的4-羟甲基苯硼酸修饰的聚乙二醇-聚丙烯酸聚合物（PPH），并基于姜黄素（Cur）和硼酸的配位作用，制备了可氧化响应释药的纳米粒（PPHC）。该Cur配位纳米粒PPHC可提高Cur在生理环境的稳定性，并能在H2O2的刺激下及时释放Cur。PPHC纳米粒对于A549细胞具有很强的抗增殖能力。第二个体系设计并合成了三苯基磷-槲皮素（TPP-Que）两亲性小分子轭合物，其可自组装成纳米粒（TQ NPs）。苯硼酸-聚乙二醇（PBA-PEG）能以非金属配位键修饰于纳米粒表面上，构建生理溶液中更稳定的长循环TQ-PEG纳米粒。肿瘤细胞内吞后，TPP-Que可聚集于线粒体上，与游离槲皮素相比，表现出更强抗肿瘤效果。当TQ-PEG纳米粒通过EPR效应富集于肿瘤组织后，由于肿瘤局部微酸环境，使得部分PEG从纳米粒上脱离，展现出类似TQ NPs的抗肿瘤作用。TQ-PEG NPs 可上调肿瘤细胞内的ROS水平，从而引起线粒体相关凋亡。另外，体内抗肿瘤效果和毒性评价表明TQ-PEG NPs较游离槲皮素具有安全和更有效的抗肿瘤作用。这个体系证明线粒体靶向的TQ-PEG NPs可作为有潜力的抗肿瘤纳米系统。第三个体系考察了不同分子量和浓度的聚乙烯醇与硼替佐米形成前药聚合物纳米粒，且具有一定缓释特性。这三个体系的研究，拓展了配位药物递送系统的研究范围，为构建新型高效低毒的药物靶向输送系统提供实践基础。通过基金委对本项目研究的资助，课题组共培养博士1名，硕士3名，申请专利1项，发表SCI文章5篇。综上，本研究达到了预期的目的。

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