Zn-MOFs用药物载体担载量与缓释功效关系的微量热学研究

The development of drug carriers with high-loading and proper sustained-release rate is one of the hot topics in deepening the clinical application of cancer drug sustained-release preparations. This project aims to emphasize harmonious matching laws among the drug-loading, sustained-release rate and drug efficacy, and explore the criterion of the influence of host-guest interactions on the drug-loading and sustained-release rate. A series of new Zn-MOFs carriers with good bio-compatibility will be controllably prepared and characterized based on designing corresponding aromatic carboxylic acids with different substituent groups. In situ microcalorimetry will be employed to real-time record the formation of the targets, revealing the association between the reaction conditions and structures. The adsorption and sustained-release processes between Zn-MOFs and 5-fluorouracil will be tracked with in situ microcalorimetry, in order to elucidate the dual influence of host-guest interactions on drug-loading and sustained-release rate both in thermodynamic and thermokinetic aspects. Finally, the anti-tumor active of the Zn-MOFs encapsulating 5-fluorouracil in vitro will be explored and evaluated. The results will reveal the harmonious matching laws among the structure of carriers, drug-loading and sustained-release effect, and screen new drug carriers with high-loading and good sustained-release efficacy, which provides a new idea and approach to rationally design MOFs-based drug sustained-release carriers with high-loading and good sustained-release effects, and is of significant importance to improving the theoretical and technical systems of drug sustained-release preparations.

开发高担载量、合适缓释速率的药物载体是深化抗癌药物缓释制剂临床应用的研究热点。本课题立意于药物担载量-缓释速率-抗癌疗效之间和谐匹配规律的探讨，寻求主客体相互作用对担载量和缓释功效影响的判据。研究项目拟通过设计含不同取代基的芳香羧酸配体，开展新型生物兼容性好的Zn-MOFs形成机理的原位微量热学研究，建立反应条件与结构的有效关联；原位跟踪Zn-MOFs对5-氟尿嘧啶 (5-Fu) 的封装和缓释过程，获得主客体相互作用对药物担载量和缓释速率的双重影响规律的热力学及热动力学阐释；试验负载5-Fu的Zn-MOFs的体外抗肿瘤活性，获得其作为药物载体的体外疗效评价。研究结果将揭示载体结构—担载量—缓释效果的和谐匹配规律并筛选出缓释功效佳的药物载体种类，为高药物担载量、合适缓释速率的MOFs载体的合理设计提供一种新思路和方法，对完善药物缓释制剂的理论和技术体系具有重要的意义。

开发高担载量、合适缓释速率的药物载体是深化抗癌药物缓释制剂临床应用的研究热点。本课题立意于药物担载量-缓释速率-抗癌疗效之间和谐匹配规律的探讨，寻求主客体相互作用对担载量和缓释功效影响的判据。研究设计合成了5种不同取代基的芳香羧酸配体，与锌离子配位得到了7例Zn-MOFs药物载体和8例其他金属的MOFs药物载体，并对其进行了较为全面的结构和理化性质表征。利用C80型微热量计原位跟踪MOFs对5-氟尿嘧啶 (5-Fu) 的封装和缓释过程，获得主客体相互作用对药物担载量和缓释速率的双重影响规律的热力学及热动力学阐释，筛选出5例高担载量与合适缓释速率的MOF药物载体。材料具有较高的药物担载量（27.2 wt %~44.7wt %)，而且在酸性条件下具有优异的生物降解性质，提高了所负载药物 5氟尿嘧啶的释放效率，增强了抗肿瘤效果。同时采用MTT比色法对载药体系进行体外抗肿瘤活性优选，结果表明，该药物递送体系对人类宫颈癌 HeLa 细胞有较强的杀伤作用，具有很好的抗癌效果。研究结果揭示载体结构—担载量—缓释效果的和谐匹配规律并筛选出缓释功效佳的药物载体种类，为高药物担载量、合适缓释速率的MOFs载体的合理设计提供了一种新思路和方法，对完善药物缓释制剂的理论和技术体系具有重要的意义。