丝胶蛋白微胶囊的仿生制备及其表面矿化修饰的研究

Polymer-based microcapsules are one of the drug carrier systems, which are hollow capsules with the micron dimension. Due to their potential application, the current research focuses on the fabrication of microcapsules and their optimization as well as the intellectualization. Here, we propose a systematic research about the fabrication of the silk sericin-based microcapsules through the protein self-assembly. Specifically, we plan the following aims: (1) to study the effect of system conditions (e.g., calcium concentration, pH value, temperature, ect.) on the fabrication of microcapsules, including capsule size, thickness of capsule wall and stabilization, and further to clarify the effect of system conditions to the self-assembly of silk sericin and structural transition mechanism; (2) to construct the organic/inorganic composite microcapsules with core-shell structure by the surface mineralization of capsule with calcium phosphate in order to improve their stabilization and permeability, and to know the pH-sensitivity of the composite microcapsule; and (3) to study the ability of drug loading, storage and controlled release of the composite microcapsules to the typical antitumor drugs, like doxorubicin and doxorubicin hydrochloride. Our objective is to understand the fabrication mechanism of composite microcapsules under different conditions, so as to control the formation of composite microcapsules. This insight has strong implications for: (1) fabrication of stable microcapsules by simple method, and (2) controllable loading and release of active factors and sensitive drugs of microcapsules as the drug carriers.

以聚合物为基材，尺寸在微米量级的中空胶囊是目前被广泛研究的一种药物载体。由于微胶囊潜在的应用前景，如何完善其制备方法、优化其功能并赋予其智能性是该研究领域的热点。本项目拟以天然蚕丝蛋白- - 丝胶为基材，利用其自组装构建微胶囊，探索反应体系中钙离子、pH、温度等对微胶囊形成过程、尺寸、囊壁厚度、稳定性等的影响，阐明体系微环境对丝胶蛋白自组装行为的影响规律；并利用磷酸钙对丝胶蛋白微胶囊进行表面矿化修饰，构筑具有核壳结构的有机（丝胶蛋白）/无机（磷酸钙）杂化微胶囊复合体，改善其通透性和结构稳定性，并探索该杂化微胶囊对环境pH的刺激响应性；以抗肿瘤药物阿霉素和盐酸阿霉素为药物模型，研究该杂化微胶囊的药物负载、储存及控释性能。本项目拟构建的丝胶蛋白内壁-无机壳杂化微胶囊的制备方法简单、结构稳定，有利于活性因子和敏感药物的包载和释放，可为微胶囊的制备及其作为药物载体的应用提供一条新的途径。

有机物微胶囊具有重要的理论研究价值，且在很多领域特别是药物载体方面具有潜在应用前景，是当今研究非常活跃的领域，完善其制备方法、优化其功能并赋予其智能性是人们孜孜以求的目标。本课题以丝胶蛋白为基材，利用蛋白自组装性质构建了有机微胶囊，探索反应体系中钙离子、pH、温度等对微胶囊形成过程、尺寸、囊壁厚度、稳定性等的影响；并采用生物仿生矿化的方法，以含有柠檬酸的过饱和的磷酸钙溶液为矿化液，在pH为7.4，温度为37℃的条件下，制得了羟基磷灰石/丝胶蛋白杂化微胶囊，该杂化微胶囊保持良好的中空性，为后续的药物负载与释放提供了基本条件。将淀粉作为模拟药物封装至丝胶蛋白微胶囊与杂化微胶囊中，研究了淀粉的释放速率和累计释放量。研究结果表明因无机矿化壳层的存在，杂化微胶囊显示出更好的稳定性，使得模拟药物在长程性释放中具有一定的优势。通过将杂化微胶囊和细胞共同培养发现该杂化微胶囊可以促进细胞的生长和增殖，具有良好的生物相容性。该羟基磷灰石/丝胶蛋白杂化微胶囊用作抗肿瘤药物盐酸阿霉素的载体，其药物负载率约为28%，药物释放趋势与模拟药物的释放趋势相似，可以用作阿霉素的控制释放。通过将有机微胶囊和功能性外壳相结合，我们为微胶囊药物载体的可控制备和功能化修饰提供了一条行之有效的思路和策略。所制得的杂化微胶囊在药物储存、药物保护、药物输送及癌症治疗等方面具有广阔的应用前景。.在国家自然科学基金的资助下，四年的研究工作均按照研究计划来开展，并已顺利完成。经过四年的研究，发表SCI刊源论文21篇，获授权国家发明专利8项，在本项目的资助下，已培养硕士毕业研究生13名，博士毕业研究生2名。全面完成了所计划研究内容和指标。