新型亲水性有序介孔纳米碳球的制备及其难溶性药物载释调控研究

Utilization of inorganic mesoporous materials in formulations of poorly water-soluble drugs to enhance their dissolution and permeation behavior is a rapidly growing area in pharmaceutical materials research. There is no doubt that mesoporous carbon possesses many advantages due to its inert nature, low toxicity, large surface area, pore volume, stronger adsorbability, and other physicochemical properties, so, it is capable of a higher degree of drug loading. Moreover, carbon materials are inert substances that are safe and nontoxic. All of these features are advantages and support the potential benefit of using mesoporous carbon as a drug delivery vehicle. Specifically aiming the drawbacks of the materials in drug delivery, such as bad hydrophilicity and poor biocompatibility，we are going to synthesis superficial hydrophilic-modified ordered mesoporous carbon spheres and evaluate the performance on drug loading and release. In previous study, ordered mesoporous carbon spheres were synthesized by low-concentration hydrothermal and self-assembly methods. Then, the hydrophilic modification is going to carry out to increase the specific surface area, hydrophilicity and insoluble drug loading efficiency, which can decrease the toxicity to acquire appropriate insoluble drug-loading ordered mesoporous carbon spheres. Further study will focus on the mechanism of carrier mediated drug loading and release by testing the insoluble drug loading and release characteristics, stability in vivo, and also cytotoxicity to estimate the loading efficiency, dissolution rate and the accumulative dissolution rate on different modal drugs. This project will contribute greatly on illuminating the relationship between structure and effects, the mediating mechanism of porous structure and surface character in drug loading and release, and exploring the exploring carbon carrier mechanism affecting drug solubility. We believe this project will provide information to improve the dissolution rate of poorly water soluble drugs and, furthermore, improve their therapeutics effects while reducing their side effects.

改善难溶性药物溶解性是药学研究中的重要问题。介孔碳纳米材料具有孔径尺寸可调节、分散性好、悬浮稳定性高、载药性能好、释药可控等特点，有望成为新型难溶性药物分子载体材料。针对介孔碳纳米材料亲水性与生物相容性差的缺点，本项目拟设计合成表面亲水修饰的有序介孔纳米碳球材料并评价其对难溶性药物的载释性能。前期我们已通过低浓度水热与自组装法合成了有序介孔纳米碳球，拟采用双氧水氧化法对碳球表面进行亲水性修饰，增大材料的比表面积和亲水性，提高其负载难溶性药物的能力，获得适合负载难溶性药物的有序介孔纳米碳球材料。进一步对难溶性模型药物的载释特性、体内稳定性、细胞毒性等进行研究，评价其对不同难溶性模型药物的负载、溶出速率以及累积溶出率的影响，探索载体调控药物载释的机制。本研究有助于阐明碳纳米药物载体的结构-性能之间的构效关系，揭示孔道结构和表面性质在药物载释过程中的调控机理，探索碳载体影响药物溶解性的机制。

改善难溶性药物溶解性是药学研究中的重要问题。介孔碳纳米材料具有孔径尺寸可调节和释药可控等特点，有望成为新型难溶性药物分子载体。针对介孔碳亲水性与生物相容性差的缺点，本项目设计合成了表面亲水的有序介孔纳米碳球并评价其对难溶性药物的载释性能。有助于阐明碳纳米药物载体的结构-性能之间的构效关系，揭示孔道结构和表面性质在药物载释过程中的调控机理，探索碳载体影响药物溶解性的机制。.首先通过低浓度水热合成技术合成有序介孔碳纳米球，采用双氧水氧化法对碳球表面进行亲水性修饰，增大材料的比表面积和亲水性，提高其负载难溶性药物的能力。选用两种BCSⅡ类难溶性药物盐酸阿霉素和紫杉醇为模型药物，考察其生物相容性，载药量以及药物释放行为，评价载药体系的体内外抗肿瘤活性。内容包括介孔碳球纳米粒用于盐酸阿霉素传递系统的研究以及用于抗肿瘤药物紫杉载体可行性的研究。.接下来，选用紫杉醇为模型药物，考察载药体系的载药量以及药物释放行为，评价载药体系的体内外抗肿瘤活性。进一步采用两亲高分子PVP和DSPE-mPEG2000对材料表面进行修饰，改善了表面性质和分散特性，考察了表面修饰对材料细胞毒性和氧化应激状态的影响，为表面修饰MCN在药物载体领域的应用提供依据。另外，磁性介孔硅纳米材料集磁性纳米粒与介孔硅材料的优点于一身，既具有磁性材料所具有的磁靶向性、磁共振成像等特点，同时又结合了介孔硅材料大的孔径及孔容、高的比表面积、稳定的骨架结构、易于修饰的内表面等特性，使其具有重大的研究意义及广阔的应用前景。构建了pH响应性磁性介孔硅纳米复合材料，初步考察了其在光动力治疗过程中的应用。内容包括用PVP和DSPE-mPEG2000表面修饰介孔碳，从细胞水平到动物水平对粒径90nm的介孔碳的生物相容性进行评价，并研究了修饰高分子PVP和PEG后对介孔碳生物安全性的影响，为介孔碳在临床医药领域的应用提供一定的毒理学理论依据。