多功能有机/无机杂化纳米粒眼用给药系统的研究

The short precorneal residence time and low corneal permeability are two obstacles for ocular drug delivery. Phacolin（PCL）will be selected as a model drug. Layered Double Hydroxides (LDHs) with high density charge, high specific surface area,high adsorption characteristic, good stability and excellent biocompatibility, will be used as carriers. Novel multifunctional organic-inorganic hybrid nanocomposites for ophthalmic drug delivery will be assembled with LDH and three kinds of chitosan-thiomers with enhancing bioadhensive and penetration enhancing effect（chitosan-glutathione, chitosan-glutathione-2-mercaptonicotinic acid and amino acid/dipeptide-chitosan-glutathione-2-mercaptonicotinic acid with active targeting for oligopeptide transporter）. The controllable assembler and multifunction will be studied for the organic-inorganic hybrid nanocomposites. With in vitro, in situ, in vivo and cells studies the optimal degree of substitution with glutathione, 2-mercaptonicotinic acid and amino acid/dipeptide of chitosan will be found and the technical parameters of this novel drug delivery system will be optimized. This study will reveal the rules between structures of organic-inorganic hybrid nanocomposites and their multifunctions of active-targeting, bioadhension, electrical adsorption and penetration enhancing effect and precorneal residence time increasing effect. It will also support theory and technology for the development of novel multifunctional organic-inorganic hybrid nanocomposites of ophthalmic drug delivery for posterior segment of the eyes. This study is important for demonstrative providing design space and application prospect for special and multifunctional organic-inorganic hybrid nanocomposites.

眼表药物滞留时间短和角膜渗透性低是眼部给药两大技术难题。法可林（PCL）为模型药，以具高电荷密度、大比表面积、吸附性好和稳定性好的生物可相容无机层状双氢氧化物（LDH）为载体。研究普通PCL-LDH纳米粒，三种生物粘附兼促渗功能递进的壳聚糖巯基物（壳聚糖－谷胱甘肽、壳聚糖－谷胱甘肽-2-巯基烟酸和具主动靶向眼表寡肽转运器的壳聚糖-氨基酸/二肽－谷胱甘肽-2-巯基烟酸）分别杂化PCL-LDH纳米粒的多尺度可控组装和功能集成调控。通过体外、离体、细胞和体内研究找到壳聚糖上谷胱甘肽、2-巯基烟酸及氨基酸/二肽修饰平衡点，优化递药系统技术参数，揭示有机/无机杂化纳米粒结构与主动靶向，巯基粘附，电性吸附和促渗，延长滞留时间等功能的构效关系，为开发新型高效眼中后段纳米给药系统提供理论和技术支撑。本研究示范性地为开发具有特殊功能的、多性能的复合杂化纳米材料提供广阔的设计空间和应用前景，具有重要指导意义。

眼表药物滞留时间短，角膜渗透性低和眼部靶组织药物浓度低是眼表给药的三大技术难题。面上项目多功能有机/无机杂化纳米粒眼用给药系统的研究（81373362）在四年的实施期内主要进行了四个子课题的研究。进行子课题A插层杂化型巯基壳聚糖（CG和CG-2MNA）-LDH纳米粒的结构和功能的关系研究；子课题B主动靶向插层杂化型壳聚糖衍生物（CG- V，CG-VV）-LDH纳米粒的结构和功能的关系研究；子课题C主动靶向型壳聚糖衍生物-LDH纳米片的结构和功能的关系研究；子课题D主动靶向插层杂化型壳聚糖衍生物（CG-GS）-LDH纳米粒的结构和功能的关系研究 基于上述四个子课题层层递进式的探索研究，通过LDH不同粒径（200nm和100nm），不同微粒形态（六角层状和球状），不同阳离子（Zn-Al-LDH和Mg-Al-LDH），不同LDH状态（层状和纳米片），不同功能化的壳聚糖巯基物（CG和CG-2MNA；主动靶向型CG-V，CG-VV和CG-GS；功能化GS和主动靶向靶头密度差异）和不同的有机/无机杂化态（嵌插杂化型纳米粒和包覆型纳米片）的研究，发现主动靶向型有机（CG-VV和CG-GS）/无机LDH嵌插杂化纳米复合物滴眼液眼部递药系统生物相容性较好，具有良好的生物粘附性及主动靶向性，可显著延长药物在眼表的滞留时间，显著提高眼表的渗透性，明显提高了眼表至中后段靶组织的药物生物利用度。该项研究通过眼表局部给药治疗眼部各段的疾病，提高了患者的顺应性，显示出良好的应用开发前景。本研究示范性地为开发具有特殊功能的、多性能的复合杂化纳米材料提供广阔的设计空间，具有重要的指导意义。该项有机/无机LDH杂化纳米复合物滴眼液眼部给药系统的研究层次在国内外处于领先水平。