预水解LCC的形成机制、定向修饰及其新型乳液递送体系

Controlled release technology is an effective approach to alleviate the toxic side effects of plant-derived anticancer drugs. In the early-stage study, the amphipathic lignin-carbohydrate compound (LCC) was extracted from poplar prehydrolysis liquor. Directional modification of LCC made the natural product a great potential candidate for preparing nanospheres, which could encapsulate paclitaxel and show controlled-release effect, by means of a simple self-emulsifying method. However, the formation mechanism of prehydrolysis LCC was still to be solved, and the relationship between modified structures and controlled-release behaviors still remained unclear. In this project, β-O-4´, 5-5´ and β-5´ lignin models will be synthesized and utilized to reveal the formation path of prehydrolysis LCC. By introducing hydrophobic aliphatic compound and reducing hydrophilic carbohydrate group, the LCC from lignocellulose prehydrolysis liquor will be modified so as to realize the regulation of composition and structure. Stable LCC nanospheres will be prepared through self-emulsification, and encapsulate plant-derived anticancer drugs to form a novel drug carrier. Controlled release efficiency will be studied for elucidating the 3D structure-activity relationship with LCC composition, structure and its microsphere conformation. The above research will provide references to the development of controlled-release materials, and give a new way for the use of LCC.

控制释放是缓解植物源抗肿瘤药物毒副作用的有效途径。申请者前期研究发现，通过杨木预水解提取的天然两亲性木质素-碳水化合物复合体（LCC），经定向修饰可获得具有自乳化能力的理想纳米微球，显示优良的药物包裹控释作用。但对预水解LCC的形成机制及其定向修饰后分子结构与包裹控释行为的关系等关键科学问题尚不清楚。本项目将采用β-O-4´型、5-5´型和β-5´型三种木质素模型物，分别与碳水化合物混合预水解，解析预水解LCC的形成途径。通过引入长链脂肪族化合物和调控木质素/碳水化合物比例，对木质纤维预水解LCC进行分子修饰，实现预水解LCC组成和结构的定向调控。自乳化形成稳定的LCC纳米微球，包裹植物源抗肿瘤药物，构建LCC组成、结构及其微球微观构象与控释效率的三维构效关系。上述研究将为LCC新的丰富来源和新的应用领域提供理论基础。

分别利用杨木（阔叶木）和马尾松（针叶木），全面研究了预水解过程中木质纤维化学组成的降解和溶出规律。在此基础上，首次实现了预水解LCC的分离、表征，并提出了预水解LCC可能存在的化学结构。阔叶木预水解液中更容易形成LCC，且LCC中木质素主要由紫丁香基结构单元组成，并通过β-O-4´键连接。同时，预水解LCC中存在苯基糖苷键和伽马酯键。葡甘露聚糖与木质素通过苯基糖苷键连接；葡萄糖醛酸木聚糖与木质素通过伽马酯键连接。此外，预水解LCC的化学组成、结构高度依赖于热水预处理条件，可通过适当调节预水解温度对LCC的组成、结构进行调控，选择性地释放甘露糖型LCC或木糖型LCC。研究发现预水解LCC中含有大量羰基，这为通过美拉德反应设计新型两亲性聚合物提供了条件。预水解LCC与十二胺接枝共聚，生成新型两亲性聚合物，接枝率为0.31-1.65。这样就可获得不同亲水/疏水比值的两亲性聚合物（HLB值8-20），满足不同药物的包裹和控释需求。通过乳化，制备的新型乳液递送体系，发现乳化性能良好，储存稳定。4℃条件下保存90天，乳液粒径仍可以保持在纳米级别。同时，研究还发现，该新型乳液递送体系具有较好的紫杉醇载药量和包封率，且表现出pH响应缓释性。这些结果表明，该新型乳液递送体系有望实现肿瘤细胞的靶向缓释功能，势必将在食品和制药领域引起广泛的兴趣，特别是作为疏水抗癌药物的递送系统。