非线型糖聚合物共输运载体的设计、制备及其在支气管哮喘中的应用

Bronchial asthma is one of the most common airway diseases. The official therapy for asthma is inhaled glucocorticoid for long-term. However, this may take considerable side-effects. Co-delivery of half-dose glucocorticoid and anti-asthmatic gene into asthmatic bodies, are expected to reduce the glucocorticoid dose but not anti-asthmatic effects. And the key to achieve this goal is to successfully construct efficient co-delivery vehicles for the treatment of bronchial asthma. Herein, this project is to find out the optimal non-linear glycopolymer nanocarriers for the co-delivery of budesonide and asthma genes in asthmatic mice. The specific content of this project is as follows : 1. We will design and prepare novel nano-carriers based on non-linear glycopolymers, which have lower CMC , toxicity and the capability to carry medicine and gene simultaneously. 2. We will screen out co-delivery vehicles which show good transfection efficiencies under serum condition and meet the in vivo study needs. 3. The effects of co-delivery of inhaled glycocorticoid (budesonide) and anti-asthmatic gene IL-23p19 on the asthmatic mice will be studied. This is the first time to put co-delivery technology into treatment of bronchial asthma which may open a new treatment mode for bronchial asthma.

将吸入性激素与抗哮喘基因共同输运至哮喘机体，可望在减少激素带来的副作用的同时增强抗哮喘效果。而达到这个目标的关键在于设计并制备适合支气管哮喘体系的共输运载体。本课题拟设计并合成新型的非线型糖纳米载体，以使其适用于布地奈德及抗哮喘基因在哮喘小鼠气道中的共输运。具体研究内容如下：1.设计并合成基于非线型糖聚合物的一系列纳米共输运载体，使其能同时携载药物与基因，且具有较小的临界胶束浓度和明显低毒优势；2.筛选出适合体内实验的糖聚合物共输运载体，使载体在有血清环境下能够成功进行基因转染；3.利用这种共输运载体同时输运糖皮质激素（布地奈德）以及抑制哮喘基因IL-23p19 ，研究其对哮喘小鼠气道炎症的影响。本课题为糖聚合物共输运载体在支气管哮喘治疗中的首次尝试，这将为开启多源化导入治疗支气管哮喘开辟新的道路。

本项目设计并合成了能够同时携载药物分子（布地奈德）和质粒DNA的新型糖聚合物纳米载体，有望作为支气管哮喘体系的共输运载体。首先，我们通过“活性-可控”聚合法制备出结构组成精确可控的可降解含糖聚电解质(PCL-b-PAMA-b-PGAMA, Dextran-g-P(DMA-co-LAMA), Curdlan-g-PDMA)。其次，通过对含糖聚电解质的接枝密度、单体聚合度以及化学组成进行调控，我们发现了含糖聚电解质的分子结构与转染效率、细胞毒性、含糖聚电解质-基因复合物稳定性之间的关系。这些新型糖聚合物具有很好的耐血清性、低细胞毒性和高基因转染效率，它们在非病毒基因转染载体方面具有较好的应用前景。