阳离子基因载体的pH敏感遮蔽材料及评价方法的构建

项目名称： 阳离子基因载体的pH敏感遮蔽材料及评价方法的构建

项目编号： No.51203132

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 有机高分子材料学科

项目作者： 夏加亮

作者单位： 湛江师范学院

项目金额： 25万元

中文摘要： 阳离子聚合物基因载体的研究已取得很大进展，但其综合性能距体内应用还有很大差距，载体/DNA复合物在体内缺乏稳定性和智能性是瓶颈问题之一。本项目将不同pKa的磺胺衍生物接枝到PEG-PLL上，制备一类含PEG链段、pH敏感且可生物降解的材料用以对载体/DNA复合物进行遮蔽。该遮蔽材料通过对复合物正电荷的有效遮蔽和PEG链对蛋白的抗拮作用，有效降低非特异性作用，提复合物在体内循环的稳定性和循环时间；磺胺单元的pH敏感性赋予遮蔽材料"在正常体液中（pH=7.4）对复合物有效遮蔽，到酸性肿瘤组织（pH<6.8）释放出复合物"的智能性。这种智能性保证了循环过程中对复合物的保护，又不影响肿瘤细胞对复合物的摄取。体内试验是评价pH敏感遮蔽的有效方式，但试验条件要求高，难实施，难普及。本项目还通过在线改变培养液pH的方式探索以体外模拟试验代替体内试验，对pH敏感遮蔽材料体内应用性能进行预评价的普适性方法。

中文关键词： 基因传输；肿瘤治疗；pH敏感；遮蔽体系；体外试验

英文摘要： Researchers made great progress on cationic gene carriers. But the lack of stability and intelligent of gene carrier/DNA polyplexes make it hard to be systemic delivery in tissue. In this project, we graft sulfa derivatives with different pKas to PEG-PLL main chain to produce a kind of shielding system, which contains PEG segments and shows pH sensitivity and biodegradability. Sulfa derivatives show negtive charges at higher pH and can shield the positive charge of polyplex by electrostatic interaction. The anti-protein property of PEG segments and positive charge shielding can both reduce the non-specific interaction and prolong the circulation time and stability during blood circulation. Because of the pH sensitivity of sulfa derivative, the shielding system can protect the polyplexes during the cycle in normal body fluid (pH=7.4) and release it when arrive the acidic tumor tissue (pH&lt;6.8). This intelligent shielding/de-shielding process not only improves the stability of polyplexes but also promotes the cellular uptake of polyplexes in tumor tissues. The most persuasive way of pH sensitivity characterization of these shielding systems is in vivo studies. But highly requirement demanding of in vivo studies made it hard to be carried out and popularized. This project explores to construct novel in vitro tests b

英文关键词： gene delivery；tumor therapy；pH sensitive；shielding system；in vitro