具有靶向及肿瘤细胞内特异释放性能的聚多肽胶束类基因药物共传递体系

Peptide gene carrier with tumor targeting and intracellular specific release properties was designed, which contain hydrophilic part P(Lys-co-Ser) and hydrophobic part PLeu, to construct P(Lys-co-Ser)-PLeu (PLSU). PLSU can self-assembly into micelles. This will make up its weakness that low molecular weight, low charge density leading to low transfection efficiency and on the other hand keep good biocompatibility, low cytotoxicity. Serine can specific response to protein kinase (PKC) in tumor cells by phosphorylated. By changing serine spatial distribution in the molecule, the negative charge distribution in the molecule, after phosphorylation, will be changed, this help to improve the DNA release behavior from carrier. In addition, we will introduce cyclic RGD to carrier, through PEG linker, to make the carrier targeting function. This will improve the gene vector stability and targeted transmission in vivo. Using different tumor cells, murine tumor models, variety of biological means, we will prove the function of the polymeric gene carrier and obtain both tumor cell targeting and intracellular specific release properties of the polymeric gene carriers.

本设计集细胞外靶向、细胞内特异释放功能，结合DNA-DOX构建共传递体系，从而设计开发一种生物相容性好的多肽、胶束载体。该载体由共聚合的赖氨酸和丝氨酸段构成亲水段，聚亮氨酸构成疏水段。通过疏水相互作用使单分子规整组装，一方面弥补其本身分子量较小、电荷密度较低的导致转染效率低的弱势，另一方面保留良好生物相容性、低细胞毒性和体内容易代谢的特点。丝氨酸对肿瘤细胞内特有的蛋白激酶PKC具有特异响应性，通过改变丝氨酸单元在分子内的空间分布，从而改变磷酸化后负电荷在分子内的分布，调控载体对复合DNA的释放行为，实现DNA特定位置的控制释放性能。通过PEG分子将具有靶向功能的环状RGD引入载体上，提高基因载体在体内的稳定性和靶向性传输。两者统一结合，既提高了载体的稳定性，又增加载体在血液的循环时间和特殊靶向识别功能。所以该设计同时实现了细胞外目标位置的靶向识别和目标细胞胞内特异控制释放的双重功能。

本设计集细胞外靶向、细胞内特异释放功能，结合DNA-DOX构建共传递体系，从而设计开发一种生物相容性好的多肽、胶束载体。该载体由共聚合的赖氨酸和丝氨酸段构成亲水段，聚亮氨酸构成疏水段。通过疏水相互作用使单分子规整组装，一方面弥补其本身分子量较小、电荷密度较低的导致转染效率低的弱势，另一方面保留良好生物相容性、低细胞毒性和体内容易代谢的特点。丝氨酸对肿瘤细胞内特有的蛋白激酶PKC具有特异响应性，通过改变丝氨酸单元在分子内的空间分布，从而改变磷酸化后负电荷在分子内的分布，调控载体对复合DNA的释放行为，实现DNA特定位置的控制释放性能。通过PEG分子将具有靶向功能的环状RGD引入载体上，提高基因载体在体内的稳定性和靶向性传输。两者统一结合，既提高了载体的稳定性，又增加载体在血液的循环时间和特殊靶向识别功能。所以该设计同时实现了细胞外目标位置的靶向识别和目标细胞胞内特异控制释放的双重功能。