通用细胞膜粘接剂的合成与局部药物递送性能的测试

Eukaryotic cell consists of a nucleus, cytoplasm and cell membrane. The cell membrane is a biological membrane that separates the interior of all cells from the outside environment. It consists of the phospholipid (Phosphatidyl Choline lipids) bilayer with embedded proteins. Cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall, glycocalyx, and intracellular cytoskeleton. However, what happens if we reverse the phosphate and choline? I didn't know but it rapidly became clear that nature did not make lipids or related species that contained the choline phosphate (CP) moiety; perhaps there was a reason that none had evolved although the structures of PC and CP ought to have similar properties unless they were oriented. As results of research, we found that simply reversing the order of the PC headgroup to CP produced a weak attraction between the two groups.The multivalent CP species could produce strong, controllable adhesion to any cell membrane containing PC-lipids, i.e. to any mammalian cell. The binding reaction can be reversed at some stage.We believe this is a new observation that will have many applications in the munipulation of biological systems at the whole cell level. This new binding mechanism will open new fields in molecular biology and cell biology, and will have broad applications in tissue engineering, locacal drug delivery et al., and will have a great impact on the development of cell biology and clinic medicine.

药物载体系统是研究如何将有效治疗成分透过生物屏障，在指定的时间输送至靶细胞，并将药物的毒副作用降至最低，与发现新的治疗成分相比显得更为重要。多价胆碱磷酸（Choline Phosphate，CP）高分子材料可以快速粘接在具有磷脂结构的细胞膜表面（所有哺乳动物细胞），并且可以可被真核细胞快速内吞到细胞质内，因此可以作为药物载体材料应用到癌症等疾病的局部治疗领域。本项目以可聚合单体2-(Methacryloyloxy)ethyl Choline Phosphate（MCP）为细胞膜粘接剂的活性中心，聚合后得到多价CP高分子PMCP，通过’click’反应将聚乳酸接枝到PMCP的链端，制备嵌段共聚物PMCP-b-PLA，然后将PMCP-b-PLA制备亲水性胶束用于包裹紫杉醇，制备药物运载系统。通过体外细胞实验检测该药物运载系统的生物安全性，稳定性和治疗效果。

药物在病灶部位的快速内在化和可控释放是癌症治疗方面的两个具有挑战性的课题。我们充分利用了多价胆碱磷酸（PCP）的优异特性，初步实现了多价胆碱磷酸——抗癌药物复合给药体系对于肿瘤细胞的快速粘接、快速内在化以及可控释放。在本项目中，我们采用了化学键接的方法制备了高分子前药给药体系，即聚甲基丙烯酸胆碱磷酸脂-聚甲基丙烯酸酰肼基阿霉素嵌段共聚物（PCPDox），该体系中阿霉素（Dox）通过酰肼键与高分子相连接，可以在微酸环境（pH 5.0-5.5）实现Dox的释放。我们还利用了高分子囊泡的方法实现对药物进行物理包覆制备复合给药体系，即利用聚甲基丙烯酸胆碱磷酸酯-聚甲基丙烯酸-2-N,N-二异丙基乙酯（PMCP-b-PDPA）和聚甲基丙烯酸胆碱磷酸酯-s-s-聚己内酯（PMCP-s-s-PCL）嵌段共聚物分别与Dox制备复合给药体系。PMCP-b-PDPA和PMCP-s-s-PCL在较温和条件下（pH≥6.4），可以和Dox组装成高分子胶束，而且Dox的负载量可以达到22.1%（质量含量）。细胞实验充分证明：PCP药物输送体系具有良好的生物兼容性、对于正常组织细胞的低毒性、可以加速肿瘤细胞的内在化作用，并且具有良好的治疗效果。因此，作为性能优异的新药物载体材料，PCPs高分子可以作为药物、蛋白及核酸的载体材料用于治疗成分的靶向输送，提高内在化效率，逐步实现对于癌症的定向/靶向治疗。