多糖基两性离子聚合物与基因工程细胞微囊化装载体系

Genetic engineering cellular therapy is one of the most exciting fields in translational medicine. Yet, despite some promising results, the field has not lived up to expectations. The host response is a potentially serious and deleterious problem to the clinical implementation of the technology. Cell microencapsulation is an effective way to promote the application of the genetic engineering cellular therapy. However, formation of fibrotic capsule in vivo around the microcapsules, easy to be borken and lack of excellent permeability have been being the two key problems. In order to prevent the fibrotic capsule formation and capsules breaking, a series of novel polysaccharide-based zwitterionic polymers (PSZP) will be designed and prepared in this project. PSZP will be endowed with highly protein-resistant ability, good mechanical strength, biocompatibility and thermo-sensitivity. Therefore, the cell microcapsules with PSZP as the outside layer will restrain the fibrosis and breaking effectively. The construction of core-shell microencapsules with alginate as core and PSZP as shell could precisely control their permeability, mainly depends on the diversity gel formation mechanism and chemical properties. The MSCs/Es that could secrete Endostatin will be used as the model cells. The novel core-shell cell microcapsules may play an important role in the inhibition of the tumor growth and metastasis. The ideas and results of this project will provide a sensible way to set up a new platform for the deep understanding of the action mechanism of the transplanted cell in vivo and push comprehensive progress of cell therapy technology.

基因工程细胞治疗是当今医学领域中的一大研究热点，但由于机体免疫排斥反应的发生，严重制约了这一治疗手段的临床应用。细胞的微囊化装载技术为基因工程细胞的应用提供了新途径。但细胞微囊在体内的囊周纤维化、易破碎及透过选择性差是该项技术所面临的三大瓶颈问题。本项目拟首先设计及合成同时具有超高抗蛋白质非特异性吸附性能、良好的力学性能、优异的生物相容性及温敏性的新材料－多糖基两性离子聚合物(PSZP)。以藻酸盐为囊芯，PSZP为囊壁，构建细胞微囊化体系，解决微囊囊周纤维化及易破碎的问题；同时，利用微囊囊芯与囊壁材料的结构与凝胶形成机理不同，精确调控微囊的透过选择性。以可分泌内抑素的干细胞MSC/Es为模型细胞，研究细胞微囊化装载体对肿瘤生长及转移的抑制效果。研究思路及结果将为深层次认识细胞移植后在体内的机制搭建科学的研究平台，有效地推动细胞治疗技术的发展，为人类疾病的治疗打开全新的思路。

细胞治疗是当今医学领域中的一大研究热点，但由于机体免疫排斥反应的发生，严重制约了这一治疗手段的临床应用。细胞装载技术为基因工程细胞的应用提供了新途径。但载体在体内的纤维化、及透过选择性差是该项技术所面临的瓶颈问题。本项目首先设计并合成了同时具有超高抗蛋白质非特异性吸附性能、良好的力学性能及优异的生物相容性的新材料－淀粉基两性离子聚合物，并揭示了其具有抗蛋白质吸附性能的作用机理；采用FRAP测量了蛋白在PSBMA水凝胶中的扩散系数。基于空间阻碍理论建立了新的扩散模型，验证了新建模型对蛋白质在水凝胶的扩散系数具有准确的预测能力。进一步通过物理聚集及点击反应，制得了淀粉基两性离子聚合物水凝胶，详细研究了其理化性能及其作为载体在细胞装载中的应用；同时以淀粉基两性离子聚合物为药物载体，构建了隐形胶束，详细研究了其在体内的长循环特性及抗癌活性。结果表明所合成的淀粉基两性离子聚合物不仅具有良好的抗蛋白非特异性吸附性能，同时具有良好的生物相容性和可降解性，研究结果为进一步拓宽其在细胞治疗及药物释放领域奠定了良好的基础。