树枝状聚缩酮的合成、自组装及应用

Dendrimers are a class of artificial macromolecules with a highly branched three-dimensional architecture and well-defined chemical structure. Since their development in the mid-80s, dendrimers have been prominent synthetic macromolecules in the field of biomedical science. Due to the unique ability to control size, structural properties, and polydispersity, dendrimers have achieved significant success in a variety of biomedical applications. While the use of dendrimers in the clinic has still not reached the success of linear polymers, this fact is attributed to the relative newness of this field and the difficulties encountered with the development of novel species with on-demand property at a larger scale. For example, most of the developed dendrimers are not degradable, and most of the degradable dendrimers are polyester-based dendrimers with hydrolytic degradation. pH-responsive degradation is an important property for biomedical applications, but there is not this kind of dendrimers developed by now. In this proposal, we will develop a novel class of pH-degradable polyketal dendrimers and their amphiphilic derivatives, investigate self-assembly and de-assembly behaviors of amphiphilic dendrimers, and explore their potential biomedical applications in drug and gene delivery. The detailed approaches are 1) to design and synthesize ketal-containing monomers with highly non-equal reactivity; 2) to adopt simple and efficient 'click' methodologies for production of novel acid-degradable dendrimers; 3) to yield amphiphilic dendrimers through further modification and coupling of dendrons; 4) to obtain several kinds of assemblies like micelles, vesicles and tubes via controlled self-assembly of the amphiphilic dendrimers; and 5) evaluate their potential applications as smart drug and gene vectors. We expect the results obtained from this project will greatly guide the further exploration of this novel polyketal dendrimers towards the successful use in the clinic for practical biomedical applications.

树枝状聚合物是一种结构完全规整和高度支化的高分子材料，在生物医学领域受到了日益广泛的关注。已开发的树枝状聚合物多数是不可降解的，可降解的树枝状聚合物大多为水解型聚酯类材料，远不能满足生物医学应用的需求，如生物选择性降解的需要。本项目的研究目标是开发一类新型酸降解的树枝状聚缩酮及其两亲性共聚物，研究自组装和解组装行为，并探索其在生物医学领域如药物和基因输送上的应用。具体研究手段是设计和合成具有高度非等活性的双缩酮单体，采用高效温和的点击加成手段制备树枝状聚缩酮，进一步改性或耦合得到一系列两亲性树枝状共聚物，研究共聚物溶液组装行为构筑多种形貌的组装体，通过体外细胞实验和裸鼠移植瘤的治疗效果评价实验，评估新型树枝状聚缩酮、共聚物及组装体在药物和基因输送上的应用前景。预计相关研究成果将为开发基于新型树枝状聚缩酮的生物医用高分子材料奠定良好的基础。

聚缩酮是一类可降解的高分子材料，其缩酮键在弱酸作用下断裂而使材料降解。本项目立项之时，树形聚缩酮的研究刚刚开始起步，特别是结构完全规整树枝状聚缩酮的制备尚未有报道，其应用研究完全是个空白。.本项目研究目的是通过分子设计合成特定单体，利用高效温和的交替选择性反应制备新型酸响应降解型的树枝状聚缩酮；通过末端基的改性，制备树枝状聚缩酮纳米药物体系，为开发基于树枝状聚缩酮的生物医用高分子材料奠定坚实的基础。.项目研究内容是合成非等活性的双缩酮单体及相对应的特定设计单体，采用多步高效点击反应制备新型树枝状聚缩酮。通过改变拓扑结构，合成了具有扇形结构的树枝状聚缩酮以及与药物键合的新型树枝状聚缩酮载药体系，探讨它们在药物输送中的应用前景。.项目研究已达到预期目标，发表了35篇通讯文章，获得中文授权专利2项(ZL201410035950.8; ZL201410200254.8)，同时有多篇相关文章在准备中。.我们分别设计合成了不对称酯类和酰胺类的缩酮单体，通过多步高效不对称选择性的交替重复反应和高效点击加成反应制备新型酯类和酰胺类的树枝状聚缩酮。将所得到的树枝状聚缩酮通过化学修饰的方法接上聚乙二醇和两性离子，研究它们在不同pH条件下的自组装行为。在此基础上，以树枝状聚缩酮为载体，研究其对药物的负载情况，以及对肿瘤癌细胞的杀伤力。.通过改变内核的结构，合成了具有扇形结构的树枝状聚缩酮以及与药物键合的新型树枝状聚缩酮载药体系，验证其在不同酸性环境下的组装行为。将模型药物如紫杉醇、阿霉素通过化学修饰或物理包裹负载到树枝状聚缩酮中，评价纳米药物载体的有效性，为其在生物医用领域的应用奠定坚实的基础。