高分子量聚缩酮的制备、性能表征及其生物医学应用的研究

Injectable long-acting protein loaded microparticles are promising in management of chronic diseases by improving protein's bioavailability and therapeutic efficacy, reducing protein's side effects and overcoming patient noncompliance. However, the successful development of long-acting protein microparticulate formulations is significantly hampered by protein's complicated structure, high molecular weight and labile property, and burst release. Polyketal, whose degradation products are neutral, is a new kind of surface-erodible polymer. Polyketal microparticles could improve the stability of protein and minimize the burst release of protein, and therefore have a great potential in developing long-acting protein loaded microparticles. However, due to lacking of facile synthetic method of high molecular weight polyketals and investigations of their properties and biomedical evaluations, application of polyketal in drug delivery and biomedical engineering is significantly limited. To solve these problems, we will design and synthesize isopropenyl ethers containing a hydroxyl group as new monomers, which can undergo self-addition polymerization; we will establish the optimum conditions for obtaining high molecular weight of polyketals and their functionalization method; we will focus on the studies of the relationship between the composition of polyketals and their physiochemical properties of polyketal microparticles, such as morphology, mechanical property and release kinetics of protein from microparticles; in vivo, we will further investigate biodegradation behaviors and biocompatibility of polyketal microparticles and pharmacokinetics of protein after intravitreal injection of protein loaded polyketal microparticles in a rabbit model. It is expected to explore a reasonable strategy to prolong the release of protein from microparticles and provide valuable guide to the exploitation of long-acting protein loaded microparticles and clinical therapy of chronic diseases.

可注射长效蛋白质微球，可提高蛋白质生物利用度和药效、降低副作用以及改善患者顺应性，可有效控制慢性病。然而蛋白质结构复杂、分子量大、稳定性差以及缺乏性能合适的药用辅料，限制了其缓释制剂的发展。聚缩酮是一种降解产物为中性的新型表面溶蚀型聚合物，用于蛋白质缓释可改善蛋白质稳定性、克服药物突释等问题。然而目前，高分子量聚缩酮的合成方法不成熟，并且缺乏对其结构与性能和生物学行为之间关系的研究，导致聚缩酮的应用受到限制。本项目拟制备新型异丙烯氧基醇类单体，通过新合成方法的建立以及合成机理、规律的揭示，解决高分子量聚缩酮的合成和功能化难题；深入揭示聚缩酮结构与其微球性能的关系，实现对微球表面结构、机械性能以及蛋白质释放特性等性能的可调控性；全面揭示聚缩酮体内生物学行为，如降解行为、生物相容性以及蛋白质缓释微球药代动力学性质等。为具有临床应用前景的长效缓释蛋白质微球的设计和慢性病临床治疗提供指导和依据。

针对聚缩酮合成难、缺乏对其结构与性能和生物学行为之间关系的研究等问题，本项目研究了聚缩酮关键单体异丙烯基醚的合成新方法学，不对称缩丙酮的可控构筑、水解行为及其影响因素，以及聚缩丙酮的制备方法，并初步揭示了缩丙酮前药的结构与其性能之间的关系。同时，还研究了新型线性聚原酸酯生物医用高分子的合成及其在蛋白质胞质递送中的应用。标志性创新成果有：（1）首次提出了Brønsted酸碱对催化醇与2-甲氧基丙烯发生转异丙烯化反应的学术思路，开发了一种有机催化剂催化醇转异丙烯基醚的合成新方法，并获得了高效Brønsted酸碱对催化剂及最佳反应条件，解决了异丙烯基醚传统合成方法存在的官能团不耐受、底物范围窄和操作难的问题，为生物医用缩丙酮材料的制备提供了方法学基础；（2）结合上述异丙烯基醚合成新方法，利用异丙烯基醚与含羟基药物的反应，成功开发了针对含羟基药物的线性缩丙酮前药技术平台，取得了线性缩丙酮前药构筑技术上的突破，率先研究了这类新型酸敏感前药的可控合成、构效关系、体内外药理活性和药物递送及疾病治疗的功效，为缩丙酮前药的应用提供了数据参考和理论依据；（3）由商业易得的乙烯基醚和二元醇制备了一系列无环双烯酮缩醛，利用酸催化无环双烯酮缩醛与二元醇发生聚加成聚合，进而首次制备线性聚原酸酯，提供了一类新型酸敏感的可降解高分子生物材料，并成功用于抗原蛋白的高效胞质递送和特异性免疫激活。.项目执行期间共发表SCI论文10篇（第一标注8篇；第四标注2篇）；在影响因子大于10的期刊（Nature Communications、Angewandte Chemie International Edition、Nano Letters、ACS Nano）上发表论文5篇；申报发明专利4项；培养博士7人（3人完成博士学位论文），培养硕士4人（3人完成硕士学位论文）。参加国内举办的学术会议13个（15人次报告或墙报展讲）。