Synthetic Biodegradable Zwitterionic Polymers

项目总结 合成聚合物生物材料在生物医学领域有着广泛的应用。然而，FDA批准的脂肪族 聚乳酸(PLA)和聚己内酯(PCL)等聚酯需要在体内进行额外的修饰 需要亲水性和功能性的应用。聚乙二醇化疗法具有广泛的临床应用前景； 然而，聚乙二醇化显著降低了治疗药物的免疫原性和生物活性 限制了它们的生物医学功效。近年来，两性离子聚合物(Zps)已成为一种很有前途的亲水性聚合物。 生物材料可以延长循环时间并保持结合疗法的生物活性，而不需要 诱导免疫反应。然而，常规ZPs不能降解可能会导致聚合物 在体内的临床应用中积累并引起严重的长期副作用。在这份R21提案中，我们 目的将FDA批准的脂肪族聚酯与两性离子相结合，开发一类新型的脂肪族聚酯 聚合物生物材料。根据重要的初步结果，提出了以下两个具体目标： 1)开发可生物降解的ZPs和ZP基交联物(即纳米胶囊和薄膜)；以及2) 了解它们与生物医学相关的特性。这一建议的假设是含有脂肪族的ZP 聚酯骨架和两性离子侧基可以通过硫醇-烯点击官能化来制备 带有两性硫醇的烯官能化脂肪族聚酯，它们不仅可生物降解，而且 生物相容，但也保持了传统ZP的良好生物医学相关特性。我们将设计 并合成具有聚乳酸或基于PCL的骨架的定义明确的ZP的文库，该骨架携带不同摩尔百分比的 基于羧基甜菜碱、磺基甜菜碱或磷甜菜碱的两性离子。此外，这些ZP可以拥有 烯-进一步修饰的官能团，以及将这些ZP转化为 将演示通过硫醇-烯交联的ZP基纳米胶囊和薄膜。全面 将采用分析方法来表征ZP及其衍生材料，以验证其 控制良好的结构。为了对它们的结构-财产关系有深刻的理解， 将进行系统的属性研究。它们的亲水性、降解性和抗生物污垢性能将 被调查。将进行细胞毒性的体外评估和全身毒性的体内研究 评估它们的生物相容性。ZP基纳米胶囊的循环时间和生物分布也将 用小鼠模型进行测量，验证它们可以长时间循环，不会造成长期的聚合物 积累。总之，拟议的R21研究承诺不仅为以下方面建立综合方法 脂肪族聚酯基可生物降解ZP和ZP基材料，但也提供了对其 依赖于结构的生物医学相关特性。这些研究将为进一步的研究奠定坚实的基础。 用于体内临床应用的可生物降解ZP修饰疗法和其他产品的开发。

PROJECT SUMMARY Synthetic polymer biomaterials have been widely used in biomedical areas. However, FDA-approved aliphatic polyesters, such as polylactide (PLA) and polycaprolactone (PCL), need additional modification for in vivo applications requiring hydrophilicity and functionalities. PEGylated therapeutics have broad clinical applications; however, PEG immunogenicity and reduced bioactivity of therapeutics resulted from PEGylation significantly restrict their biomedical efficacy. Recently zwitterionic polymers (ZPs) have emerged as promising hydrophilic biomaterials that can promote circulation time and maintain the bioactivity of conjugated therapeutics, without inducing immunological response. However, the inability of conventional ZPs to degrade can result in polymer accumulation and cause severe long term side effects for in vivo clinical applications. In this R21 proposal, we aim to integrate the FDA-approved aliphatic polyesters with zwitterions for the development of a class of novel polymer biomaterials. Based on the significant preliminary results, the following two specific aims are proposed: 1) to develop biodegradable ZPs and ZP-based crosslinked materials (i.e. nanocapsules and films), and 2) to understand their biomedical-related properties. The hypothesis of this proposal is that ZPs with aliphatic polyester backbones and zwitterionic side groups can be prepared by thiol-ene click functionalization of ene-functionalized aliphatic polyesters with zwitterionic thiols, and they not only are biodegradable and biocompatible, but also maintain the favorable biomedical-related properties of conventional ZPs. We will design and synthesize a library of well-defined ZPs with PLA or PCL-based backbones that carry different mol% of carboxybetaine, sulfobetaine, or phosphobetaine-based zwitterions. Moreover, these ZPs can possess ene-functionalities for further modification, and the synthetic principle for the conversion of these ZPs to ZP-based nanocapsules and films through thiol-ene crosslinking will be demonstrated. Comprehensive analytical approaches will be employed to characterize the ZPs and their derived materials for verifying their well-controlled structures. To achieve insightful understanding on their structure-property relationship, systematic property studies will be performed. Their hydrophilicity, degradability, and anti-biofouling property will be investigated. In vitro assessment of cytotoxicity and in vivo study of systemic toxicity will be conducted to evaluate their biocompatibility. Circulation time and biodistribution of the ZP-based nanocapsules will also be measured using mouse model to verify that they can have long circulation, without causing long-term polymer accumulation. Together, the proposed R21 studies promise to not only establish the synthetic methodology for aliphatic polyester-based biodegradable ZPs and ZP-based materials, but also provide key insights into their structure-dependent biomedical-relevant properties. These studies will lay a solid foundation for the further development of biodegradable ZP-modified therapeutics and other products for in vivo clinical applications.