Synthetic Biodegradable Zwitterionic Polymers

合成可生物降解两性离子聚合物

• 批准号: 9300079
• 负责人: Chong Cheng
• 金额: $ 19.68万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9300079
• 关键词: Adverse effects; Amaze; Area; Arthritis; Behavior; Biocompatible Materials; Biodistribution; Blood Circulation; Categories; Charge; Clinical Treatment; Development; Disease; Environment; FDA approved; Film; Foundations; Future; Goals; Gout; Hepatitis; Hydrophobicity; Immune response; In Vitro; Industry; Libraries; Malignant Neoplasms; Measures; Methodology; Modification; Patients; Polyesters; Polymers; Property; Regenerative Medicine; Reporting; Research; Sales; Side; Solid; Structure; Sulfhydryl Compounds; Therapeutic; Time; Tissue Engineering; Toxic effect; Vertebral column; base; biodegradable polymer; biomaterial compatibility; clinical application; crosslink; cytotoxicity; design; ethylene glycol; hydrophilicity; immunogenicity; improved; in vivo; insight; mouse model; nanocapsule; novel; poly(lactide); polycaprolactone; systemic toxicity

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.

项目概要 合成高分子生物材料已广泛应用于生物医学领域。然而，FDA 批准的脂肪族 聚酯，例如聚丙交酯（PLA）和聚己内酯（PCL），需要额外的改性以适应体内 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； 然而，PEG 化显着导致 PEG 免疫原性和治疗生物活性降低 限制了它们的生物医学功效。最近，两性离子聚合物（ZP）已成为有前途的亲水性聚合物 可以促进循环时间并维持结合疗法的生物活性的生物材料，无需 诱导免疫反应。然而，传统 ZP 无法降解可能会导致聚合物 积累并对体内临床应用造成严重的长期副作用。在这个 R21 提案中，我们 旨在将 FDA 批准的脂肪族聚酯与两性离子相结合，开发一类新型 高分子生物材料。根据重要的初步结果，提出以下两个具体目标： 1) 开发可生物降解的 ZP 和基于 ZP 的交联材料（即纳米胶囊和薄膜），以及 2) 了解它们的生物医学相关特性。该提案的假设是具有脂肪族的 ZP 聚酯主链和两性离子侧基可以通过硫醇-烯点击官能化来制备 具有两性离子硫醇的烯官能化脂肪族聚酯，它们不仅可生物降解， 生物相容性，而且还保持了传统 ZP 的有利生物医学相关特性。我们将设计 并合成具有基于 PLA 或 PCL 的主链的明确定义的 ZP 库，这些主链携带不同 mol% 的 羧基甜菜碱、磺基甜菜碱或磷酸甜菜碱基两性离子。此外，这些 ZP 可以拥有 进一步修饰的烯官能团，以及将这些 ZP 转化为 将展示通过硫醇-烯交联形成的基于 ZP 的纳米胶囊和薄膜。综合的 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。为了深入了解它们的结构-性能关系， 将进行系统的属性研究。它们的亲水性、可降解性和抗生物污垢特性将 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。基于 ZP 的纳米胶囊的循环时间和生物分布也将受到影响。 使用小鼠模型进行测量，验证它们可以具有长循环，而不引起长期聚合物 积累。总之，拟议的 R21 研究不仅有望建立 脂肪族聚酯基可生物降解 ZP 和 ZP 基材料，还提供了对其的重要见解 结构依赖的生物医学相关特性。这些研究将为进一步的研究打下坚实的基础 开发可生物降解的 ZP 修饰疗法和其他体内临床应用产品。