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.

项目摘要 合成高分子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 聚酯，如聚乳酸（PLA）和聚己内酯（PCL），需要额外的改性， 需要亲水性和功能性的应用。PEG化治疗剂具有广泛的临床应用; 然而，PEG化显著导致PEG免疫原性和治疗剂生物活性降低， 限制其生物医学功效。近年来，两性离子聚合物（ZPs）已成为一种有前途的亲水性聚合物， 可以促进循环时间并保持缀合治疗剂的生物活性的生物材料， 诱导免疫应答。然而，常规ZP不能降解可导致聚合物降解。 积累并导致严重的长期副作用，用于体内临床应用。在这份R21提案中，我们 目的是将FDA批准的脂肪族聚酯与两性离子结合，用于开发一类新的 高分子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ZP和基于ZP的交联材料（即纳米胶囊和膜），以及2） 了解它们与生物医学相关的特性。该建议的假设是，具有脂肪族的ZPs 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，并且它们不仅是可生物降解的， 生物相容性，而且还保持了常规ZPs的有利的生物医学相关性质。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的文库，所述主链携带不同摩尔%的 羧基甜菜碱、磺基甜菜碱或基于磷酸甜菜碱的两性离子。此外，这些ZP可以具有 进一步修饰的烯官能度，以及将这些ZPs转化为 将展示通过硫醇-烯交联的基于ZP的纳米胶囊和膜。全面 将采用分析方法来表征ZPs及其衍生材料，以验证其 良好的控制结构。为了深入了解它们的结构-性质关系， 将进行系统的性能研究。它们的亲水性、可降解性和抗生物污染特性将 追究将进行体外细胞毒性评估和体内全身毒性研究， 评价其生物相容性。基于ZP的纳米胶囊的循环时间和生物分布也将被确定。 使用小鼠模型测量，以验证它们可以具有长循环，而不会引起长期聚合物 积累总之，拟议的R21研究不仅有望建立合成方法， 脂肪族聚酯基可生物降解的ZPs和ZP基材料，但也提供了关键的见解， 结构依赖性生物医学相关性质。这些研究将为今后的研究奠定坚实的基础 开发可生物降解的ZP修饰的治疗剂和其他用于体内临床应用的产品。