CAREER: Synthesis and Application of Bioorthogonally Degradable Polymers

职业：生物正交降解聚合物的合成及应用

• 批准号: 2238040
• 负责人: Justin Kim
• 金额: $ 77万
• 依托单位: Dana-Farber Cancer Institute
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2238040&HistoricalAwards=false
• 关键词: CAREER; Synthesis; Application; Bioorthogonally; Degradable

With support of the Chemical Synthesis Program in the Division of Chemistry, Justin Kim of the Dana-Farber Cancer Institute is studying chemical processes for the reversible assembly and functionalization of polymers relevant to biology. The processes of interest are designed to be compatible with biological systems (so-called 'bioorthogonal reactions') and are expected to enable the generation of new functionally adaptable biomaterials with many potential applications, including eventually as vehicles for drug delivery and as tissue adhesives for wound closure. The results of this interdisciplinary research are anticipated to lead to important advances in polymer design, synthesis and deployment in biological systems. As part of the broader impacts of the funded project, the PI and other members of the Kim research group will engage in educational outreach activities to help broaden participation in science fields by individuals from groups that have been traditionally underrepresented. A highlight of these efforts will be an interactive workshop for local area high school students that will demonstrate important concepts such as bioorthogonal chemistry (an exciting frontier in science that was recently recognized by the 2022 Nobel Prize in Chemistry) and reversible gelation in materials science.The funded project will explore the use of associative and dissociative bioorthogonal click reactions based on enamine N-oxide motifs with allylic functionalization, to assemble and degrade hydrogels in biologically relevant contexts in a precise stimulus-induced manner. Hydrolytic or enzymatic degradation pathways are commonly used to dissociate polymers or hydrogels from their biological substrates in applications of synthetic biomaterials; however, the reliance on such spontaneous environmentally-driven mechanisms for degradation means that the physical properties of the biomaterial steadily deteriorate over time. This work instead focuses on the synthesis of permanent covalently linked polymer networks whose structural integrity remains intact and uncompromised until such time that removal of the biomaterial is desired: degradation is then triggered by a bioorthogonal chemical reaction. The research explores synthetic methods for accessing enamine N-oxide polymer crosslinkers of varying properties (typically formed by pericyclic group transfer between hydroxylamines and alkynes), strategies for the assembly of step- and chain-growth polymers containing these moieties, and the development of bioorthogonal chemical reactions to reductively cleave the covalent crosslinks. Methods to induce functional changes to the biomaterials of interest through the attachment and removal of various ancillary groups will also be investigated. Efficient chemical reactions that make and break molecular connections in complex biological environments are powerful. As such, the fundamental findings of this work have the potential to impact both academic and industrial science in areas ranging from chemical biology to bioengineering.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系化学合成项目的支持下，达纳法伯癌症研究所的 Justin Kim 正在研究与生物学相关的聚合物的可逆组装和功能化的化学过程。感兴趣的过程被设计为与生物系统兼容（所谓的“生物正交反应”），并有望生成具有许多潜在应用的新型功能适应性生物材料，包括最终作为药物输送的载体和作为伤口闭合的组织粘合剂。这项跨学科研究的结果预计将在生物系统中的聚合物设计、合成和部署方面取得重要进展。作为资助项目更广泛影响的一部分，PI 和 Kim 研究小组的其他成员将参与教育推广活动，以帮助扩大传统上代表性不足的群体中的个人对科学领域的参与。这些努力的一个亮点将是为当地高中生举办的互动研讨会，将展示生物正交化学（最近获得 2022 年诺贝尔化学奖的一个令人兴奋的科学前沿）和材料科学中的可逆凝胶等重要概念。该资助项目将探索基于烯胺 N-氧化物基序和烯丙基的缔合和解离生物正交点击反应的使用 功能化，以精确的刺激诱导方式在生物相关环境中组装和降解水凝胶。在合成生物材料的应用中，水解或酶降解途径通常用于将聚合物或水凝胶与其生物基质分离；然而，对这种自发的环境驱动降解机制的依赖意味着生物材料的物理特性随着时间的推移而稳步恶化。这项工作的重点是合成永久共价连接的聚合物网络，其结构完整性保持完整且不受影响，直到需要去除生物材料：然后通过生物正交化学反应触发降解。该研究探索了获得不同性质的烯胺氮氧化物聚合物交联剂（通常由羟胺和炔烃之间的周环基团转移形成）的合成方法、包含这些部分的逐步和链增长聚合物的组装策略，以及开发生物正交化学反应以还原性裂解共价交联。还将研究通过附着和去除各种辅助基团来诱导感兴趣的生物材料功能变化的方法。在复杂的生物环境中建立和破坏分子连接的有效化学反应是强大的。 因此，这项工作的基本发现有可能影响从化学生物学到生物工程等领域的学术和工业科学。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。