CAREER: Synthesis and Application of Bioorthogonally Degradable Polymers

在化学系化学合成项目的支持下，丹娜-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。感兴趣的工艺被设计为与生物系统兼容（所谓的“生物正交反应”），并有望产生具有许多潜在应用的新功能适应性生物材料，包括最终作为药物输送载体和伤口闭合的组织粘合剂。这项跨学科研究的结果有望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的个人参与科学领域。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，该研讨会将展示重要的概念，如生物正交化学（一个令人兴奋的科学前沿，最近获得了2022年诺贝尔化学奖）和材料科学中的可逆凝胶。该资助项目将探索基于烯丙基功能化的enamine N-oxide基序的结合和解离生物正交点击反应的使用，以精确的刺激诱导方式在生物学相关背景下组装和降解水凝胶。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从其生物底物中解离；然而，依赖于这种自发的环境驱动的降解机制意味着生物材料的物理性质随着时间的推移而稳步恶化。相反，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，不受损害，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。该研究探索了获取不同性质的烯胺n-氧化物聚合物交联剂的合成方法（通常由羟胺和炔之间的周环基团转移形成），包含这些部分的阶梯生长和链式生长聚合物的组装策略，以及生物正交化学反应的发展，以还原切割共价交联。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也将被研究。在复杂的生物环境中，有效的化学反应是强大的。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。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.