CAREER: Synthesis and Application of Bioorthogonally Degradable Polymers

在化学部化学合成计划的支持下，Dana-Farber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”），并预计能够产生具有许多潜在应用的新的功能适应性生物材料，包括最终作为药物递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导致生物系统中聚合物设计，合成和部署的重要进展。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在科学领域的参与。这些努力的一个亮点将是为当地高中学生举办的互动研讨会，该研讨会将展示生物正交化学等重要概念（这是一个令人兴奋的科学前沿，最近获得了2022年诺贝尔化学奖的认可）和材料科学中的可逆凝胶化。该资助项目将探索基于烯胺N-氧化物基序与烯丙基官能化，组装和降解水凝胶在生物相关的背景下，在一个精确的刺激诱导的方式。在合成生物材料的应用中，水解或酶促降解途径通常用于使聚合物或水凝胶从其生物基质解离;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时间稳定地劣化。相反，这项工作的重点是永久共价连接的聚合物网络的合成，其结构完整性保持完整和不受损害，直到这样的时间，去除生物材料是期望的：降解，然后引发的生物正交化学反应。该研究探索了获得不同性质的烯胺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），包含这些部分的步骤和链增长聚合物的组装策略，以及生物正交化学反应的发展，以还原裂解共价交联。还将研究通过连接和去除各种辅助基团来诱导感兴趣的生物材料的功能变化的方法。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，并被认为值得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来支持。

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.