CAREER: Synthesis and Application of Bioorthogonally Degradable Polymers

点击翻译按钮获取中文摘要

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.