CO Releasing Organic Polymers for Biomedical Applications

用于生物医学应用的释放 CO 的有机聚合物

• 批准号: 10501153
• 负责人: Brady Worrell
• 金额: $ 36.34万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501153
• 关键词: Acute; Carbon Monoxide; Cardiovascular Diseases; Chronic; Collaborations; Colorado; Complex; Development; Future; Gases; Health; Human; Human body; Inflammation; Laboratories; Neurons; Pathway interactions; Polymers; Production; Research; Signaling Molecule; Solubility; Stimulus; System; Technology; Therapeutic; Transition Elements; Universities; Water; Work; analog; base; biological systems; biomaterial compatibility; cytotoxic; gastrointestinal; improved; learning materials; medical schools; metal complex; method development; new therapeutic target; organ transplant rejection; photolysis; polymerization; programs; response; small molecule; targeted treatment; tool

PROJECT SUMMARY/ABSTRACT Over the last several decades it has become apparent that carbon monoxide (CO) gas is an important small molecule that greatly impacts human health. Indeed, CO is created endogenously in small concentrations and has been shown to be an essential signaling molecule in the human neuronal system. Moreover, CO gas has been revealed to be a valuable therapeutic, specifically, it can ameliorate acute and chronic inflammation, can reduce rejection of organ transplants, and can treat cardiovascular diseases. However, the direct study or use of CO in biological systems is inherently complex because it is a gas, has limited solubility in water, and is toxic at high concentrations. As such, many of the mechanisms and pathways by which CO operates in the human body remain elusive. In response to these complications, CO Releasing Molecules (CORMs) have emerged as a class of materials that can release CO in response to an external stimulus. As transition metals readily ligate to and release CO under various conditions, these materials were the first class of CORMs developed and remain the most popular and frequently utilized to date. Unfortunately, CORMs based on transition metal carbonyl complexes are cytotoxic, form poorly defined products following release of CO, and cannot be directly polymerized to form macromolecular targeted therapeutics. Research in the Worrell laboratory is inspired by the shortcomings in current CORM technology, and we are actively engaged in creating stable, modular, and efficient organic CO releasing molecules. Our work has been concentrated on analogs of diphenylcyclopropenone (DPCP), a uniquely stable and bio-orthogonal molecule that features a highly strained 3 membered ring. Previous work in a small molecule setting has shown that DPCP is unrivaled in its ability to cleanly and efficiently produce CO gas. Proof-of-concept demonstrations have shown that analogs of DPCP can be effectively synthesized, can be directly polymerized, and can release CO gas by photolysis, however, for application as a CORM, this must be demonstrated in a biological system. Future work over the five-year course of this program will concentrate on the development of methods for the controlled polymerization of DPCP to create tailored macromolecular materials that are soluble, targeted, non-toxic, and biocompatible. We will further concentrate on improving the rate and efficacy of CO release by leveraging the unique photophysics of DPCPs while creating well-defined photoproducts. Ultimately, the most impactful extension of this work will be related to its development in studying and treating gastrointestinal inflammation as part of a long-term collaboration with the Colgan/Onyiah group at the University of Colorado Medical School. Although there are significant challenges associated with this program, its scientific impacts will be far-reaching. If successful, organic CORMs will supersede those based on transition metal complexes, stimulating the development of new targeted therapeutics based on the production of CO gas.

项目总结/摘要 在过去的几十年中，一氧化碳（CO）气体是一种重要的小分子化合物， 对人类健康有很大影响的分子。事实上，CO是以小浓度内源性地产生的， 已显示是人类神经系统中的必需信号分子。此外，CO气体具有 已被发现是一种有价值的治疗剂，具体地说，它可以改善急性和慢性炎症， 减少器官移植的排斥反应，并可治疗心血管疾病。然而，直接研究或使用 生物系统中的CO是天然复杂的，因为它是一种气体，在水中的溶解度有限，并且有毒 在高浓度下。因此，CO在人体内运作的许多机制和途径， 尸体仍然难以捉摸。为了应对这些并发症，CO释放分子（CORM）已经出现， 一类能够响应外部刺激而释放CO的材料。由于过渡金属容易配位， 在各种条件下释放CO，这些材料是开发的第一类CORM， 是迄今为止最受欢迎和最常用的。不幸的是，基于过渡金属羰基的CORM 复合物是细胞毒性的，在CO释放后形成不明确的产物，并且不能直接 聚合形成大分子靶向治疗剂。沃雷尔实验室的研究灵感来自于 目前CORM技术的缺点，我们正在积极参与创建稳定，模块化和高效的 有机CO释放分子。我们的工作主要集中在二苯基环丙烯酮的类似物上 （DPCP），一种独特稳定的生物正交分子，具有高度应变的3元环。先前 在小分子环境中的工作表明，DPCP在清洁和有效生产的能力方面是无与伦比的 一氧化碳气体概念验证证明已经表明，DPCP的类似物可以有效地合成， 可以直接聚合，并且可以通过光解释放CO气体，然而，对于作为CORM的应用，这必须 在一个生物系统中得到证实。未来五年的工作将集中在这一计划的 开发DPCP的可控聚合方法，以产生定制的大分子 可溶性、靶向、无毒和生物相容的材料。我们将进一步集中力量， 通过利用DPCPs独特的物理特性，同时创建定义明确的 照片产品最终，这项工作最有影响力的延伸将与其在研究中的发展有关 作为与Colgan/Onyiah小组长期合作的一部分， 科罗拉多大学医学院。尽管这方面存在重大挑战， 计划，其科学影响将是深远的。如果成功，有机CORM将取代那些基于 过渡金属配合物，刺激基于其生产的新型靶向疗法的开发 一氧化碳气体