Degradation by transesterification on demand: RNA-inspired degradation motifs in synthetic poly(phospho)esters

按需酯交换降解：合成聚（磷酸）酯中受 RNA 启发的降解基序

• 批准号: 267144673
• 负责人: Professor Dr. Frederik Wurm
• 金额: --
• 依托单位: Sustainable Polymer Chemistry Group
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/267144673?language=en
• 关键词: Degradation; transesterification; demand; RNA; inspired

Degradable polymers are important materials for medical applications ("drug delivery", implants, "tissue engineering") and are in great demand as alternatives to traditional plastics, e.g. in the packaging industry. Most degradable polymers are based on polyesters or their copolymers. The degradation rates are only limited variable. This project proposal uses the versatile polyphosphoesters (PPE) to realize polymers with molecularly adjustable degradation rates (from seconds to months). The hydrolysis of PPE does not occur by random cleavage of the ester functions in the main chain, but preferably follows a so-called "back-biting" mechanism of the terminal OH group with the polymer chain. This motif will be synthetically introduced into the side chain of polymers in order to achieve a molecular control of the degradation rates. This mechanism is reminiscent of RNA, which transesterifies rapidly in water due to the large number of OH groups in the ribose units and thereby degrades. The project presents the systematic synthesis of cyclic phosphate and phosphonate monomers bearing blocked OH functions, which are released after polymerization. Due to the adjustable proximity and nucleophilicity of the OH functions to the polyester backbone, the degradation rates are to be controlled. Also, a variation of phosphate and phosphonate backbone with additional OH functions allows further control of degradation rate. In addition, protected ("photocaged") polymers are to be synthesized, which allow degradation “on demand”, by very rapid transesterification after cleavage of the protective groups. These PPEs will be investigated in enzyme-polymer conjugates and hydrogels with adjustable degradation rates. The developed synthetic cleavage sites for PPE are also expected to accelerate the degradation kinetics of polylactide, the most common "biodegradable" plastic today, as it degrades much too slowly in many areas. Overall, with the proposed project, the production of degradable poly(phospho) esters with precisely adjustable degradation rates will be possible, which to the best of my knowledge cannot be achieved with any other polymer class today. The findings of these syntheses will allow the use of the developed "cleavage sites" in a variety of applications in medicine and materials science.

可降解的聚合物是医疗应用的重要材料（“药物输送”，Impliants，“组织工程”），并且需要作为传统塑料的替代品，例如在包装行业。大多数可降解的聚合物基于聚酯或其共聚物。降解速率仅有限。该项目提案使用多功能多磷酸酯（PPE）来实现具有可调节降解速率的聚合物（从秒到几个月）。 PPE的水解不是通过在主链中的酯函数随机切割而发生的，但是更喜欢与聚合物链的末端OH基团的所谓“背咬”机制。该基序将合成地引入聚合物的侧链中，以实现对降解速率的分子控制。这种机制让人联想起RNA，由于核糖单元中的OH基团数量大量，因此在水中迅速迁移了RNA，从而降解。该项目介绍了循环磷酸盐和磷酸单体的系统合成，其功能被阻断，它们在聚合后释放。由于OH函数与聚酯主链的可调节性接近性和亲核性，因此应控制降解速率。同样，具有其他OH功能的磷酸盐和磷酸主链的变化允许进一步控制降解速率。此外，应合成受保护的（“光塑料”）聚合物，这会通过在受保护组的切割后非常快速地延迟降解“按需”降解。这些PPE将在具有可调降解速率的酶聚合物结合物和水凝胶中进行研究。预计开发的PPE的合成裂解位点也有望加速polylactide的降解动力学，这是当今最常见的“生物降解”塑料，因为它在许多地区降解的降解速度太慢。总体而言，随着拟议的项目，将有可能具有准确调节的降解速率的可降解聚（磷酸酯）的产生，据我所知，今天的任何其他聚合物类别都无法实现。这些合成的发现将允许在医学和材料科学中的各种应用中使用开发的“切割站点”。