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

可降解聚合物是用于医疗应用（“药物递送”、植入物、“组织工程”）的重要材料，并且作为传统塑料的替代品（例如在包装工业中）有很大的需求。大多数可降解聚合物基于聚酯或其共聚物。降解速率仅为有限变量。该项目建议书使用多功能聚磷酸酯（PPE）来实现具有分子可调降解速率（从数秒到数月）的聚合物。PPE的水解不是通过主链中酯官能团的无规裂解发生的，而是优选遵循末端OH基团与聚合物链的所谓“反咬”机制。该基序将被合成引入聚合物的侧链中，以实现对降解速率的分子控制。这种机制让人联想到RNA，由于核糖单元中的大量OH基团，RNA在水中迅速转化，从而降解。该项目提出了系统的合成环状磷酸酯和膦酸酯单体轴承封闭的OH功能，这是聚合后释放。由于OH官能团与聚酯主链的可调节接近性和亲核性，降解速率将被控制。此外，具有额外OH官能团的磷酸盐和膦酸盐主链的变化允许进一步控制降解速率。此外，将合成受保护的（“光笼”）聚合物，其允许在保护基团裂解后通过非常快速的酯交换“按需”降解。这些PPE将在酶-聚合物缀合物和水凝胶中进行研究，降解速率可调。PPE的合成裂解位点也有望加速聚乳酸的降解动力学，聚乳酸是当今最常见的“可生物降解”塑料，因为它在许多领域降解得太慢。总的来说，通过拟议的项目，可以生产具有精确可调降解速率的可降解聚（磷酸酯）酯，据我所知，这是目前任何其他聚合物类别都无法实现的。这些合成的发现将允许在医学和材料科学的各种应用中使用开发的“切割位点”。

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.