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

可降解聚合物是医疗应用（“药物输送”、植入物、“组织工程”）的重要材料，作为传统塑料的替代品需求量很大，例如在包装工业中。大多数可降解聚合物是基于聚酯或其共聚物。降解率只是有限的变量。本项目建议使用多功能聚磷酸酯（PPE）来实现具有分子可调节降解速率（从秒到月）的聚合物。PPE的水解不是通过主链上酯功能的随机断裂而发生的，而是通过末端OH基团与聚合物链的所谓“背咬”机制发生的。该基序将被合成引入到聚合物的侧链中，以实现对降解速率的分子控制。这种机制让人想起RNA，由于核糖单位中大量的OH基团，RNA在水中迅速酯交换，从而降解。该项目系统合成了具有阻断OH功能的环磷酸盐和膦酸盐单体，聚合后释放。由于羟基功能与聚酯主链的亲核性和可调节的接近性，降解速率是可控的。此外，磷酸盐和膦酸盐骨架的变化具有额外的OH功能，可以进一步控制降解速率。此外，将合成受保护的（“光笼化”）聚合物，在裂解保护基团后，通过非常迅速的酯交换作用，使其“按需”降解。这些ppe将在酶-聚合物缀合物和可调节降解率的水凝胶中进行研究。开发的合成PPE裂解位点也有望加速聚丙交酯的降解动力学，聚丙交酯是当今最常见的“生物可降解”塑料，因为它在许多领域降解太慢。总的来说，在这个项目中，生产具有精确可调降解率的可降解聚（磷酸）酯是可能的，据我所知，这是目前任何其他聚合物类都无法实现的。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已开发的“裂解位点”。

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.