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

• Applicant: Professor Dr. Frederik Wurm
• Subject Area: Preparatory and Physical Chemistry of Polymers ; Polymer Materials
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267144673

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.

• DFG Programme: Research Grants
• International Connection: Netherlands