Overcoming Limiting Side Reactions Associated with an NHS-Activated Precursor of Polymethacrylamide-Based Polymers

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Abstract

Combinatorial polymer libraries have recently gained popularity for the development of novel materials for a variety of biomedical applications including non-viral gene delivery systems and biodegradable polymers for tissue engineering. To streamline the nontrivial task of library synthesis, activated ester homopolymers have been used to serve as a backbone to which primary amine-containing functional groups (NH2-FGs) can be covalently bound at varying ratios. Polymethacryloxysuccinimide (poly(MAOS)) is one such homopolymer that was previously reported to be an attractive precursor for polymeric drug and gene delivery systems. The reported functionalization protocols entailed conjugating the precursor with 2 equiv of the NH2-FG at a reaction concentration of 25 mg poly(MAOS)/150 microL DMSO for either 5 h at 50 degrees C or 16 h at 25 degrees C. More recently, both protocols were revealed to be associated with ring-opening and glutarimide-forming side reactions that compromise the utility of the homopolymer. Using 1-dimensional and 2-dimensional NMR spectroscopy techniques, we have characterized the side product distributions that result from conjugations performed at 50 degrees C/5 h and 25 degrees C/16 h. Moreover, by systematically altering the equivalents of the NH2-FGs, polymer concentration, reaction time, and reaction temperature, we have established a protocol that overcomes these side reactions. Using a final reaction protocol of 5 equiv of the NH2-FG at a reaction concentration of 25 mg poly(MAOS)/600 microL DMSO for 24 h at 75 degrees C, we have obtained functionalized polymers with minimal side products. This protocol is applicable for polymers ranging from 5000 to 50,000 g/mol, compatible with a variety of functional groups, and amenable to conjugating combinations of functional groups.

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