Polyesters have been employed as biodegradable materials for myriad therapeutic biomedical applications. The organocatalytic ring-opening polymerization of N-acyl morpholin-2-ones occurs readily to generate functionalized poly(α-aminoesters). Deprotection of the N-Boc protected poly(aminoesters) yields water-soluble, cationic materials. These materials are stable in neutral D<sub>2</sub>O for over two days, however, upon exposure to alkaline or buffered conditions, these cationic poly(a-aminoesters) rapidly degrade to afford the hydroxyethyl diketopiperazine. Mechanistic investigations suggest a remarkable immolative mechanism allows for the rapid degradation of these water-soluble polymers, the rate of which is dependent on environmental pH. Poly(carbonate-co-aminoesters) that feature a segment of the rapidly degrading poly(a-aminoester) backbone were employed for the complexation, delivery and translation of mRNA both in vitro and in vivo, resulting in robust protein expression. Mechanistic studies indicate that the degradation of these cationic oligomers contributes to the efficient release and expression of mRNA inside cells.

Synthesis and enviornmentally-responsive properties of poly(α-aminoesters): Applications for the delivery of messenger RNA

253rd National Meeting (2017)

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