Elucidating the Effect of Amine Charge State on Poly(β-amino ester) Degradation Using Permanently Charged Analogs

Abstract

With synthetic ease and tunable degradation lifetimes, poly(β-amino ester)s (PBAEs) have found use in increasingly diverse applications, from gene therapy to thermosets. Protonatable amines in each repeating unit impart pH-dependent solution behavior and lifetimes, with acidic conditions favoring solubility, yet slowing hydrolysis. Due in part to these interconnected phenomena governing pH-dependent PBAE degradation, predictive degradation models, which would enable user-defined lifetimes, remain elusive. To separate the effects of charge state and solution pH on PBAE degradation, we synthesized poly(β-quaternary ammonium ester)s (PBQAEs), which differ from their parent PBAEs only by an additional methyl group, generating polymers with pH-independent cationic charge. Like PBAEs, PBQAE hydrolysis accelerates with increasing pH, although at a given pH, PBAE degradation outpaces PBQAE degradation. This difference is more pronounced in basic solutions, suggesting that deprotonated PBAE amines accelerate hydrolysis, providing an additional tuning parameter to PBAE lifetime and informing the degradation of PBAEs and other pHresponsive polymers.

Fluorescent poly(β-amino ester)s containing aza-BODIPYs as theranostic agents for bioimaging and photodynamic therapy

“…EDA) or extended reaction times may cause degradation of PBAEs during the amine end-capping process. 66 Therefore, the reaction duration and the amount of the amine (EDA) were optimized. The appropriate amount of amine was determined to be 0.29 molar equivalents of the overall acrylate monomers.…”

Oxidative Polymer Degradation via Cope Elimination

“…For most biological applications, PBAEs and PAMAMs are typically employed in their protonated form to impart polycationic character and maximize solubility for DNA polyplexing in gene therapy applications. − Despite this, PBAEs only exhibit significant rates of hydrolysis at elevated pH, thereby limiting degradability under the conditions in which the polymers are typically used . A recent report by Letteri and co-workers found that a combination of localized pH change, , water organization, − dielectric change, and/or amine-catalyzed hydrolysis − resulted in hydrolytic rate differentiation at higher pHs . While this study focused on hydrophilic PBAEs, hydrophobic PBAEs have been found to primarily undergo hydrolysis via surface erosion, significantly reducing degradation kinetics. , Meanwhile, hydrophilic PAMAMs have been reported to undergo slow hydrolysis on a scale of months at high pH. , To address challenges with PBAE and PAMAM degradability, pH- and substrate-independent degradation techniques must be developed.…”

“…33 A recent report by Letteri and co-workers found that a combination of localized pH change, 34,35 water organization, 36−38 dielectric change, 39 and/or amine-catalyzed hydrolysis 39−43 resulted in hydrolytic rate differentiation at higher pHs. 44 While this study focused on hydrophilic PBAEs, hydrophobic PBAEs have been found to primarily undergo hydrolysis via surface erosion, significantly reducing degradation kinetics. 25,45 Meanwhile, hydrophilic PAMAMs have been reported to undergo slow hydrolysis on a scale of months at high pH.…”