(102c) Poly(ß-amino ester) Derivatives and Their Complexes: Tailoring Molecular Structure to Tune Solution Properties and Lifetime

Poly(β-aminoester)s (PBAEs) are a class of pH-responsive, cationic, degradable polymers best known for their applications in gene therapy due to their ability to complex anionic nucleic acids. Yet, their impressively simple synthesis from a diverse range of monomers suggests their promise in many other contexts and sectors. To unlock the full potential of PBAEs, we sought to better understand the interplay between their solution behavior and degradation and to tailor PBAEs for complexation with a range of therapeutic peptides and with other polyelectrolytes. The tertiary amines on each repeating unit of PBAEs impart pH-responsive solution properties and can change solution pH by accepting protons, yielding complex pH-dependent degradation behavior. To determine the role of the amine charge state on PBAE degradation, we converted the tertiary amines to quaternary ammonium groups by reaction with methyl iodide, yielding quaternary ammonium PBAE derivatives termed PBQAEs that cannot accept protons from solution. Using NMR spectroscopy, we examined changes to the chemical environment around amines upon conversion to ammoniums and compared the resulting pH-dependent degradation rates. Even in the presence of excess buffer to block the polymer from changing solution pH, the tertiary amine-containing PBAEs degraded faster than their quaternary ammonium analogs. To open opportunities to complex cationic therapeutics and to prepare polyelectrolyte complexes entirely from degradable PBAEs, we synthesized net anionic PBAE by installing two anionic groups per amine. These net anionic PBAEs are most soluble at high pH, where they have the highest net anionic charge, and at low pH, where they have high charge density. In intermediate pH ranges, including physiological pH, these polymers aggregate in a way that we anticipate will be quite useful for encapsulation of therapeutics. Blending net anionic PBAEs with a model cationic peptide, (glycine-arginine)₁₀, afforded a turbid suspension suggestive of complexation; this suspension then clarified over time as the polymer hydrolyzed. This proof-of-concept experiment demonstrates the feasibility of employing net anionic PBAEs to complex cationic cargo and release them as the polymer degrades. By continuing to understand and tailor PBAEs, we can leverage the synthetic accessibility and high degree of tunability of these versatile polymers to address challenges in delivery of sensitive therapeutics, among other applications requiring tunable degradable polymers.