(129i) Synthesis, Purification, and Solution Properties of Net Anionic Poly(?-amino ester)s

Charged polymers enable multilayer films, coacervates, and encapsulation of sensitive therapeutics. These therapeutics are often bound by multiple electrostatic interactions making cargo release from the complexes challenging. Using degradable polymers to form complexes can prompt cargo release without external stimuli as the polymer degradation causes the complex to disintegrate, releasing the therapeutic. One such class of fast-hydrolyzing polyelectrolytes, poly(β-amino ester)s (PBAEs), are cationic, owing to a protonatable amine in each repeating unit, and have been used to complex and deliver anionic DNA. Despite a straightforward synthesis that is tolerant of several backbone (e.g., hydrophilic/hydrophobic) and pendant functional groups, anionic PBAEs capable of complexing cationic therapeutics (e.g., antimicrobial peptides) remain elusive. A net anionic PBAE requires the installation of two anionic groups in each repeating unit (one neutralizes the cationic amine, one imparts anionic character). We reasoned that thiol-yne click chemistry would provide an efficient route to attaching two anionic thiols across an alkyne (easily installed in PBAEs). However, pushing this reaction to completely consume the pendant alkynes necessitates excess thiol, which must be removed after functionalization. Traditional purification methods, such as dialysis, take days, triggering significant PBAE hydrolysis, demanding an alternative purification strategy. Using size exclusion chromatography, we removed >90 wt% of the remaining thiol in ca. 20 min without causing significant polymer degradation. These resultant sulfonate-functionalized PBAEs demonstrate pH- and backbone hydrophobicity- dependent solution behavior with hydrophilic net anionic PBAEs remaining soluble in both acidic and basic pH while hydrophobic net anionic PBAEs are insoluble in 6 < pH < 8. Mixing the hydrophobic polymers at pH 10 with a model cationic peptide, (glycine-arginine)₁₀, yields a turbid solution which decreases in turbidity over 6 h as the polymer degrades. In summary, we established methods for the synthesis and purification of net anionic PBAEs enabling cationic peptide complexation and release.