Degradable poly(beta-amino esters): Synthesis, characterization, and self-assembly with plasmid DNA

Poly(beta -aminoesters) 1-3 were synthesized via the addition of N,N'-dimet hylethylenediamine, piperazine, and 4,4'-trimethylenedipiperidine to 1,4-bu tanediol diacrylate. Polymerization proceeded exclusively via the conjugate addition of the secondary amines to the bis(acrylate ester). Polymers were isolated in up to 86% yields with molecular weights ranging up to 31 200 r elative to polystyrene standards. The polymers degraded hydrolytically in a cidic and alkaline media to yield 1,4-butanediol and beta -amino acids 4a-6 a and the degradation kinetics were investigated at pH 5.1 and 7.4. In gene ral, the polymers degraded more rapidly at pH 7.4 than at pH 5.1. In initia l screening assays, both the polymers and their degradation products were d etermined to be noncytotoxic relative to poly(ethylene imine), a polymer co nventionally employed as a synthetic transfection vector. Polymers 1-3 inte racted electrostatically with polyanionic plasmid DNA in water and buffer a t physiological pH, as determined by agarose gel electrophoresis, quasi-ela stic dynamic light scattering (QELS), and zeta -potential measurements. All three polymers condensed DNA into soluble DNA/polymer particles on the ord er of 50-200 nm. Particles formed from polymers 1 and 2 aggregated extensiv ely, while particles formed from polymer 3 exhibited positive zeta -potenti als (e.g., +10 to +15 mV) and did not aggregate for up to 18 h. The nanomet er-sized dimensions and reduced cytotoxicities of these DNA/polymer complex es suggest that these types of polymers may be useful as degradable polymer ic gene transfer vectors.