Poly(beta-amino ester)s for DNA delivery

Nucleotide-based therapeutics have the potential to treat many inherited and acquired diseases. However, for this form of therapy to become clinically successful, safe and efficient delivery vehicles need to be developed. In this article, we review the synthesis, properties, and use of poly(beta-amino ester)s as vectors for gene delivery. High-throughput synthesis and screening studies have identified poly(beta-amino ester)s that can complex DNA and mediate transfection with efficiencies that are superior to the best commercially available polymer- and lipid-based transfection reagents. Structure-function studies show that high-molecular-weight (> 10 kDa) amine-terminated polymers with primary alcohol side chains are the most efficient vectors to date. In vivo, the most effective polymer, C32, delivers plasmid DNA at high levels following intra-tumor injection, with excellent biocompatibility. Interestingly, C32 inhibits transfection to surrounding muscle tissue, making it a good candidate for local gene therapy. In addition to simple polymer/DNA complexes insoluble microparticles can be formed using poly(beta-amino ester)s to physically encapsulate DNA and with sizes appropriate for phagocytosis by antigen-presenting cells. Uptake of these particles by macrophages results in protein expression levels up to 5 orders of magnitude higher than traditional poly(lactic-co-glycolic acid) microparticles containing DNA and can be potent stimulators of antigen presenting cells. Furthermore, in vivo delivery of poly(beta-amino ester) microparticle genetic vaccines leads to an antigen-specific, immune-mediated rejection of a lethal tumor dosage. Taken together, these results show that poly(beta-amino ester)s have broad potential as delivery systems for drug and gene therapies.