Effect of molecular weight of amine end-modified poly(β-amino ester)s on gene delivery efficiency and toxicity

Ahmed A. Eltoukhy, Daniel J. Siegwart, Christopher A. Alabi, Jay S. Rajan, Robert Langer, Daniel G. Anderson

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Amine end-modified poly(β-amino ester)s (PBAEs) have generated interest as efficient, biodegradable polymeric carriers for plasmid DNA (pDNA). For cationic, non-degradable polymers, such as polyethylenimine (PEI), the polymer molecular weight (MW) and molecular weight distribution (MWD) significantly affect transfection activity and cytotoxicity. The effect of MW on DNA transfection activity for PBAEs has been less well studied. We applied two strategies to obtain amine end-modified PBAEs varying in MW. In one approach, we synthesized four amine end-modified PBAEs with each at 15 different monomer molar ratios, and observed that polymers of intermediate length mediated optimal DNA transfection in HeLa cells. Biophysical characterization of these feed ratio variants suggested that optimal performance was related to higher DNA complexation efficiency and smaller nanoparticle size, but not to nanoparticle charge. In a second approach, we used preparative size exclusion chromatography (SEC) to obtain well-defined, monodisperse polymer fractions. We observed that the transfection activities of size-fractionated PBAEs generally increased with MW, a trend that was weakly associated with an increase in DNA binding efficiency. Furthermore, this approach allowed for the isolation of polymer fractions with greater transfection potency than the starting material. For researchers working with gene delivery polymers synthesized by step-growth polymerization, our data highlight the potentially broad utility of preparative SEC to isolate monodisperse polymers with improved properties. Overall, these results help to elucidate the influence of polymer MWD on nucleic acid delivery and provide insight toward the rational design of next-generation materials for gene therapy.

Original languageEnglish (US)
Pages (from-to)3594-3603
Number of pages10
JournalBiomaterials
Volume33
Issue number13
DOIs
StatePublished - May 1 2012

Keywords

  • DNA
  • Gene therapy
  • Gene transfer
  • Molecular weight
  • Nanoparticle
  • Polymer

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Fingerprint Dive into the research topics of 'Effect of molecular weight of amine end-modified poly(β-amino ester)s on gene delivery efficiency and toxicity'. Together they form a unique fingerprint.

  • Cite this