Effects of trehalose click polymer length on pDNA complex stability and delivery efficacy

Sathya Srinivasachari, Yemin Liu, Lisa E. Prevette, Theresa M. Reineke

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Cationic polymers are currently being studied as non-viral vectors to deliver therapeutic DNA into cells. In this study, a series of trehalose-based glycopolymers containing four secondary amines in the repeat unit were synthesized via the 'click reaction' [degrees of polymerization (nw)=35, 53, 75, or 100] to elucidate how the polymer length affects the bioactivity. The four structures bound and charge-neutralized pDNA with similar affinity that was independent of the length, as determined through gel electrophoresis, heparin competitive displacement, and isothermal titration calorimetric assays. Dynamic light scattering measurements revealed that the polyplexes formed with the longer polymers (nw=53, 75, or 100) inhibited flocculation in media containing serum, whereas the polyplexes formed with the shorter polymer (nw=35) aggregated rapidly. Similar results were observed via transmission electron microscopy studies, where the nanoparticles formed with the polymers having longer degrees of polymerization showed discrete particles in media containing 10% serum. Transfection experiments revealed that the polymers exhibited low cytotoxicity at low N/P ratios and could facilitate high cellular uptake and gene expression in HeLa and H9c2(2-1) cells, and the results were dependent on the degrees of polymerization (longer polymers yielded higher transfection and toxicity).

Original languageEnglish (US)
Pages (from-to)2885-2898
Number of pages14
JournalBiomaterials
Volume28
Issue number18
DOIs
StatePublished - 2007
Externally publishedYes

Bibliographical note

Funding Information:
The authors gratefully acknowledge Dr. Guodong Zhang for his help in the initial synthesis of the Tr4 100 polymers. The authors also gratefully acknowledge Dr. Matt Lynch, Tom Kodger, and the Procter and Gamble Co. for generously offering ITC use and expertise. The funding of this work was provided by the NIH (1-R21-EB003938), the NSF CAREER (CHE-0449774), and the Beckman Young Investigators programs.

Keywords

  • Bioactivity
  • Copolymer
  • DNA
  • Gene transfer
  • In vitro
  • Polymerization

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