Critical Length of PEG Grafts on lPEI/DNA Nanoparticles for Efficient in Vivo Delivery

John Michael Williford, Maani M. Archang, Il Minn, Yong Ren, Mark Wo, John Vandermark, Paul B. Fisher, Martin G. Pomper, Hai Quan Mao

Research output: Contribution to journalArticlepeer-review

Abstract

Nanoparticle-mediated gene delivery is a promising alternative to viral methods; however, its use in vivo, particularly following systemic injection, has suffered from poor delivery efficiency. Although PEGylation of nanoparticles has been successfully demonstrated as a strategy to enhance colloidal stability, its success in improving delivery efficiency has been limited, largely due to reduced cell binding and uptake, leading to poor transfection efficiency. Here we identified an optimized PEGylation scheme for DNA micellar nanoparticles that delivers balanced colloidal stability and transfection activity. Using linear polyethylenimine (lPEI)-g-PEG as a carrier, we characterized the effect of graft length and density of polyethylene glycol (PEG) on nanoparticle assembly, micelle stability, and gene delivery efficiency. Through variation of PEG grafting degree, lPEI with short PEG grafts (molecular weight, MW 500-700 Da) generated micellar nanoparticles with various shapes including spherical, rodlike, and wormlike nanoparticles. DNA micellar nanoparticles prepared with short PEG grafts showed comparable colloidal stability in salt and serum-containing media to those prepared with longer PEG grafts (MW 2 kDa). Corresponding to this trend, nanoparticles prepared with short PEG grafts displayed significantly higher in vitro transfection efficiency compared to those with longer PEG grafts. More importantly, short PEG grafts permitted marked increase in transfection efficiency following ligand conjugation to the PEG terminal in metastatic prostate cancer-bearing mice. This study identifies that lPEI-g-PEG with short PEG grafts (MW 500-700 Da) is the most effective to ensure shape control and deliver high colloidal stability, transfection activity, and ligand effect for DNA nanoparticles in vitro and in vivo following intravenous administration.

Original languageEnglish (US)
Pages (from-to)567-578
Number of pages12
JournalACS Biomaterials Science and Engineering
Volume2
Issue number4
DOIs
StatePublished - Apr 11 2016

Keywords

  • DNA
  • nanomedicine
  • nonviral
  • shape
  • tumor-specific promoter

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering

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