Highly PEGylated DNA Nanoparticles Provide Uniform and Widespread Gene Transfer in the Brain

Panagiotis Mastorakos, Clark Zhang, Sneha Berry, Yumin Oh, Seulki Lee, Charles G. Eberhart, Graeme F. Woodworth, Jung Soo Suk, Justin Hanes

Research output: Contribution to journalArticle

Abstract

Gene delivery to the central nervous system (CNS) has potential as a means for treating numerous debilitating neurological diseases. Nonviral gene vector platforms are tailorable and can overcome key limitations intrinsic to virus-mediated delivery; however, lack of clinical efficacy with nonviral systems to date may be attributed to limited gene vector dispersion and transfection in vivo. It is shown that the brain extracellular matrix (ECM) strongly limits penetration of polymer-based gene vector nanoparticles (NP) through the brain parenchyma, even when they are very small (<60 nm) and coated with a polyethylene glycol (PEG) corona of typical density. Following convection enhanced delivery (CED), conventional gene vectors are confined to the injection site, presumably by adhesive interactions with the brain ECM and do not provide gene expression beyond the point of administration. In contrast, it is found that incorporating highly PEGylated polymers allows the production of compacted (≈43 nm) and colloidally stable DNA NP that avoid adhesive trapping within the brain parenchyma. When administered by CED into the rat striatum, highly PEGylated DNA NP distribute throughout and provide broad transgene expression without vector-induced toxicity. The use of these brain-penetrating gene vectors, in conjunction with CED, offers an avenue to improve gene therapy for CNS diseases.

Original languageEnglish (US)
Pages (from-to)1023-1033
Number of pages11
JournalAdvanced Healthcare Materials
Volume4
Issue number7
DOIs
StatePublished - May 1 2015

Keywords

  • Brain tissue barrier
  • Central nervous system diseases
  • Convection enhanced delivery
  • Extracellular matrix
  • Nonviral gene therapy

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science

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