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

doi:10.1002/adhm.201400800

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

Adv Healthc Mater. 2015 May;4(7):1023-33. doi: 10.1002/adhm.201400800. Epub 2015 Mar 11.

Authors

Panagiotis Mastorakos^{1

2}, Clark Zhang^{1

3}, Sneha Berry^{1

4}, Yumin Oh^{1

5}, Seulki Lee^{1

5}, Charles G Eberhart⁶, Graeme F Woodworth⁷, Jung Soo Suk^{1

2}, Justin Hanes^{1

2

3

8}

Affiliations

¹ Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21231, USA.
² Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21297, USA.
³ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
⁴ Center for Biotechnology Education, Krieger School of Arts and Sciences, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD, 21218, USA.
⁵ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 601 N. Caroline Street, Baltimore, MD, 21287, USA.
⁶ Department of Pathology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.
⁷ Departments of Neurological Surgery Anatomy and Neurobiology, University of Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD, 21201, USA.
⁸ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD, 21218, USA.

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.

Keywords: brain tissue barrier; central nervous system diseases; convection enhanced delivery; extracellular matrix; nonviral gene therapy.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain / metabolism*
Cell Line, Tumor
DNA / administration & dosage*
DNA / genetics*
Extracellular Matrix / genetics
Gene Transfer Techniques
Genetic Therapy / methods
Genetic Vectors / genetics
Nanoparticles / administration & dosage*
Polyethylene Glycols / administration & dosage*
Polymers / administration & dosage
Rabbits
Rats
Transfection / methods
Transgenes / genetics

Substances

Polymers
Polyethylene Glycols
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding