Polymeric Nanoparticles for Nonviral Gene Therapy Extend Brain Tumor Survival in Vivo

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Abstract

Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat glioma cell lines, 9L and F98, to discover nanoparticle formulations more effective than the leading commercial reagent Lipofectamine 2000. The lead polymer structure, poly(1,4-butanediol diacrylate- co-4-amino-1-butanol) end-modified with 1-(3-aminopropyl)-4-methylpiperazine, is a poly(β-amino ester) (PBAE) and formed nanoparticles with HSVtk DNA that were 138 ± 4 nm in size and 13 ± 1 mV in zeta potential. These nanoparticles containing HSVtk DNA showed 100% cancer cell killing in vitro in the two glioma cell lines when combined with GCV exposure, while control nanoparticles encoding GFP maintained robust cell viability. For in vivo evaluation, tumor-bearing rats were treated with PBAE/HSVtk infusion via convection-enhanced delivery (CED) in combination with systemic administration of GCV. These treated animals showed a significant benefit in survival ( p = 0.0012 vs control). Moreover, following a single CED infusion, labeled PBAE nanoparticles spread completely throughout the tumor. This study highlights a nanomedicine approach that is highly promising for the treatment of malignant glioma.

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Most cited references 67

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Progress and problems with the use of viral vectors for gene therapy.

Clare Thomas, Anja Ehrhardt, Mark Kay (2003)

Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.

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Genetic pathways to primary and secondary glioblastoma.

Hiroko Ohgaki, Paul Kleihues (2007)

Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16(INK4a) deletion (31%), and PTEN mutations (25%). Secondary glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C-->A:T mutations at CpG sites. During progression to glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter ( approximately 70%), which is the most frequent genetic alteration in both primary and secondary glioblastomas. Primary and secondary glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.

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Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance.

Andrew Burgess, Suzanne Vigneron, Estelle Brioudes … (2010)

Here we show that the functional human ortholog of Greatwall protein kinase (Gwl) is the microtubule-associated serine/threonine kinase-like protein, MAST-L. This kinase promotes mitotic entry and maintenance in human cells by inhibiting protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates cyclin B-Cdc2 substrates. The complete depletion of Gwl by siRNA arrests human cells in G2. When the levels of this kinase are only partially depleted, however, cells enter into mitosis with multiple defects and fail to inactivate the spindle assembly checkpoint (SAC). The ability of cells to remain arrested in mitosis by the SAC appears to be directly proportional to the amount of Gwl remaining. Thus, when Gwl is only slightly reduced, cells arrest at prometaphase. More complete depletion correlates with the premature dephosphorylation of cyclin B-Cdc2 substrates, inactivation of the SAC, and subsequent exit from mitosis with severe cytokinesis defects. These phenotypes appear to be mediated by PP2A, as they could be rescued by either a double Gwl/PP2A knockdown or by the inhibition of this phosphatase with okadaic acid. These results suggest that the balance between cyclin B-Cdc2 and PP2A must be tightly regulated for correct mitotic entry and exit and that Gwl is crucial for mediating this regulation in somatic human cells.

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Author and article information

Journal

Journal ID (nlm-ta): ACS Nano

Journal ID (iso-abbrev): ACS Nano

Journal ID (publisher-id): nn

Journal ID (coden): ancac3

Title: ACS Nano

Publisher: American Chemical Society

ISSN (Print): 1936-0851

ISSN (Electronic): 1936-086X

Publication date (Electronic): 02 February 2015

Publication date (Print): 24 February 2015

Volume: 9

Issue: 2

Pages: 1236-1249

Affiliations

[† ]Department of Neurosurgery, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States

[‡ ]Department of Biomedical Engineering, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States

[§ ]The Institute for Nanobiotechnology and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States

[∥ ]Department of Ophthalmology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States

[⊥ ]Department of Oncology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States

[# ]Department of Material Science and Engineering, Johns Hopkins University , Baltimore, Maryland 21231, United States

[∇ ]Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University , Xi’an 710032, China

[¶ ]Department of Chemical Engineering, Ben Gurion University of the Negev , Be’er Sheva 84105, Israel

[⊗ ]Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States

[○ ]Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta , Milan 20133, Italy

Author notes

[* ]Address correspondence to btyler@ 123456jhmi.edu , green@ 123456jhu.edu .

Article

DOI: 10.1021/nn504905q

PMC ID: 4342728

PubMed ID: 25643235

SO-VID: 24b365c4-3383-4e51-8f41-72a76f017c67

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This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

History

Date received : 01 September 2014

Date accepted : 02 February 2015

Funding

National Institutes of Health, United States

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document-id-old-9 nn504905q

document-id-new-14 nn-2014-04905q

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ScienceOpen disciplines: Nanotechnology

Keywords: nanomedicine,brain tumor,dna,gene therapy,polymer,nonviral gene delivery

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ScienceOpen disciplines: Nanotechnology

Keywords: nanomedicine, brain tumor, dna, gene therapy, polymer, nonviral gene delivery

Polymeric Nanoparticles for Nonviral Gene Therapy Extend Brain Tumor Survival in Vivo

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Abstract

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Quaternary ammonium surfactants as nanoparticles against infection

Most cited references 67

Progress and problems with the use of viral vectors for gene therapy.

Genetic pathways to primary and secondary glioblastoma.

Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance.

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