Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo

Antonella Mangraviti; Stephany Yi Tzeng; Kristen Lynn Kozielski; Yuan Wang; Yike Jin; David Gullotti; Mariangela Pedone; Nitsa Buaron; Ann Liu; David R. Wilson; Sarah K. Hansen; Fausto J. Rodriguez; Guo Dong Gao; Francesco Dimeco; Henry Brem; Alessandro Olivi; Betty Tyler; Jordan J. Green

doi:10.1021/nn504905q

Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo

Antonella Mangraviti, Stephany Yi Tzeng, Kristen Lynn Kozielski, Yuan Wang, Yike Jin, David Gullotti, Mariangela Pedone, Nitsa Buaron, Ann Liu, David R. Wilson, Sarah K. Hansen, Fausto J. Rodriguez, Guo Dong Gao, Francesco Dimeco, Henry Brem, Alessandro Olivi, Betty Tyler, Jordan J. Green

School of Medicine

Research output: Contribution to journal › Article › peer-review

143 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1236-1249
Number of pages	14
Journal	ACS Nano
Volume	9
Issue number	2
DOIs	https://doi.org/10.1021/nn504905q
State	Published - Feb 24 2015

Keywords

DNA
brain tumor
gene therapy
nanomedicine
nonviral gene delivery
polymer

ASJC Scopus subject areas

General Materials Science
General Engineering
General Physics and Astronomy

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10.1021/nn504905q

Cite this

Mangraviti, A., Tzeng, S. Y., Kozielski, K. L., Wang, Y., Jin, Y., Gullotti, D., Pedone, M., Buaron, N., Liu, A., Wilson, D. R., Hansen, S. K., Rodriguez, F. J., Gao, G. D., Dimeco, F., Brem, H., Olivi, A., Tyler, B., & Green, J. J. (2015). Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo. ACS Nano, 9(2), 1236-1249. https://doi.org/10.1021/nn504905q

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title = "Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo",

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.",

keywords = "DNA, brain tumor, gene therapy, nanomedicine, nonviral gene delivery, polymer",

author = "Antonella Mangraviti and Tzeng, {Stephany Yi} and Kozielski, {Kristen Lynn} and Yuan Wang and Yike Jin and David Gullotti and Mariangela Pedone and Nitsa Buaron and Ann Liu and Wilson, {David R.} and Hansen, {Sarah K.} and Rodriguez, {Fausto J.} and Gao, {Guo Dong} and Francesco Dimeco and Henry Brem and Alessandro Olivi and Betty Tyler and Green, {Jordan J.}",

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AU - Mangraviti, Antonella

AU - Tzeng, Stephany Yi

AU - Kozielski, Kristen Lynn

AU - Wang, Yuan

AU - Jin, Yike

AU - Gullotti, David

AU - Pedone, Mariangela

AU - Buaron, Nitsa

AU - Liu, Ann

AU - Wilson, David R.

AU - Hansen, Sarah K.

AU - Rodriguez, Fausto J.

AU - Gao, Guo Dong

AU - Dimeco, Francesco

AU - Brem, Henry

AU - Olivi, Alessandro

AU - Tyler, Betty

AU - Green, Jordan J.

PY - 2015/2/24

Y1 - 2015/2/24

N2 - 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.

AB - 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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KW - gene therapy

KW - nanomedicine

KW - nonviral gene delivery

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Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo

Abstract

Keywords

ASJC Scopus subject areas

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