Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies

John Choi; Yuan Rui; Jayoung Kim; Noah Gorelick; David R. Wilson; Kristen Kozielski; Antonella Mangraviti; Eric Sankey; Henry Brem; Betty Tyler; Jordan J. Green; Eric M. Jackson

doi:10.1016/j.nano.2019.102115

Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies

John Choi, Yuan Rui, Jayoung Kim, Noah Gorelick, David R. Wilson, Kristen Kozielski, Antonella Mangraviti, Eric Sankey, Henry Brem, Betty Tyler, Jordan J. Green, Eric M. Jackson

School of Medicine

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

12 Scopus citations

Abstract

Together, medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT) represent two of the most prevalent pediatric brain malignancies. Current treatment involves radiation, which has high risks of developmental sequelae for patients under the age of three. New safer and more effective treatment modalities are needed. Cancer gene therapy is a promising alternative, but there are challenges with using viruses in pediatric patients. We developed a library of poly(beta-amino ester) (PBAE) nanoparticles and evaluated their efficacy for plasmid delivery of a suicide gene therapy to pediatric brain cancer models—specifically herpes simplex virus type I thymidine kinase (HSVtk), which results in controlled apoptosis of transfected cells. In vivo, PBAE-HSVtk treated groups had a greater median overall survival in mice implanted with AT/RT (P = 0.0083 vs. control) and MB (P < 0.0001 vs. control). Our data provide proof of principle for using biodegradable PBAE nanoparticles as a safe and effective nanomedicine for treating pediatric CNS malignancies.

Original language	English (US)
Article number	102115
Journal	Nanomedicine: Nanotechnology, Biology, and Medicine
Volume	23
DOIs	https://doi.org/10.1016/j.nano.2019.102115
State	Published - Jan 2020

Keywords

Atypical teratoid/rhabdoid tumor
Cancer
Medulloblastoma
Pediatrics
Poly(beta-amino ester) nanoparticle

ASJC Scopus subject areas

Bioengineering
Medicine (miscellaneous)
Molecular Medicine
Biomedical Engineering
Materials Science(all)
Pharmaceutical Science

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10.1016/j.nano.2019.102115

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@article{a307148bbcfa41c39d9b6ed0828cdccc,

title = "Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies",

abstract = "Together, medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT) represent two of the most prevalent pediatric brain malignancies. Current treatment involves radiation, which has high risks of developmental sequelae for patients under the age of three. New safer and more effective treatment modalities are needed. Cancer gene therapy is a promising alternative, but there are challenges with using viruses in pediatric patients. We developed a library of poly(beta-amino ester) (PBAE) nanoparticles and evaluated their efficacy for plasmid delivery of a suicide gene therapy to pediatric brain cancer models—specifically herpes simplex virus type I thymidine kinase (HSVtk), which results in controlled apoptosis of transfected cells. In vivo, PBAE-HSVtk treated groups had a greater median overall survival in mice implanted with AT/RT (P = 0.0083 vs. control) and MB (P < 0.0001 vs. control). Our data provide proof of principle for using biodegradable PBAE nanoparticles as a safe and effective nanomedicine for treating pediatric CNS malignancies.",

keywords = "Atypical teratoid/rhabdoid tumor, Cancer, Medulloblastoma, Pediatrics, Poly(beta-amino ester) nanoparticle",

author = "John Choi and Yuan Rui and Jayoung Kim and Noah Gorelick and Wilson, {David R.} and Kristen Kozielski and Antonella Mangraviti and Eric Sankey and Henry Brem and Betty Tyler and Green, {Jordan J.} and Jackson, {Eric M.}",

note = "Funding Information: Acknowledgments: The authors would like to thank the NIH (R01CA228133) for support of this work. The authors would also like to thank the Wilmer Equipment Core for use of Cellomics Arrayscan VTI for automated image acquisition and quantification (Microscopy Core Grant EY001765). JC thanks the Johns Hopkins University Deans Research Fund for their fellowship support. YR (DGE-1232825) and DRW (DGE-0707427) thank the NSF for fellowship support, and JK thanks Samsung for scholarship support. JG thanks the Bloomberg~Kimmel Institute for Cancer Immunotherapy for support. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2020",

month = jan,

doi = "10.1016/j.nano.2019.102115",

language = "English (US)",

volume = "23",

journal = "Nanomedicine: Nanotechnology, Biology, and Medicine",

issn = "1549-9634",

publisher = "Elsevier Inc.",

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T1 - Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies

AU - Choi, John

AU - Rui, Yuan

AU - Kim, Jayoung

AU - Gorelick, Noah

AU - Wilson, David R.

AU - Kozielski, Kristen

AU - Mangraviti, Antonella

AU - Sankey, Eric

AU - Brem, Henry

AU - Tyler, Betty

AU - Green, Jordan J.

AU - Jackson, Eric M.

N1 - Funding Information: Acknowledgments: The authors would like to thank the NIH (R01CA228133) for support of this work. The authors would also like to thank the Wilmer Equipment Core for use of Cellomics Arrayscan VTI for automated image acquisition and quantification (Microscopy Core Grant EY001765). JC thanks the Johns Hopkins University Deans Research Fund for their fellowship support. YR (DGE-1232825) and DRW (DGE-0707427) thank the NSF for fellowship support, and JK thanks Samsung for scholarship support. JG thanks the Bloomberg~Kimmel Institute for Cancer Immunotherapy for support. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2020/1

Y1 - 2020/1

N2 - Together, medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT) represent two of the most prevalent pediatric brain malignancies. Current treatment involves radiation, which has high risks of developmental sequelae for patients under the age of three. New safer and more effective treatment modalities are needed. Cancer gene therapy is a promising alternative, but there are challenges with using viruses in pediatric patients. We developed a library of poly(beta-amino ester) (PBAE) nanoparticles and evaluated their efficacy for plasmid delivery of a suicide gene therapy to pediatric brain cancer models—specifically herpes simplex virus type I thymidine kinase (HSVtk), which results in controlled apoptosis of transfected cells. In vivo, PBAE-HSVtk treated groups had a greater median overall survival in mice implanted with AT/RT (P = 0.0083 vs. control) and MB (P < 0.0001 vs. control). Our data provide proof of principle for using biodegradable PBAE nanoparticles as a safe and effective nanomedicine for treating pediatric CNS malignancies.

AB - Together, medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT) represent two of the most prevalent pediatric brain malignancies. Current treatment involves radiation, which has high risks of developmental sequelae for patients under the age of three. New safer and more effective treatment modalities are needed. Cancer gene therapy is a promising alternative, but there are challenges with using viruses in pediatric patients. We developed a library of poly(beta-amino ester) (PBAE) nanoparticles and evaluated their efficacy for plasmid delivery of a suicide gene therapy to pediatric brain cancer models—specifically herpes simplex virus type I thymidine kinase (HSVtk), which results in controlled apoptosis of transfected cells. In vivo, PBAE-HSVtk treated groups had a greater median overall survival in mice implanted with AT/RT (P = 0.0083 vs. control) and MB (P < 0.0001 vs. control). Our data provide proof of principle for using biodegradable PBAE nanoparticles as a safe and effective nanomedicine for treating pediatric CNS malignancies.

KW - Atypical teratoid/rhabdoid tumor

KW - Cancer

KW - Medulloblastoma

KW - Pediatrics

KW - Poly(beta-amino ester) nanoparticle

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JO - Nanomedicine: Nanotechnology, Biology, and Medicine

JF - Nanomedicine: Nanotechnology, Biology, and Medicine

M1 - 102115

ER -

Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies

Abstract

Keywords

ASJC Scopus subject areas

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