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

Nanomedicine. 2020 Jan:23:102115. doi: 10.1016/j.nano.2019.102115. Epub 2019 Oct 23.

Authors

Affiliations

¹ Department of Neurosurgery, Johns Hopkins University School of Medicine.
² Department of Biomedical Engineering, Johns Hopkins University School of Medicine; The Institute for Nanobiotechnology and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine.
³ Department of Neurosurgery, Johns Hopkins University School of Medicine; Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Department of Ophthalmology, Johns Hopkins University School of Medicine; Department of Oncology, Johns Hopkins University School of Medicine.
⁴ Department of Neurosurgery, Johns Hopkins University School of Medicine; Department of Biomedical Engineering, Johns Hopkins University School of Medicine; The Institute for Nanobiotechnology and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine; Department of Ophthalmology, Johns Hopkins University School of Medicine; Department of Oncology, Johns Hopkins University School of Medicine; Department of Materials Science & Engineering, Johns Hopkins University; Department of Chemical & Biomolecular Engineering, Johns Hopkins University; Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine. Electronic address: [email protected].
⁵ Department of Neurosurgery, Johns Hopkins University School of Medicine. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Brain Neoplasms* / enzymology
Brain Neoplasms* / genetics
Brain Neoplasms* / pathology
Brain Neoplasms* / therapy
Cell Line, Tumor
Child
Genetic Therapy*
Herpesvirus 1, Human* / enzymology
Herpesvirus 1, Human* / genetics
Humans
Male
Mice
Mice, Nude
Nanoparticles* / chemistry
Nanoparticles* / therapeutic use
Thymidine Kinase* / biosynthesis
Thymidine Kinase* / genetics
Viral Proteins* / biosynthesis
Viral Proteins* / genetics
Xenograft Model Antitumor Assays

Substances

Viral Proteins
Thymidine Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding