Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies

doi:10.1016/j.nano.2019.102115

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 23, January 2020, 102115

https://doi.org/10.1016/j.nano.2019.102115 Get rights and content

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.

Graphical Abstract

Poly(beta-amino ester)s (PBAEs) are biodegradable, cationic polymers that can self-assemble into nanoparticles with nucleic acids. Nanoparticles formulated with plasmid DNA for intracellular gene delivery to pediatric brain cancer cells enabled >50% transfection in both cell lines tested. In vivo intracranial administration of nanoparticles carrying the HSVtk suicide gene to mice bearing orthotopic tumor xenografts significantly enhanced survival.

Section snippets

Materials

Small molecule monomers: 1,4-butanediol diacrylate (B4; CAS 1070-70-8), 3-amino-1-propanol (S3, CAS 156-87-6), 4-amino-1-butanol (S4, CAS 13325-10-05), 5-amino-1-pentanol (S5, CAS 2508-29-4), and 1-(3-aminopropyl)-4-methylpiperazine (E7, CAS 4572-031) were purchased from Alfa Aesar (Ward Hill, MA, USA); 1,5-pentanediol diacrylate (B5, CAS 36840-85-4) was purchased from Dajac Laboratories (Feasterville-Trevose, PA, USA); 2-(3-aminopropylamino)ethanol (E6; CAS 4461-39-6) was purchased from Sigma

PBAE nanoparticles enable efficient DNA delivery to AT/RT and MB cells in vitro

We synthesized a small library of PBAEs by co-polymerizing small molecule monomers via Michael addition reactions between amines and diacrylates following previously reported protocols (Figure 1, A).²⁶ Briefly, diacrylate “B” monomers were reacted with primary amine-containing “S” monomers (90°C, overnight) to produce acrylate-terminated polymers, which were then end-capped with amine-containing “E” monomers (25°C, 1 h). The presence of acrylate-terminated polymers following the first step of

Discussion

In this work, we synthesized a small library of poly(beta-amino ester)s (PBAEs) and examined their ability to functionally deliver plasmid DNA encoding a suicide gene to pediatric CNS malignancies. The small size of the nanoparticles (Figure 1) contributed to successful delivery to BT-12 (an AT/RT cell line) and D425 (a MB cell line) in vitro. Within the same polymer type, transfection efficacy generally increased with increasing polymer-DNA w/w ratio while cell viability decreased (Figure 2);

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: There are no conflicts of interest pertinent to the development of manuscript.

: 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.

¹: These authors contributed equally

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Original ArticleNonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies

Abstract

Graphical Abstract

Section snippets

Materials

PBAE nanoparticles enable efficient DNA delivery to AT/RT and MB cells in vitro

Discussion

J Clin Neurosci

Cancer Cell Int

J Control Release

J Control Release

Biomaterials

Mol Ther

J Biotechnol

Euro J Cancer

Mol Ther Oncolytics

Biomaterials

Biomaterials

Proton therapy for paediatric CNS tumours—improving treatment-related outcomes

Nat Rev Neurol

Atypical teratoid/rhabdoid tumors: challenges and search for solutions

Cancer Manag Res

Atypical teratoid/rhabdoid tumor of the spinal cord in a child: case report and comprehensive review of the literature

Pediatr Neurosurg

The treatment of malignant brain tumors in infants and very young children: an update of the Pediatric Oncology Group experience

Neuro Oncol

Atypical teratoid/rhabdoid tumors (Atrt): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy

J Clin Oncol

Clinicopathologic prognostic factors in childhood atypical teratoid and rhabdoid tumor of the central nervous system: a multicenter study

Cancer

Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor

J Clin Oncol

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

ACS Nano

Original Article
Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies