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Structure-optimized interpolymer polyphosphazene complexes for effective gene delivery against glioblastoma

Hsu, Wei-Hsin; Sánchez-Gómez, Pilar; Gomez-Ibarlucea, Esther; Ivanov, Delyan P.; Rahman, Ruman; Grabowska, Anna M.; Csaba, Noemi; Alexander, Cameron; Garcia-Fuentes, Marcos

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Authors

Wei-Hsin Hsu

Pilar Sánchez-Gómez

Esther Gomez-Ibarlucea

Delyan P. Ivanov

ANNA GRABOWSKA ANNA.GRABOWSKA@NOTTINGHAM.AC.UK
Professor of Cancer Microenvironment

Noemi Csaba

Marcos Garcia-Fuentes



Abstract

Safe and efficient gene delivery vectors will enhance the prospects for polynucleotide-based therapies. Herein a new approach toward structurally optimized gene vector design based on the preparation of clickable poly(allylamino-phosphazene)s that can be converted to several cationic and anionic derivatives via thiol–ene addition is described. Simultaneous co-incubation of alkylamine- and alkylcarboxylate-poly(phosphazenes) with polynucleotide generates binary polyelectrolyte nanoparticles. Screening of a series of these complexes for transfection in glioblastoma cells shows that the inclusion of 6-mercaptohexanoic acid substituted poly(phosphazene)s in the complexes results in six-fold and 19-fold higher luciferase expression in U87MG cells and GBM1 primary cells, respectively. This effect is attributed to the specific ionization properties of these materials that improved polyplex intracellular trafficking. Transfection in 3D-spheroid models and subcutaneous xenograft U87MG tumors confirms higher transgene expression for the binary cationic/anionic poly(phosphazene) complexes compared to the related polycation-pDNA complexes and to PEI-pDNA complexes. The data also indicate a notable capacity of the mixed complexes to deliver genes to the inner cores of tumor spheroids. Extension of this approach to siRNA delivery shows that the mixed poly(phosphazene) complexes can silence DYRK1A, a gene implicated in glioblastoma initiation and progression, reducing U87MG cell renewal in vitro and delaying tumor growth in vivo.

Journal Article Type Article
Acceptance Date Nov 16, 2018
Online Publication Date Nov 26, 2018
Publication Date Mar 12, 2019
Deposit Date Dec 5, 2018
Publicly Available Date Dec 5, 2018
Journal Advanced Therapeutics
Electronic ISSN 2366-3987
Publisher Wiley-VCH Verlag
Peer Reviewed Peer Reviewed
Volume 2
Issue 3
Article Number 1800126
DOI https://doi.org/10.1002/adtp.201800126
Public URL https://nottingham-repository.worktribe.com/output/1368015
Publisher URL https://onlinelibrary.wiley.com/doi/full/10.1002/adtp.201800126

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