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

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.

Citation

Hsu, W., Sánchez-Gómez, P., Gomez-Ibarlucea, E., Ivanov, D. P., Rahman, R., Grabowska, A. M., …Garcia-Fuentes, M. (2019). Structure-optimized interpolymer polyphosphazene complexes for effective gene delivery against glioblastoma. Advanced Therapeutics, 2(3), Article 1800126. https://doi.org/10.1002/adtp.201800126

• 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