Structure-optimized interpolymer polyphosphazene complexes for effective gene delivery to glioblastoma
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|Title:||Structure-optimized interpolymer polyphosphazene complexes for effective gene delivery to glioblastoma
Ivanov, Delyan P.
Grabowska, Anna M.
Csaba, Noemi Stefania
García Fuentes, Marcos
|Affiliation:||Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas
|Subject:||Poly(phosphazene)s | Click chemistry | Polymeric gene delivery | siRNA delivery | Glioblastoma | Tumor initiating cells ||
|Date of Issue:||2019
|Citation:||Hsu, W. H., 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), 1800126
|Abstract:||Safe and efficient gene delivery vectors would enhance the prospects for polynucleotide-based therapies. Herein we describe a new approach towards 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. Simultaneous co-incubation of alkylamine- and alkylcarboxylate-poly(phosphazenes) with polynucleotides generated binary-polyelectrolyte nanoparticles. Screening of a series of these complexes for transfection in glioblastoma cells showed that the inclusion of 6-mercaptohexanoic acid substituted poly(phosphazene)s in the complexes resulted in 6-fold and 19-fold higher luciferase expression in U87MG cells and primary GBM1 cell- line, respectively. This effect was attributed to the specific ionization properties of this materials that improved polyplex intracellular trafficking. Transfection in 3D-spheroid models and subcutaneous xenograft U87MG tumors confirmed 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 indicated a notable capacity of the mixed complexes to deliver genes to the inner cores of tumor spheroids. Extension of this approach to siRNA delivery showed that the mixed poly(phosphazene) complexes were able to silence DYRK1A, a gene implicated in tumor initiation and progression, reducing U87MG cell renewal in vitro and delaying tumor growth in vivo.|
|Description:||This is the peer reviewed version of the following article: Hsu, W.‐H., Sánchez‐Gómez, P., Gomez‐Ibarlucea, E., Ivanov, D.P., Rahman, R., Grabowska, A.M., Csaba, N., Alexander, C. and Garcia‐Fuentes, M. (2019), Structure‐Optimized Interpolymer Polyphosphazene Complexes for Effective Gene Delivery against Glioblastoma. Adv. Therap., 2: 1800126. doi:10.1002/adtp.201800126, which has been published in final form at https://doi.org/10.1002/adtp.201800126. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
|Rights:||© 2018 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
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