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Biodegradable Poly(2-Dimethylamino Ethylamino)Phosphazene for In Vivo Gene Delivery to Tumor Cells. Effect of Polymer Molecular Weight

PURPOSE: Previously, we have shown that complexes of plasmid DNA with the biodegradable polymer poly(2-dimethylamino ethylamino)phosphazene (p(DMAEA)-ppz) mediated tumor selective gene expression after intravenous administration in mice. In this study, we investigated the effect of p(DMAEA)-ppz mole...

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Detalles Bibliográficos
Autores principales: de Wolf, Holger K., de Raad, Markus, Snel, Cor, van Steenbergen, Mies J., Fens, Marcel H. A. M., Storm, Gert, Hennink, Wim E.
Formato: Texto
Lenguaje:English
Publicado: Kluwer Academic Publishers-Plenum Publishers 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1915646/
https://www.ncbi.nlm.nih.gov/pubmed/17435970
http://dx.doi.org/10.1007/s11095-007-9299-z
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author de Wolf, Holger K.
de Raad, Markus
Snel, Cor
van Steenbergen, Mies J.
Fens, Marcel H. A. M.
Storm, Gert
Hennink, Wim E.
author_facet de Wolf, Holger K.
de Raad, Markus
Snel, Cor
van Steenbergen, Mies J.
Fens, Marcel H. A. M.
Storm, Gert
Hennink, Wim E.
author_sort de Wolf, Holger K.
collection PubMed
description PURPOSE: Previously, we have shown that complexes of plasmid DNA with the biodegradable polymer poly(2-dimethylamino ethylamino)phosphazene (p(DMAEA)-ppz) mediated tumor selective gene expression after intravenous administration in mice. In this study, we investigated the effect of p(DMAEA)-ppz molecular weight on both in vitro and in vivo tumor transfection, as well as on complex induced toxicity. MATERIALS AND METHODS: p(DMAEA)-ppz with a broad molar mass distribution was fractionated by preparative size exclusion chromatography. Polyplexes consisting of plasmid DNA and the collected polymer fractions were tested for biophysical properties, (cyto)toxicity and transfection activity. RESULTS: Four p(DMAEA)-ppz fractions were collected with weight average molecular weights ranging from 130 to 950 kDa, and with narrow molecular mass distributions (M(w)/M(n) from 1.1 to 1.3). At polymer-to-DNA (N/P) ratios above 6, polyplexes based on these polymers were all positively charged (zeta potential 25–29 mV), and had a size of 80–90 nm. The in vitro cytotoxicity of the polyplexes positively correlated with polymer molecular weight. The in vitro transfection activity of the different polyplexes depended on their N/P ratio, and was affected by the degree of cytotoxicity, as well as the colloidal stability of the different polyplexes. Intravenous administration of polyplexes based on the high molecular weight polymers led to apparent toxicity, as a result of polyplex-induced erythrocyte aggregation. On the other hand, administration of polyplexes based on low molecular weight p(DMAEA)-ppz’s (M(w) 130 kDa) did not show signs of toxicity and resulted in tumor selective gene expression. CONCLUSION: Polymer molecular weight fractionation enabled us to optimize the transfection efficiency/toxicity ratio of p(DMAEA)-ppz polyplexes for in vitro and in vivo tumor transfection.
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spelling pubmed-19156462007-07-13 Biodegradable Poly(2-Dimethylamino Ethylamino)Phosphazene for In Vivo Gene Delivery to Tumor Cells. Effect of Polymer Molecular Weight de Wolf, Holger K. de Raad, Markus Snel, Cor van Steenbergen, Mies J. Fens, Marcel H. A. M. Storm, Gert Hennink, Wim E. Pharm Res Research Paper PURPOSE: Previously, we have shown that complexes of plasmid DNA with the biodegradable polymer poly(2-dimethylamino ethylamino)phosphazene (p(DMAEA)-ppz) mediated tumor selective gene expression after intravenous administration in mice. In this study, we investigated the effect of p(DMAEA)-ppz molecular weight on both in vitro and in vivo tumor transfection, as well as on complex induced toxicity. MATERIALS AND METHODS: p(DMAEA)-ppz with a broad molar mass distribution was fractionated by preparative size exclusion chromatography. Polyplexes consisting of plasmid DNA and the collected polymer fractions were tested for biophysical properties, (cyto)toxicity and transfection activity. RESULTS: Four p(DMAEA)-ppz fractions were collected with weight average molecular weights ranging from 130 to 950 kDa, and with narrow molecular mass distributions (M(w)/M(n) from 1.1 to 1.3). At polymer-to-DNA (N/P) ratios above 6, polyplexes based on these polymers were all positively charged (zeta potential 25–29 mV), and had a size of 80–90 nm. The in vitro cytotoxicity of the polyplexes positively correlated with polymer molecular weight. The in vitro transfection activity of the different polyplexes depended on their N/P ratio, and was affected by the degree of cytotoxicity, as well as the colloidal stability of the different polyplexes. Intravenous administration of polyplexes based on the high molecular weight polymers led to apparent toxicity, as a result of polyplex-induced erythrocyte aggregation. On the other hand, administration of polyplexes based on low molecular weight p(DMAEA)-ppz’s (M(w) 130 kDa) did not show signs of toxicity and resulted in tumor selective gene expression. CONCLUSION: Polymer molecular weight fractionation enabled us to optimize the transfection efficiency/toxicity ratio of p(DMAEA)-ppz polyplexes for in vitro and in vivo tumor transfection. Kluwer Academic Publishers-Plenum Publishers 2007-04-11 2007-08 /pmc/articles/PMC1915646/ /pubmed/17435970 http://dx.doi.org/10.1007/s11095-007-9299-z Text en © Springer Science+Business Media, LLC 2007
spellingShingle Research Paper
de Wolf, Holger K.
de Raad, Markus
Snel, Cor
van Steenbergen, Mies J.
Fens, Marcel H. A. M.
Storm, Gert
Hennink, Wim E.
Biodegradable Poly(2-Dimethylamino Ethylamino)Phosphazene for In Vivo Gene Delivery to Tumor Cells. Effect of Polymer Molecular Weight
title Biodegradable Poly(2-Dimethylamino Ethylamino)Phosphazene for In Vivo Gene Delivery to Tumor Cells. Effect of Polymer Molecular Weight
title_full Biodegradable Poly(2-Dimethylamino Ethylamino)Phosphazene for In Vivo Gene Delivery to Tumor Cells. Effect of Polymer Molecular Weight
title_fullStr Biodegradable Poly(2-Dimethylamino Ethylamino)Phosphazene for In Vivo Gene Delivery to Tumor Cells. Effect of Polymer Molecular Weight
title_full_unstemmed Biodegradable Poly(2-Dimethylamino Ethylamino)Phosphazene for In Vivo Gene Delivery to Tumor Cells. Effect of Polymer Molecular Weight
title_short Biodegradable Poly(2-Dimethylamino Ethylamino)Phosphazene for In Vivo Gene Delivery to Tumor Cells. Effect of Polymer Molecular Weight
title_sort biodegradable poly(2-dimethylamino ethylamino)phosphazene for in vivo gene delivery to tumor cells. effect of polymer molecular weight
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1915646/
https://www.ncbi.nlm.nih.gov/pubmed/17435970
http://dx.doi.org/10.1007/s11095-007-9299-z
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