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Biodegradable poly(2-dimethylamino ethylamino)phosphazene for in vivo gene delivery to tumor cells. Effect of polymer molecular weight.

Abstract：

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 (Mw/Mn 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 (Mw 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.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

de Wolf HK,de Raad M,Snel C,van Steenbergen MJ,Fens MH,Storm G,Hennink WE

doi

10.1007/s11095-007-9299-z

subject

Has Abstract

pub_date

2007-08-01 00:00:00

pages

1572-80

issue

eissn

0724-8741

issn

1573-904X

journal_volume

pub_type

杂志文章

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Biodegradable poly(2-dimethylamino ethylamino)phosphazene for in vivo gene delivery to tumor cells. Effect of polymer molecular weight.