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• W1485517138 abstract "In this thesis several new cationic and biodegradable polymers have been synthesized, characterized and evaluated in vitro for their transfection capabilities. Some of the polyplexes were also evaluated in in vivo tumour models. In Chapter 1 an overview about the current literature of degradable polymers for gene delivery is given. In Chapter 2 a new class of biodegradable cationic gene delivery polymers based on polyphosphazenes is described. The synthesized polyphosphazenes, poly(2-dimethylaminoethylamine)phosphazene and poly(2-dimethylaminoethanol)phosphazene, were able to bind plasmid DNA yielding positively charged particles (polyplexes). The polyphosphazene-based polyplexes were able to transfect COS-7 cells in vitro. The toxicity of both polyphosphazenes was lower than pDMAEMA. Degradation of the polymers occurred by acid catalyzed hydrolysis. Chapter 3 reports on the design of a new cationic biodegradable polyphosphazene, bearing both pendant primary and tertiary amine side groups, poly(2-dimethylaminoethylamine-co-diaminobutane)phosphazene (poly(DMAEA-co-BA)phosphazene). PEG and PEG-folate were coupled to polyplexes based on this poly(DMAEA-co-BA)phosphazene, leading to small and almost neutral particles. Low cytotoxicity was observed for both uncoated and coated polyplex systems. By coupling PEG-folate instead of PEG to the uncoated polyplexes the transfection activity was increased 3 times. When free folate was added to the transfection medium, only the transfection activity of the targeted polyplexes decreased, indicating internalization of the folate decorated PEG polyplexes via the folate receptor endocytosis. Chapter 4 describes a series of cationic methacrylamide polymers with hydrolyzable side groups. These polymers with biocompatible main chains of poly(N-(1-hydroxypropan-2-yl)methacrylamide) (pHPMA) were derivatized with cationic groups via hydrolyzable linkers. These polymers form stable polyplexes at 37 C and pH 5.0. The rate of hydrolysis at 37 C and pH 7.4 of the side groups differed widely (from 2 h to 70 h). Two polyplexes based on were almost twice as active as pEI based systems. Importantly, all polymers investigated showed a substantial lower in vitro cytotoxicity than pEI. In Chapter 5 polyplexes composed of plasmid DNA and biodegradable polymer (p(DMAEA)phosphazene or pHPMA-DMAE) were evaluated for in vivo application. P(DMAEA)phosphazene polyplexes were studied after intravenous administration in tumour bearing mice. The polyplex systems showed considerable liver and lung disposition. In time, redistribution of the polyplexes from the lung was observed and more importantly, p(DMAEA)phosphazene polyplex system showed a substantial tumour accumulation of 5% ID/g at 240 min after administration. The tumour disposition was associated with considerable expression levels of the reporter gene. In contrast to pEI22 polyplexes, p(DMAEA)phosphazene polyplexes did not display substantial gene expression in the lung or other organs (organ gene expression < 1/100 of tumour gene expression). pHPMA-DMAE polyplexes were investigated after intraperitoneal injection into mice bearing an ovarian cancer xenograft. Polyplexes based on the polymer pHPMA-DMAE showed transfection activity similar to polyplexes based on the non-degradable and rather toxic polymer poly(ethylenimine) (pEI22). Polyplexes based on pHPMA-DMAE did not show any cytotoxicity and mediated highest transfection activity at the highest N/P ratio investigated. This chapter shows that biodegradable polymers have good potential for in vivo delivery of DNA after local and intra venous administration. Finally Chapter 6 summarizes the results of this thesis and gives suggestions for future research." @default.
• W1485517138 created "2016-06-24" @default.
• W1485517138 creator A5005362066 @default.
• W1485517138 date "2007-12-10" @default.
• W1485517138 modified "2023-09-27" @default.
• W1485517138 title "Biodegradable cationic polymers as gene delivery carriers: From synthesis to in vivo application" @default.
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