Thesis

The synthesis and characterisation of modified polyethylenimine polymers for gene delivery

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Awarding institution
  • University of Strathclyde
Date of award
  • 2002
Thesis identifier
  • T10437
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Department, School or Faculty
Abstract
  • Polyethylenimine (PEI) has previously been shown to be an efficient gene delivery vector in both in vitro and in vivo. Despite this efficient transfection response PEI suffers from high toxicity when administered in vivo. We report the synthesis of four modified PEI polymers for use as gene delivery vectors. PEI was modified through attachment of Palmitoyl groups to give P-PEI, the attachment of Palmitoyl and Polyethylene glycol groups to give PP-PEI, the quaternisation of PEI and P-PEI to give QPEI and QP-PEI respectively. The successful modification of the PEI polymer was confirmed using various analytical techniques Nuclear Magnetic Resonance, Fourier Transform Infrared spectroscopy, Ultra Violet spectroscopy and Gel Permeation Chromatography Multi Angle Laser Light Scattering. The polymers ability to interact with plasmid DNA and their subsequent morphologies were also investigated. P-PEI was found to self assemble into a vesicular structure upon sonication. This vesicular structure was retained upon complexation with DNA (~200nm). PP-PEI was found to produce worm like structures when sonicated (~700nm). QPEI was shown to produce small tightly packed spheres with DNA (~50nm). The condensation of DNA by QPPEI produced flattened vesicular structures (~200nm). PP-PEI (~700nm) and QPPEI (200nm) were also sonicated in the presence of cholesterol to produce vesicular structures. In vitro studies showed the modified polymer/DNA complexes were found to be more resistant to degradation in the presence of plasma proteins and blood erythrocytes, with the exception of QPEI. Haemolytic activity of the modified polymers was found to be very low and less than that of the parent PEI polymer. MTT assays showed that the modified polymer/DNA complexes were less cytotoxic than PEI alone. The modified polymers were found to be less efficient transfection agents in vitro, with the best modified polymer (QPPEI) producing around 60% of the response shown by PEI. In Vivo studies using a green fluorescent protein marker revealed P-PEI, QPPEI and QPPEI/cholesterol to be more efficient transfection agents than the parent molecule PEI.
Advisor / supervisor
  • Uchegbu, Ijeoma F.
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Note
  • Please note, when this thesis scan was produced it was discovered that page 88 is a blank page in both hardbound copies of this thesis.
DOI
EThOS ID
  • uk.bl.ethos.248766

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