Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369187
Title: Characterisation of poly(amidoamine)s and chitosan as potential intracytoplasmic delivery systems
Author: Richardson, Simon Clifford Wainwright
ISNI:       0000 0001 3517 8464
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1998
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Abstract:
In recent years, gene, antisense and ribozyme therapies have been proposed. These systems all share one common challenge, that of efficient delivery into the cytoplasm of the cell. Immunogenicity is often a significant limiting factor for the viral gene delivery systems used in clinical trials. Synthetic polymers have the advantage of reduced immunogenicity and potentially, they may be tailored, through the application of rational design, to improve cytoplasmic access and modulate cell specific targeting. Consequently, two potential polymeric nucleic acid delivery systems were selected for investigation; highly purified chitosans (three molecular weights) and poly(amidoamine)s. The latter contain amido and amino groups in the polymer chain affording the polymer the ability to change tertiary conformation in response to pH. First polymer biocompatibility was studied by evaluating cytotoxicity in vitro and polymer-mediated rat red blood cell (RBC) lysis. Chitosan and poly(amidoamine) polymers were 10-100 fold less toxic than poIy(L-lysine) and nearly 1000 times less toxic than poly(ethylenimine). In addition, the poly(amidoamine)s showed the ability to lyse rat RBC in a pH-dependent manner suggesting endosomolytic potential. Chitosan and poly(amidoamine)s formed interpolyelectrolyte complexes with DNA affording protection against DNase II. The body distribution profile of 125I-labelled chitosan and poly(amidoamine), here reported for the first time, showed that certain 125I-labelled poly(amidoamine)s avoid rapid clearance by the liver in the rat and consequently showed time dependent (5h) accumulation in a subcutaneous B16 F10 tumours in the mouse. Preliminary experiments with selected poly(amidoamine)s examined their ability to promote transfection in Hep G2 cells using a pSV-β-galactosidase reporter system. In conclusion, all of the polymers, especially the poly(amidoamine)s warrant further investigation as components of a nucleic acid delivery system.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.369187  DOI: Not available
Keywords: Immunogenicity; Cytoplasmic; Pharmacogenetics; Tumours
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