Thesis

Preparation and evaluation of amino acid-bearing polymers for enhanced gene expression in tumours

Downloadable Content

Download PDF
Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2011
Thesis identifier
  • T12799
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Non-viral gene delivery is emerging as potential safer alternative to the use of viral vectors for the treatment of various gene related diseases including cancer. Although non-viral vectors may not be as effective as the viral ones, the continuous research on rationally designing multifunctional non-viral polymeric gene delivery carriers resulted in improved delivery. In this study, our aim was to develop polyethyleneimine (PEI) and generation 3 diaminobutyric polypropyleneimine (DAB) polyplex formulations that could efficiently deliver the therapeutic genes to tumours after intravenous administration through the use of three different amino acids. Conjugation of amino acids such as arginine, lysine and leucine seems an attractive tool in virtue of their excellent cell penetration properties, which results in enhancing DNA transportation into cells and improving the transfection efficacy. The conjugation of arginine, lysine and leucine with PEI led to an increase of the in vitro anti-proliferative activity in A431 cells, respectively by 34-fold, 51-fold and 40-fold compared to the unmodified polyplex. In T98G cells, the conjugation of the amino acids to PEI improved the anti-proliferative activity of the polyplex, by 2-fold for PEI-Arg, 89-fold for PEI-Lys and 269-fold for PEI-Leu. The intravenous administration of arginine-, lysine- and Leucine-bearing PEI polyplexes led to a significant increase of gene expression in the tumour, with a β-galactosidase expression at least 3-fold higher than that obtained after treatment with unmodified polyethyleneimine polyplex. The grafting of arginine, lysine and leucine to DAB led to a significant increase of in vitro anti-proliferative activity in A431 cells, respectively by 30-fold, 22-fold and 20-fold compared to the unmodified DAB polyplex. In T98G cells, the conjugation of the amino acids to DAB improved the anti-proliferative activity of the polyplex, by 43-fold for DAB-Arg, by 47-fold for DAB-Lys and by 35-fold for DAB-Leu compared to the unmodified DAB polyplex. In vivo, the intravenous administration of amino acid-bearing DAB polyplexes resulted in an improved tumour gene expression, with the highest gene expression level observed after treatment with DAB-Lys polyplex. This work corresponds to the first evaluation of gene expression of amino acid bearing non-viral delivery nanosystems in tumours following intravenous administration. In conclusion, these results, together with the lack of toxicity, make arginine-, lysine- and leucine-bearing polyethyleneimine and generation 3 polypropyleneimine polymers highly promising gene delivery systems.
Resource Type
Note
  • This thesis was previously held under moratorium from 26th July 2011 until 26th July 2013.
DOI
Date Created
  • 2011
Former identifier
  • 823981

Relations

Items

Thumbnail Title Date Uploaded Visibility Actions
file details PDF of thesis T12799 2021-07-02 Public Download