Mohammadi, A;
(2013)
Design and Development of Tuneable Cationic Lipopolyplexes as Vectors in Gene Therapy.
Doctoral thesis , UCL (University College London).
Abstract
Gene therapy is a promising technique that offers great potential for the treatment of inherited and acquired disorders. However, one of the major obstacles is identifying suitable vectors with high targeting and transfection efficiency. A literature review on gene therapy and studies on the developments of vectors in gene therapy is presented in Chapter 1. The results and discussion for the development of novel targeting peptides is outlined in Chapter 2. Biophysical analyses of the peptides were performed in PD (peptide-DNA) and LPD (lipid-peptide-DNA) formulations, and found to be stable over time. The protection and release of DNA within the PD and LPD complexes was studied by using gel assays. The DNA binding affinity and transfection efficiencies are presented and discussed. Chapter 3 outlines the synthetic procedures to generate novel glycerol-based cationic lipids. The cationic headgroup was shielded with n-(ethylene glycol) (nEG) chains attached through non degradable and biodegradable linkers. It was noted that the transfection efficiency of formulations of lipid-nEG conjugate with DOPE was increasing with time. Further investigations using mass spectroscopy indicated the transacylation of an oleoyl group from DOPE to the terminal hydroxyl group of lipid-nEG conjugate, resulting in the formation of a new product compromised of three acyl chains (tri-chain lipids). This finding led to the synthesis of several series of novel tri-chain lipids. It was noted that most tri-chained analogues offered an enhanced transfection efficiency and DNA packaging compared to their original di-chained analogues. The synthetic routes towards the formation of novel glycerol-based lipids bearing a disulfide linker are given in Chapter 4. An overall summary and possible areas of future research are discussed in Chapter 5. A formal description of the experimental methods and procedures is presented in Chapter 6.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Design and Development of Tuneable Cationic Lipopolyplexes as Vectors in Gene Therapy |
| Language: | English |
| Additional information: | Permission for digitisation not received. |
| Keywords: | Gene therapy, lipopolyplexes, peptides, cationic lipids |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1389064 |
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