Protein-based drug delivery systems
| dc.contributor.author | Squire, Marie A. | en |
| dc.date.accessioned | 2012-04-18T02:42:26Z | |
| dc.date.available | 2012-04-18T02:42:26Z | |
| dc.date.issued | 2004 | en |
| dc.description.abstract | The targeted delivery of drugs is one of the most actively pursued goals in anti-HIV and anti-cancer chemotherapy. This project takes a proof-of-concept approach to the development of protein-based drug delivery systems - delivery systems that would package, target, and deliver cytotoxins to diseased cells. Primarily, this project explores the use of the potent anti-HN protein, cyanovirin-N (CV-N), to actively target and deliver cytotoxic natural products to HN-infected cells. This project also investigates the use of human serum albumin (HSA), a 66 kDa protein, as a macromolecular carrier to passively target and deliver cytotoxic natural products to cancerous cells. To facilitate release of the toxin within infected cells, an enzymatically-cleavable tetra peptide was incorporated in the conjugates. Maleimido-activated tetra peptide toxin constructs were prepared in readiness for selective reaction with proteins carrying thiol functionalities. Release of the toxin, norhomohalichondrin B, was demonstrated in vitro. Native CV -N conjugates were prepared by thiolation of the lysine ε-amino groups, and the subsequent reaction with maleimido-activated compounds. Reaction across all lysine residues was demonstrated. A singly-substituted tyrosinamide conjugate of CV-N was prepared. Two recombinantly produced mutant CV-N proteins allowed for the production of selectively modified, double- and single-norhomohalichondrin B conjugates of CV-N. The conjugates retained the anti-HN activity of the parent protein. Homohalichondrin B, doxorubicin, and tyrosinamide conjugates of HSA were prepared. The syntheses exploited the availability of a free thiolmoiety at cysteine-34 of HSA, and the specific and selective reaction of this thiol with the maleimido-activated tetra peptide derivatives. All toxin conjugates demonstrate excellent cell toxicity. Further research to investigate whether this is targeted toxicity is currently underway. | en |
| dc.identifier.uri | http://hdl.handle.net/10092/6518 | |
| dc.identifier.uri | http://dx.doi.org/10.26021/5891 | |
| dc.language.iso | en | |
| dc.publisher | University of Canterbury. Chemistry | en |
| dc.relation.isreferencedby | NZCU | en |
| dc.rights | Copyright Marie A. Squire | en |
| dc.rights.uri | https://canterbury.libguides.com/rights/theses | en |
| dc.title | Protein-based drug delivery systems | en |
| dc.type | Theses / Dissertations | |
| thesis.degree.discipline | Chemistry | en |
| thesis.degree.grantor | University of Canterbury | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
| uc.bibnumber | 906142 | en |
| uc.college | Faculty of Science | en |
Files
Original bundle
1 - 1 of 1