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Title: Peptide nanofibres for drug delivery
Author: Mazza, Mariarosa
ISNI:       0000 0004 2721 5749
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2012
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It is possible that peptides and proteins may be used to treat a wide range of Central Nervous System diseases if these molecules were able to cross the blood brain barrier (BBB). Currently these molecules do not cross the BBB due to their hydrophilic nature and large size. The aim of this work was to investigate the therapeutic applicability of peptide nanofibres as a new peptide brain delivery system. We hypothesise that hydrophilic peptides, when made lipophilic by attaching an acyl chain via a cleavable ester linkage, are able to cross the blood brain barrier and that the resulting lipidic peptides nanofibres assist in the delivery of these molecules to the brain. Dalargin, a neuropeptide and hexapeptide analogue of Leu-enkephalin that is unable to cross the blood brain barrier, was chosen as model drug; on direct injection into the brain, dalargin acts on brain opioid receptors, resulting in analgesia. An amphiphilic derivative of dalargin, palmitoyl dalargin (pDal) was synthesized which self assembled into high-axial-ratio nanostructures in aqueous environments. We have investigated the physicochemical interactions that control to the formation of peptide nanofibres and found that hydrophobic interactions as well as the formation of amino acid ~-sheets are the main drivers of self-assembly. Brain peptide delivery was assessed following intravenous administration of formulations containing pDal nanofibres, nanofibres prepared from pDal and a chitosan amphiphile - quaternary ammonium palmitoyl glycol chitosan (GCPQA) and dalargin (in the absence and presence of GCPQA). While the administration of control samples of dalargin did not result in dalargin being detected in any tissues (only the primary metabolite was detected), pDal was clearly detected in the brain both in the presence and absence of GCPQA. Furthermore only animals administered with pDal experienced analgesia when assayed using the tail flick test. We conclude that peptide nanofibres offer a unique method for delivering hydrophilic peptides across the blood brain barrier.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available