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Title: Peptide nanofibres for drug delivery
Author: Mazza, Mariarosa
ISNI:       0000 0004 2721 5749
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2012
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Peptide and proteins are involved in a wide range of brain disease but they don't cross the blood brain barrier because of their hydrophilic nature and size. Nanofibrous systems are attracting increasing interest in the field of drug delivery and regenerative medicine. The aim of this work is to investigate the therapeutic applicability of peptide nanofibres as new drug delivery system to the Central Nervous System. Our working hypothesis was to choose a model hydrophilic peptide unable to enter the brain, make a lipophylic derivative from which monodomain nanofibres were constructed, in order to test them as a peptide carrier to the brain. Dalargin, a hexapeptide analogue of Leu-enkephalin, which is unable to cross the blood brain barrier was chosen as a model drug. On direct injection into the brain, Dalargin acts on brain opioid receptors, resulting in analgesia. An amphipatic derivative of dalargin, palmitoyl Dalargin (pDal) was synthesized resulting in a surfactant like peptide able to form high-axial-ratio nanostructures in aqueous environments. The self-assembly of the peptide amphilphile has been assessed experimentally and in silico. Intravenous injection of formulation of nanofibres resulted in analgesic response in mice. Brain peptide delivery was assessed with Raman microscopy as well as by measuring analgesia and peptide nanofibres pharmacokinetic profiles in biological matrices. While Dalargin was not detected in any of the tissue samples, palmitoyl Dalargin was measured in the brain tissue confirming the ability of peptide palmitoyl dalargin nanofibres to deliver the peptide across the blood brain barrier. Furthermore Raman microscopy revealed the presence of palmitoyl dalargin in the brain parenchyma. 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