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Title: Carbohydrate nanoparticles for peptide delivery to the CNS
Author: Lalatsa, Aikaterini
ISNI:       0000 0004 2683 4927
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2009
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Many existing peptide pharmaceuticals are rendered ineffective or poorly absorbed after oral administration or are unable to cross the blood-brain barrier (BBB) mainly due to their hydrophilicity, size and charge. Leucine[5]-Enkephalin (LENK) is an endogenous opioid neuropentapeptide with a blood half-life of approximately 3 minutes in man. The aim of this study is to evaluate the oral delivery potential of water soluble peptides such as LENK to the brain utilising two strategies: (i) lipidisation by creating a lipophilic bioreversible prodrug, palmitoylated Leucine[5]-Enkephalin (TPLENK), comprising a cleavable ester bond susceptible to blood, liver and brain esterases and/or (ii) encapsulation in a carbohydrate central nervous system (CNS) bioavailability enhancer. Quaternary Ammonium Palmitoyl Glycol Chitosan (GCPQ). The lipophilic prodrug was converted into the LENK by plasma and liver esterases with apparent half-lives for the disappearance of the pro-drug of ~73 and ~44 minutes in homogenates respectively. The plasma half-life of LENK on intravenous (IV) administration was increased 1.4 fold when the nanoparticulate formulation was used and by 3.2 fold when TPLENK was administered with GCPQ. More importantly the brain area under the curve (AUC) of LENK was increased almost 2-fold by lipidisation of the peptide and encapsulation of the lipid prodrug within GCPQ aggregates after intravenous and oral administration, while maintaining analgesia in the tail-flick bioassay. We hypothesise that the increase in brain bioavailability following the strategy adopted is due to: (i) an increase in plasma levels of LENK leading to an increase in brain levels of LENK and (ii) the lipophilic prodrug promoting passage of the drug across the BBB, with GCPQ enabling the lipid prodrug to be transported in the blood to the BBB.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available