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Carbohydrate Nanoparticles for Peptide Delivery to the CNS

Lalatsa, Aikaterini; (2009) Carbohydrate Nanoparticles for Peptide Delivery to the CNS. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Carbohydrate Nanoparticles for Peptide Delivery to the CNS
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10106907
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