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Prodrug approaches to reduce treprostinil toxicity

Picken, Christina; (2019) Prodrug approaches to reduce treprostinil toxicity. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Pulmonary arterial hypertension is a chronic inflammatory condition of the peripheral pulmonary vessels which is thought to affect up to 52 in every million people. Vasoconstriction, proliferation and vascular remodelling mechanisms dominate which narrow and occlude pulmonary vessels, ultimately leading to right ventricular heart failure. Lung transplantation with all its associated complications remains the only cure. Prostacyclin mimetics are used as long-term therapy to slow disease progression and manage symptoms. Treprostinil is a clinically registered prostacyclin mimetic which is available in parenteral, oral and inhaled dosage forms, although the parenteral form provides the best treatment. Treprostinil shows some efficacy for PAH treatment, but is dose limited by adverse events that are a major burden to patients. The aims of the project were to develop a prodrug strategy to increase the maximum tolerated dose of treprostinil. A meta-analysis was first conducted using clinical data for prostacyclin and treprostinil treatments to determine which adverse events caused the greatest impact on the dose of treprostinil that could be given. The meta-analysis was also designed to understand the likely mechanistic causes for the most limiting adverse events. The dose limiting adverse event causing the greatest limitation to dosing is the pain at the site of administration that is associated with subcutaneously administered treprostinil. Prostanoid EP2 and DP1 receptors for which treprostinil has potent affinity are present in the vasculature in the skin which gives rise to the swelling, flushing and pain upon exposure to high concentrations of treprostinil present in subcutaneous infusion Although polymer-treprostinil prodrugs and their constituent components were examined, treprostinil N-acyl sulfonamide was first considered as a potential prodrug candidate. The N-acyl sulfonamide was evaluated because it has the potential to undergo subsequent enzymatic degradation in the liver to release active treprostinil. Although the in vitro activity of the prodrug treprostinil N-acyl sulfonamide was found to be less than treprostinil, there was concern from the industry collaborators about the stability of this prodrug version of treprostinil. Since treprostinil is as an agonist, treprostinil N-acyl sulfonamide was also considered for a polyvalent strategy. Unfortunately linking treprostinil to a polymer without undue loss of activity did not appear to be feasible. So treprostinil was used as a monomer to be conjugated within a degradable polyacetal mainchain. Water-soluble polyacetals undergo accelerated degradation at mildly acidic pH values which may be present in PAH diseased tissue. Treprostinil was conjugated within the mainchain using divinyl ether ethylene glycol and poly(ethylene glycol) as co-monomers. Treprostinil oligoacetal was obtained and was found to degrade in acidic conditions. The use of treprostinil as a co-monomer for polyacetal synthesis requires further optimisation because the two secondary hydroxyl groups in treprostinil may not be reactive enough and better masking of the treprostinil carboxylic acid moiety during storage is required. Developing a polymer-pendent drug conjugate strategy for the targeted release of treprostinil was also investigated. A targeting moiety, CAR peptide, was synthesised and investigated for the extent of specific localisation in disease cells over healthy cells. A treprostinil release linker based on tryptase which is an enzyme present in the PAH diseased lung was also examined in parallel. A method to prepare the tryptase substrate prodrug derivative of treprostinil on-resin was pursued. The method outlined shows promise in forming the treprostinil linker derivatives via a scalable route. It is envisaged that such treprostinil-linker adducts could be used in a polymeric conjugate or potentially in an antibody-drug conjugate. Methods to derivatise treprostinil were identified highlighting routes that could be pursued further. Polymeric-derivatisation of treprostinil may be a promising strategy to overcome current existing limitations with prostacyclin mimetic therapies. It is hoped that the progress described in this thesis will aid and guide future investigations in polymeric derivatives of treprostinil.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Prodrug approaches to reduce treprostinil toxicity
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10070149
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