Wilson, Gayle (2016) The design and synthesis of drug carrier molecules to improve oral bioavailability via hPepT1. Doctoral thesis, Keele University.

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Abstract

PepT1 (SLC15A1) is a low affinity high capacity, di- and tri-peptide transmembrane
transporter primarily located in the brush border membrane in the small intestines. As well as
transporting oligopeptides, PepT1 has been discovered to transport a wide range of xenobiotics including, β–lactams and ACE inhibitors. This broad substrate capacity makes PepT1 ideal as a vehicle for the targeted delivery of xenobiotic prodrugs. It has been shown that our hydrolysis resistant thiodipeptide PepT1 substrates (e.g. A and B) can be used as ‘carriers’ for the prodrug
targeting of poorly bioavailable drugs towards PepT1 via the strategy illustrated below.

In this thesis, using this approach, the xenobiotics attached to our carriers will be expanded from commercially available drugs to new chemical entities which display undesirable physiochemical properties, such as the Aurora kinase inhibitor C.

The discovery that PepT1 is over-expressed in pancreatic adenocarcinoma cell lines, AsPc-1 and Capan-2,4 has also led to research being undertaken into targeted anti-cancer therapy via our thiodipeptide carriers. The use of PepT1 targeting in cancer therapy has the potential to
reduce side effects due to the minimisation of off target delivery. Pancreatic cancer often has a poor prognosis, with only a 5% survival rate 5 years after diagnosis. Thiodipeptide D will be shown in this research to significantly reduce cell proliferation and vitality in AcPc1 cells. This is the first time that reduced cell proliferation by ibuprofen or an ibuprofen prodrug has been reported in this cell line. The use of our thiodipeptides to improve the oral bioavailability of an
oncology drug through PepT1 targeting will also be explored.

The development of new hydrolysis resistant dipeptide carriers will also be explored as the presence of a sulfur atom in our present carriers has historically resulted in non-crystalline prodrugs being synthesised, which is not ideal for formulation.

Item Type: Thesis (Doctoral)
Subjects: Q Science > Q Science (General)
Divisions: Faculty of Natural Sciences > School of Physical and Geographical Sciences
Depositing User: Lisa Bailey
Date Deposited: 13 Apr 2017 11:19
Last Modified: 13 Apr 2017 11:19
URI: http://eprints.keele.ac.uk/id/eprint/3274

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