Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.733423
Title: Optimising combinatorial microbicide delivery for prevention of colorectal HIV infection
Author: Swedrowska, Magda
ISNI:       0000 0004 6498 1506
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Abstract:
A combination of antiretroviral drugs, tenofovir, dapivirine and darunavir, provide enhanced antiviral activity compared to a single agent when tested in-vitro. However, the impact of co-formulation on drug absorption after topical delivery to the colorectal mucosa is unclear, and methods are required to screen for drug-drug interactions. The main aim of this project was to establish methods to determine drug transport mechanisms and interactions of three antiretroviral drugs for colorectal topical delivery to permit the rational composition of an optimized formulation. The first stage of the project focused on developing and optimizing a colorectal model for studying drug permeability across in-vitro and ex-vivo models, which comprised of a Caco-2 cell line and colorectal tissue mucosal segments, respectively. Once experimental conditions were optimized, the permeability of tenofovir, dapivirine and darunavir were measured experimentally. Selected inhibitors and substrates of ABC-efflux pump transporters were used to establish the mechanism of drug transport. Furthermore, drugs were co-formulated and tested for drug-drug interactions, cross reaction between transporters and effect on net drug transport across the monolayer. An in-silico screening was also performed to identify the potential for molecular interactions of tenofovir, dapivirine and darunavir with the P-glycoprotein transporter. The combination of in-vitro, ex-vivo and in-silico studies for tenofovir and darunavir showed that tenofovir is passively paracellularly transported across the epithelium, whereas darunavir is transported transcellularly and is a substrate for P-gp and MRP2 transporters. Dapivirine did not exhibit any active transport in the in-vitro model, although it showed very strong binding affinity to P-gp structure in the in-silico model. The permeability of the compounds ranked in accordance with their lipophilicity: tenofovir < darunavir < dapivirine. Co-administration of the ARV drugs did not influence the permeability or intracellular accumulation of the individual drugs. Film formulations containing darunavir were tested and demonstrated drug release and uptake by epithelial cells showing potential for further development as a protective microbicide formulation for the prevention of colorectal transmission of human immunodeficiency virus.
Supervisor: Forbes, Benjamin John ; Kelly, Charles George Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.733423  DOI: Not available
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