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dc.contributor.advisorPhillips, Roger M.
dc.contributor.advisorLoadman, Paul M.
dc.contributor.authorMakeen, Hafiz Antar Mohammad
dc.date.accessioned2013-11-20T16:49:52Z
dc.date.available2013-11-20T16:49:52Z
dc.date.issued2013-11-20
dc.identifier.urihttp://hdl.handle.net/10454/5681
dc.description.abstractHigh interstitial fluid pressure (IFP) in tumours is recognized as a barrier to drug delivery resulting in reduced efficacy. High IFP impedes the normal process of convective fluid flow (CFF) from blood vessels into the interstitium. The aim of this study was to develop an in vitro model that could be used to measure CFF and to study its effects on drug delivery. The model consists of a transwell cell culture insert which supports the growth of multicell layers (MCL) on collagen coated membranes. A graduated tube is inserted into the transwell and a pressure gradient is applied across the membrane by raising the volume of medium in the tube above that of the bottom chamber. CFF is determined by measuring the weight of medium in the bottom chamber as a function of time. CFF was inversely proportional to MCL thickness and 41.1±3.6µm thick MCL has completely stopped CFF. Using a physiologically relevant hydrostatic pressure of 28mmHg, a CFF of 21µL/min was recorded using a DLD-1 MCL that was 12.21±3.2µm thick. Under these conditions, the rates of penetration of doxorubicin, imatinib and gefitinib were respectively 42, 26 and 13 folds greater than when no CFF exists. Reversing the CFF so that it opposed the drug diffusion gradient significantly impairs drug penetration. In conclusion, a novel in vitro model for assessing the impact of CFF on drug delivery has been developed. This model could be used to evaluate strategies designed to increase drug delivery to solid tumours by modifying the CFF.en_US
dc.language.isoenen_US
dc.rights<a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>.eng
dc.subjectDrug penetrationen_US
dc.subjectDrug deliveryen_US
dc.subjectSolid tumoursen_US
dc.subjectMulticell layeren_US
dc.subjectInterstitial fluid pressureen_US
dc.subjectConvective fluid flowen_US
dc.subjectConvectionen_US
dc.subjectHydrostatic pressureen_US
dc.subjectChemotherapy resistanceen_US
dc.subjectCanceren_US
dc.titleAnalysis of anti-cancer drug penetration through multicell layers in vitro. The development and evaluation of an in vitro model for assessing the impact of convective fluid flow on drug penetration through avascular cancer tissues.en_US
dc.type.qualificationleveldoctoralen_US
dc.publisher.institutionUniversity of Bradfordeng
dc.publisher.departmentInstitute of Cancer Therapeutics (ICT)en_US
dc.typeThesiseng
dc.type.qualificationnamePhDen_US
dc.date.awarded2012
refterms.dateFOA2018-07-19T12:00:52Z


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