{"id":{"repo_id":"salford","oai_identifier":"oai:salford-repository.worktribe.com:1405575"},"canonical_url":"https://search.dev.ndltd.org/etd/salford/oai:salford-repository.worktribe.com:1405575","repository":{"repo_id":"salford","name":"U. of Salford","base_url":"https://salford-repository.worktribe.com/oaiprovider"},"display":{"title":"Two-Photon Microscopy of E-Combretastatin uptake and activation in live mammalian cells","abstract":"Cancer is one of the most common causes of death in the Western world. Hence, thedevelopment of novel effective treatment modalities to combat this disease is important.Combretastatins are powerful anticancer drugs that are being evaluated in phase I/II clinicaltrials. Combretastatins act by binding to p-tubulin, preventing microtubule assembly andinhibiting angiogenesis in developing tumours. Most widely studied is the natural productc/5(Z)-combretastatin A4 that was originally isolated from the African bush willowCombretum caffrum by Pettit and co-workers. Chemically Combretastatins are substitutedstilbenes, exhibiting major activity in the cis-form, whereas the corresponding fr-am'-isomersare ~ 2 - 3 orders of magnitude less cytotoxic.Combretastatins undergo reversible photoisomerization upon irradiation with UV/visiblelight. Here a novel form of two-photon phototherapy is proposed, in which the \"inactive\"fnms(£)-combretastatins are used as anticancer pro-drugs that may be activated (converted tothe cw-isomer) by localized irradiation with light at the tumour site. The use of near-infrared(NIR) light to trigger a nonlinear two-photon excited photoactivation process provides deeperlight penetration into tissues and minimizes cellular autofluorescence compared withUV/visible light.The work described in this thesis is highly multidisciplinary. A major task was the synthesisof a range of combretastatin derivatives as target compounds for the novel form oftwo-photon excited anticancer phototherapy proposed herein. The cytotoxicity of the drugcandidates was assessed on live mammalian cell lines. Photochemical properties such asfluorescence quantum yields, fluorescence lifetimes, photoisomerization quantum yields andtwo-photon absorption characteristics of the combretastatin derivatives were investigatedspectroscopically. The fact that the trans-isomers fluoresce in most cases, whereas ds-isomersare virtually non-fluorescent has allowed multiphoton fluorescence lifetime imaging (FLIM)of the real-time uptake of the inactive pro-drugs into live mammalian cells, as well asmonitoring their intracellular distribution and concentration. Two-photon excitation of^-Combretastatins on monolayers of live cells led to effective conversion of the inactivepro-drugs to the highly cytotoxic Z-derivatives leading to apoptosis in the irradiated areaswithin 24 h. In conclusion, the two-photon excited activation of £-combretastatins on livecells was demonstrated, making £-combretastatins promising pro-drug candidates fortwo-photon excited anticancer phototherapy.","abstract_html":"Cancer is one of the most common causes of death in the Western world. Hence, thedevelopment of novel effective treatment modalities to combat this disease is important.Combretastatins are powerful anticancer drugs that are being evaluated in phase I/II clinicaltrials. Combretastatins act by binding to p-tubulin, preventing microtubule assembly andinhibiting angiogenesis in developing tumours. Most widely studied is the natural productc/5(Z)-combretastatin A4 that was originally isolated from the African bush willowCombretum caffrum by Pettit and co-workers. Chemically Combretastatins are substitutedstilbenes, exhibiting major activity in the cis-form, whereas the corresponding fr-am'-isomersare ~ 2 - 3 orders of magnitude less cytotoxic.Combretastatins undergo reversible photoisomerization upon irradiation with UV/visiblelight. Here a novel form of two-photon phototherapy is proposed, in which the "inactive"fnms(£)-combretastatins are used as anticancer pro-drugs that may be activated (converted tothe cw-isomer) by localized irradiation with light at the tumour site. The use of near-infrared(NIR) light to trigger a nonlinear two-photon excited photoactivation process provides deeperlight penetration into tissues and minimizes cellular autofluorescence compared withUV/visible light.The work described in this thesis is highly multidisciplinary. A major task was the synthesisof a range of combretastatin derivatives as target compounds for the novel form oftwo-photon excited anticancer phototherapy proposed herein. The cytotoxicity of the drugcandidates was assessed on live mammalian cell lines. Photochemical properties such asfluorescence quantum yields, fluorescence lifetimes, photoisomerization quantum yields andtwo-photon absorption characteristics of the combretastatin derivatives were investigatedspectroscopically. The fact that the trans-isomers fluoresce in most cases, whereas ds-isomersare virtually non-fluorescent has allowed multiphoton fluorescence lifetime imaging (FLIM)of the real-time uptake of the inactive pro-drugs into live mammalian cells, as well asmonitoring their intracellular distribution and concentration. Two-photon excitation of^-Combretastatins on monolayers of live cells led to effective conversion of the inactivepro-drugs to the highly cytotoxic Z-derivatives leading to apoptosis in the irradiated areaswithin 24 h. In conclusion, the two-photon excited activation of £-combretastatins on livecells was demonstrated, making £-combretastatins promising pro-drug candidates fortwo-photon excited anticancer phototherapy.","abstract_has_math":false,"creators":["Scherer, KM"],"institution":null,"degree_name":null,"degree_level":"Doctoral (Level 8)","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026","date_published":"2026","updated_at":"2026-07-24T04:26:44Z","subjects":[],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:salford-repository.worktribe.com:1405575"],"render_values":[{"text":"oai:salford-repository.worktribe.com:1405575","href":null,"code":true}]}]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.sponsor","label":"Sponsor","values":["University of Salford"]},{"key":"dc:creator","label":"Author","values":["Scherer, KM"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2026-07-24"]},{"key":"dc:date.issued","label":"Date","values":["2026"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://salford-repository.worktribe.com/output/1405575"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral (Level 8)"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:salford-repository.worktribe.com:1405575"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://salford-repository.worktribe.com/file/1405575/1/K.%20M.%20Scherer%20-%202012.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Cancer is one of the most common causes of death in the Western world. Hence, thedevelopment of novel effective treatment modalities to combat this disease is important.Combretastatins are powerful anticancer drugs that are being evaluated in phase I/II clinicaltrials. Combretastatins act by binding to p-tubulin, preventing microtubule assembly andinhibiting angiogenesis in developing tumours. Most widely studied is the natural productc/5(Z)-combretastatin A4 that was originally isolated from the African bush willowCombretum caffrum by Pettit and co-workers. Chemically Combretastatins are substitutedstilbenes, exhibiting major activity in the cis-form, whereas the corresponding fr-am'-isomersare ~ 2 - 3 orders of magnitude less cytotoxic.Combretastatins undergo reversible photoisomerization upon irradiation with UV/visiblelight. Here a novel form of two-photon phototherapy is proposed, in which the \"inactive\"fnms(£)-combretastatins are used as anticancer pro-drugs that may be activated (converted tothe cw-isomer) by localized irradiation with light at the tumour site. The use of near-infrared(NIR) light to trigger a nonlinear two-photon excited photoactivation process provides deeperlight penetration into tissues and minimizes cellular autofluorescence compared withUV/visible light.The work described in this thesis is highly multidisciplinary. A major task was the synthesisof a range of combretastatin derivatives as target compounds for the novel form oftwo-photon excited anticancer phototherapy proposed herein. The cytotoxicity of the drugcandidates was assessed on live mammalian cell lines. Photochemical properties such asfluorescence quantum yields, fluorescence lifetimes, photoisomerization quantum yields andtwo-photon absorption characteristics of the combretastatin derivatives were investigatedspectroscopically. The fact that the trans-isomers fluoresce in most cases, whereas ds-isomersare virtually non-fluorescent has allowed multiphoton fluorescence lifetime imaging (FLIM)of the real-time uptake of the inactive pro-drugs into live mammalian cells, as well asmonitoring their intracellular distribution and concentration. Two-photon excitation of^-Combretastatins on monolayers of live cells led to effective conversion of the inactivepro-drugs to the highly cytotoxic Z-derivatives leading to apoptosis in the irradiated areaswithin 24 h. In conclusion, the two-photon excited activation of £-combretastatins on livecells was demonstrated, making £-combretastatins promising pro-drug candidates fortwo-photon excited anticancer phototherapy."]},{"key":"dc:title","label":"Title","values":["Two-Photon Microscopy of E-Combretastatin uptake and activation in live mammalian cells"]}]}],"canonical_facts":{"dc:contributor.sponsor":["University of Salford"],"dc:creator":["Scherer, KM"],"dc:date":["2026-07-24"],"dc:date.issued":["2026"],"dc:description.abstract":["Cancer is one of the most common causes of death in the Western world. Hence, thedevelopment of novel effective treatment modalities to combat this disease is important.Combretastatins are powerful anticancer drugs that are being evaluated in phase I/II clinicaltrials. Combretastatins act by binding to p-tubulin, preventing microtubule assembly andinhibiting angiogenesis in developing tumours. Most widely studied is the natural productc/5(Z)-combretastatin A4 that was originally isolated from the African bush willowCombretum caffrum by Pettit and co-workers. Chemically Combretastatins are substitutedstilbenes, exhibiting major activity in the cis-form, whereas the corresponding fr-am'-isomersare ~ 2 - 3 orders of magnitude less cytotoxic.Combretastatins undergo reversible photoisomerization upon irradiation with UV/visiblelight. Here a novel form of two-photon phototherapy is proposed, in which the \"inactive\"fnms(£)-combretastatins are used as anticancer pro-drugs that may be activated (converted tothe cw-isomer) by localized irradiation with light at the tumour site. The use of near-infrared(NIR) light to trigger a nonlinear two-photon excited photoactivation process provides deeperlight penetration into tissues and minimizes cellular autofluorescence compared withUV/visible light.The work described in this thesis is highly multidisciplinary. A major task was the synthesisof a range of combretastatin derivatives as target compounds for the novel form oftwo-photon excited anticancer phototherapy proposed herein. The cytotoxicity of the drugcandidates was assessed on live mammalian cell lines. Photochemical properties such asfluorescence quantum yields, fluorescence lifetimes, photoisomerization quantum yields andtwo-photon absorption characteristics of the combretastatin derivatives were investigatedspectroscopically. The fact that the trans-isomers fluoresce in most cases, whereas ds-isomersare virtually non-fluorescent has allowed multiphoton fluorescence lifetime imaging (FLIM)of the real-time uptake of the inactive pro-drugs into live mammalian cells, as well asmonitoring their intracellular distribution and concentration. Two-photon excitation of^-Combretastatins on monolayers of live cells led to effective conversion of the inactivepro-drugs to the highly cytotoxic Z-derivatives leading to apoptosis in the irradiated areaswithin 24 h. In conclusion, the two-photon excited activation of £-combretastatins on livecells was demonstrated, making £-combretastatins promising pro-drug candidates fortwo-photon excited anticancer phototherapy."],"dc:identifier":["oai:salford-repository.worktribe.com:1405575"],"dc:identifier.uri":["https://salford-repository.worktribe.com/file/1405575/1/K.%20M.%20Scherer%20-%202012.pdf"],"dc:language":["en"],"dc:relation.isreferencedby":["https://salford-repository.worktribe.com/output/1405575"],"dc:title":["Two-Photon Microscopy of E-Combretastatin uptake and activation in live mammalian cells"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral (Level 8)"]},"updated_at":"2026-07-24T04:26:44Z"}