{"id":{"repo_id":"de-montfort","oai_identifier":"oai:dora.dmu.ac.uk:2086/25351"},"canonical_url":"https://search.dev.ndltd.org/etd/de-montfort/oai:dora.dmu.ac.uk:2086/25351","repository":{"repo_id":"de-montfort","name":"De Montfort University","base_url":"https://dora.dmu.ac.uk/server/oai/request"},"display":{"title":"Development of a TSM Biosensor for the Determination of DNA- Drug Interactions: A Novel Method to Assist Drug Development","abstract":"Current methods to determine the mechanism and kinetics of binding of chemotherapeutic drugs to DNA are generally time consuming and/or expensive. Moreoxer. a combination of approaches is required if both the mechanism and the kinetics of binding are to he determined, e.g. LJV spectroscopy can be used to determine the kinetics of binding and NMR can be used to determine the mechanism of binding. The aim of this project was to develop a sensitive, and inexpensive high-throughput method to determine the extent and possibly the mode of binding of chemotherapeutic drugs to DNA. based on the development of a TSM biosensor. DNA was immobilised on the TSM sensor to provide the biosensor for which drug-DNA interactions could be measured. Impedance analysis of the DNA coated sensor showed that DNA was bound rigidly to the sensor surface, and meant that the Sauerbrey relationship could be used to calculate the amount of DNA deposited. Immobilised DNA was exposed, in solution, to several classilications of potential anticancer drugs, each w ith different modes of binding. These were mitoxantrone. and two other anthraquinones, which exhibit intercalation and surface binding; bisbenzamide that exhibits groo\\e binding, and cisplatin that forms cross-links with DNA. Measurement of the resonant frequency of the coated DNA sensors gave comparative binding ratios with those obtained using LJV spectroscopy. Mitoxantrone interactions, at high and low ionic strength. ga\\e binding ratios of 3.7 and 1.5. respectively. These results showed that at low ionic strength, both intercalation and electrostatic surface binding takes place, howcwer at high ionic strength buffer the electrostatic surface binding has been eliminated and intercalation alone takes place. Cisplatin is a platinum anticancer drug that binds by covalent bonding to the DNA strand and does not possess nuorescence properties. I SM results for cisplatin gave a binding ratio of 1.4. thereby demonstrating the application of the I SM method to the investigation of drug-DNA binding which cannot be investigated by CV/VIS spectroscopy. Bisbenzamide results showed high levels of DNA binding, with a binding ratio of 0.3. which was again comparable to that obtained by UV spectroscopy. Bisbenzimide binding can be difficult to examine using nuorescence spectroscopy, as quenching of lluorescence occurs, and therefore the TSM approach can he considered as a more versatile alternative method. I he TSM biosensor has shown we can measure DNA-drug interactions, and quantify the extent of binding, the binding ratio.s tell us the amount of drug binding and w hilst the I SM result.s were comparable to those obtained with IIV spectroscopy, they do not provide inionnation on the binding process. The I SM also provides information on the physical properties of the DNA-drug binding it has the potential to pro\\ ide not only the amount of drug binding but also the type of binding process taking place. The impedance data can be vised to provide further information on the on the changes in material properties taking place. The |X|„„ii values was ten fold larger for mitoxantrone (0.3) in comparison to cisplatin (0.03). Viscous losses are taking place for the mitoxantrone and that is the Him i.s ' iscoelastic. it is proposed that this i.s due to a reduction in drug binding a.s only intercalation is taking place gi\\ ing rise to the higher viscoelasticity of the Him on the sensor surface. We can also see a difference in the binding between the ().5M buffer mitoxantrone (0.33) and the ().()5M buffer mitoxantrone (0.10) and other anthraquinones (0.10-0.15). The impedance analysis provides further information on the binding mechanisms taking place and may help to distinguish the type of binding process w hich are not so evident by looking at the drug binding ratios with IJV spectroscopy.","abstract_html":"Current methods to determine the mechanism and kinetics of binding of chemotherapeutic drugs to DNA are generally time consuming and/or expensive. Moreoxer. a combination of approaches is required if both the mechanism and the kinetics of binding are to he determined, e.g. LJV spectroscopy can be used to determine the kinetics of binding and NMR can be used to determine the mechanism of binding. The aim of this project was to develop a sensitive, and inexpensive high-throughput method to determine the extent and possibly the mode of binding of chemotherapeutic drugs to DNA. based on the development of a TSM biosensor. DNA was immobilised on the TSM sensor to provide the biosensor for which drug-DNA interactions could be measured. Impedance analysis of the DNA coated sensor showed that DNA was bound rigidly to the sensor surface, and meant that the Sauerbrey relationship could be used to calculate the amount of DNA deposited. Immobilised DNA was exposed, in solution, to several classilications of potential anticancer drugs, each w ith different modes of binding. These were mitoxantrone. and two other anthraquinones, which exhibit intercalation and surface binding; bisbenzamide that exhibits groo\\e binding, and cisplatin that forms cross-links with DNA. Measurement of the resonant frequency of the coated DNA sensors gave comparative binding ratios with those obtained using LJV spectroscopy. Mitoxantrone interactions, at high and low ionic strength. ga\\e binding ratios of 3.7 and 1.5. respectively. These results showed that at low ionic strength, both intercalation and electrostatic surface binding takes place, howcwer at high ionic strength buffer the electrostatic surface binding has been eliminated and intercalation alone takes place. Cisplatin is a platinum anticancer drug that binds by covalent bonding to the DNA strand and does not possess nuorescence properties. I SM results for cisplatin gave a binding ratio of 1.4. thereby demonstrating the application of the I SM method to the investigation of drug-DNA binding which cannot be investigated by CV/VIS spectroscopy. Bisbenzamide results showed high levels of DNA binding, with a binding ratio of 0.3. which was again comparable to that obtained by UV spectroscopy. Bisbenzimide binding can be difficult to examine using nuorescence spectroscopy, as quenching of lluorescence occurs, and therefore the TSM approach can he considered as a more versatile alternative method. I he TSM biosensor has shown we can measure DNA-drug interactions, and quantify the extent of binding, the binding ratio.s tell us the amount of drug binding and w hilst the I SM result.s were comparable to those obtained with IIV spectroscopy, they do not provide inionnation on the binding process. The I SM also provides information on the physical properties of the DNA-drug binding it has the potential to pro\\ ide not only the amount of drug binding but also the type of binding process taking place. The impedance data can be vised to provide further information on the on the changes in material properties taking place. The |X|„„ii values was ten fold larger for mitoxantrone (0.3) in comparison to cisplatin (0.03). Viscous losses are taking place for the mitoxantrone and that is the Him i.s ' iscoelastic. it is proposed that this i.s due to a reduction in drug binding a.s only intercalation is taking place gi\\ ing rise to the higher viscoelasticity of the Him on the sensor surface. We can also see a difference in the binding between the ().5M buffer mitoxantrone (0.33) and the ().()5M buffer mitoxantrone (0.10) and other anthraquinones (0.10-0.15). The impedance analysis provides further information on the binding mechanisms taking place and may help to distinguish the type of binding process w hich are not so evident by looking at the drug binding ratios with IJV spectroscopy.","abstract_has_math":false,"creators":["Ramsden, Justine"],"institution":"De Montfort University","degree_name":"PhD","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2003,"date_issued":"2003","date_published":"2003","updated_at":"2026-07-24T06:18:33Z","subjects":[],"languages":[],"rights":[],"rights_urls":["https://dora.dmu.ac.uk/bitstreams/984ad642-e118-4072-869c-96b960dbd679/download"],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Ramsden, Justine"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2003"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Faculty of Health and Life Sciences"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["De Montfort University"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://hdl.handle.net/2086/25351"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or dissertation"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["https://dora.dmu.ac.uk/bitstreams/984ad642-e118-4072-869c-96b960dbd679/download"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://dora.dmu.ac.uk/bitstreams/22709509-eabf-4706-95ad-a8c8e10be24d/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Current methods to determine the mechanism and kinetics of binding of chemotherapeutic drugs to DNA are generally time consuming and/or expensive. Moreoxer. a combination of approaches is required if both the mechanism and the kinetics of binding are to he determined, e.g. LJV spectroscopy can be used to determine the kinetics of binding and NMR can be used to determine the mechanism of binding. The aim of this project was to develop a sensitive, and inexpensive high-throughput method to determine the extent and possibly the mode of binding of chemotherapeutic drugs to DNA. based on the development of a TSM biosensor. DNA was immobilised on the TSM sensor to provide the biosensor for which drug-DNA interactions could be measured. Impedance analysis of the DNA coated sensor showed that DNA was bound rigidly to the sensor surface, and meant that the Sauerbrey relationship could be used to calculate the amount of DNA deposited. Immobilised DNA was exposed, in solution, to several classilications of potential anticancer drugs, each w ith different modes of binding. These were mitoxantrone. and two other anthraquinones, which exhibit intercalation and surface binding; bisbenzamide that exhibits groo\\e binding, and cisplatin that forms cross-links with DNA. Measurement of the resonant frequency of the coated DNA sensors gave comparative binding ratios with those obtained using LJV spectroscopy. Mitoxantrone interactions, at high and low ionic strength. ga\\e binding ratios of 3.7 and 1.5. respectively. These results showed that at low ionic strength, both intercalation and electrostatic surface binding takes place, howcwer at high ionic strength buffer the electrostatic surface binding has been eliminated and intercalation alone takes place. Cisplatin is a platinum anticancer drug that binds by covalent bonding to the DNA strand and does not possess nuorescence properties. I SM results for cisplatin gave a binding ratio of 1.4. thereby demonstrating the application of the I SM method to the investigation of drug-DNA binding which cannot be investigated by CV/VIS spectroscopy. Bisbenzamide results showed high levels of DNA binding, with a binding ratio of 0.3. which was again comparable to that obtained by UV spectroscopy. Bisbenzimide binding can be difficult to examine using nuorescence spectroscopy, as quenching of lluorescence occurs, and therefore the TSM approach can he considered as a more versatile alternative method. I he TSM biosensor has shown we can measure DNA-drug interactions, and quantify the extent of binding, the binding ratio.s tell us the amount of drug binding and w hilst the I SM result.s were comparable to those obtained with IIV spectroscopy, they do not provide inionnation on the binding process. The I SM also provides information on the physical properties of the DNA-drug binding it has the potential to pro\\ ide not only the amount of drug binding but also the type of binding process taking place. The impedance data can be vised to provide further information on the on the changes in material properties taking place. The |X|„„ii values was ten fold larger for mitoxantrone (0.3) in comparison to cisplatin (0.03). Viscous losses are taking place for the mitoxantrone and that is the Him i.s ' iscoelastic. it is proposed that this i.s due to a reduction in drug binding a.s only intercalation is taking place gi\\ ing rise to the higher viscoelasticity of the Him on the sensor surface. We can also see a difference in the binding between the ().5M buffer mitoxantrone (0.33) and the ().()5M buffer mitoxantrone (0.10) and other anthraquinones (0.10-0.15). 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I SM results for cisplatin gave a binding ratio of 1.4. thereby demonstrating the application of the I SM method to the investigation of drug-DNA binding which cannot be investigated by CV/VIS spectroscopy. Bisbenzamide results showed high levels of DNA binding, with a binding ratio of 0.3. which was again comparable to that obtained by UV spectroscopy. Bisbenzimide binding can be difficult to examine using nuorescence spectroscopy, as quenching of lluorescence occurs, and therefore the TSM approach can he considered as a more versatile alternative method. I he TSM biosensor has shown we can measure DNA-drug interactions, and quantify the extent of binding, the binding ratio.s tell us the amount of drug binding and w hilst the I SM result.s were comparable to those obtained with IIV spectroscopy, they do not provide inionnation on the binding process. The I SM also provides information on the physical properties of the DNA-drug binding it has the potential to pro\\ ide not only the amount of drug binding but also the type of binding process taking place. The impedance data can be vised to provide further information on the on the changes in material properties taking place. The |X|„„ii values was ten fold larger for mitoxantrone (0.3) in comparison to cisplatin (0.03). Viscous losses are taking place for the mitoxantrone and that is the Him i.s ' iscoelastic. it is proposed that this i.s due to a reduction in drug binding a.s only intercalation is taking place gi\\ ing rise to the higher viscoelasticity of the Him on the sensor surface. We can also see a difference in the binding between the ().5M buffer mitoxantrone (0.33) and the ().()5M buffer mitoxantrone (0.10) and other anthraquinones (0.10-0.15). 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