Dokument: Polymer-Metallodrug Conjugates for Cancer Diagnostics and Therapy
| Titel: | Polymer-Metallodrug Conjugates for Cancer Diagnostics and Therapy | |||||||
| Weiterer Titel: | Polymer-Metallwirkstoff-Konjugate für Krebsdiagnostik und -therapie | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=17114 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20110126-133208-8 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Brückmann, Nadine [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Kläui, Wolfgang [Gutachter] Prof. Dr. Ganter, Christian [Gutachter] | |||||||
| Stichwörter: | Radiopharmaceuticals, Tumor targeting, Polymers, Fluorescence, N ligands | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibung: | Polymeric carrier systems have the capability of transporting pharmaceuticals specifically to tumour tissue, where they accumulate due to the so called EPR-effect. By incorporation of cleavable linkers, the drugs can be released at the target site. Polymer-drug conjugates are too large to pass through blood vessel walls and are therefore restricted to the vascular system. This prevents the drugs from distributing throughout the body and causing drug- related side effects. Using this approach, early tumour detection can be improved, because the signal to background noise ratio is enhanced when radiopharmaceuticals are specifically transported to the tumour. Tumour therapy can be similarly improved, since the amount of applied drug at the tumour site in relation to the total applied dose is significantly increased compared to low molecular chemotherapy drugs. In this work, design, synthesis and appli- cation related properties of two types of drug conjugates are presented: a multimodal con- jugate, incorporating properties for in vitro (fluorescence microscopy) and in vivo (SPECT) diagnostic imaging as well as therapeutic properties and a conjugate solely for therapeu- tic purposes. Both carrier systems consist of a non-toxic poly-hydroxypropylmethacrylate (HPMA) backbone with cleavable polylactide side chains. Degradation of the side chain to lactide acid molecules, which occur naturally in the body, releases the attached drug. Suit- able ligands were incorporated in the side chains as binding sites for the metallodrugs. The multimodal conjugate bears rhenium tricarbonyl moieties as the bioactive unit. Bisimine ligands were coordinated to the rhenium cores, because they are known to introduce fluo- rescence to the complexes. Three bisimine ligands were investigated: 2,2’-bipyridine (bipy), 1,10-phenanthroline (phen) and dipyrido[3,2-a:2’,3’-c]phenazine (dppz), the first two of which were shown to have fluorescence properties useful for in vitro diagnostic imaging. Selecting the radioactive β-emitter 186/188Re instead of the stable 185/187Re isotope results in conjugates useful for radiotherapy, selecting the radioactive γ-emitter 99mTc leads to conjugates useful for radiodiagnostics. The other carrier system was designed to bear gold(I) cores, which were bound to the carrier by phosphane type ligands. Gold(I)phosphane complexes have shown promising anti-tumour as well as anti-inflammatory activity. The polymer-gold(I) conjugates could thus prove useful not only in cancer therapy but also in the therapy of diseases as- sociated with chronic inflammation such as autoimmune diseases, glaucoma or Alzheimer’s. Both types of polymer-metallodrug conjugates were investigated in light of their applicabil- ity for drug transport and release. Their molecular mass exceeds 40 kDa and is thus high enough for the polymers to accumulate in tumour tissue. Polyactide scission kinetics were calculated, showing degradation half lives from 90 minutes to up to 25 hours, depending on the chain length. Since accumulation occurs within one hour, the release kinetics are useful for in vivo drug release. The degradation products are small enough, less than 50 kDa, and can be excreted by the kidneys. The fluorescence properties of the rhenium conjugates were determined and live cell confocal fluorescence microscopy images taken. The large stokes shifts of about 11100 cm−1 of the bipy and phen rhenium tricarbonyls make identification of the compounds easy, even in a biological context, because it is distinguishable from tissue autofluorescence. Furthermore, toxicity was determined using cytotoxicity assays, viability tests, as well as membrane integrity tests on the A2780 tumour cell line. The compounds show some cytotoxicity (with IC50 values in the magnitude of 10 μM) and do not compromise cell membrane integrity, which is suitable for pharmaceutical purposes. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Chemie » Anorganische Chemie und Strukturchemie | |||||||
| Dokument erstellt am: | 26.01.2011 | |||||||
| Dateien geändert am: | 26.01.2011 | |||||||
| Promotionsantrag am: | 17.11.2010 | |||||||
| Datum der Promotion: | 13.01.2011 |
