Metallodrugs for therapy and imaging: investigation of their mechanism of action Spreckelmeyer, Sarah

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1 University of Groningen Metallodrugs for therapy and imaging: investigation of their mechanism of action Spreckelmeyer, Sarah IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2018 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Spreckelmeyer, S. (2018). Metallodrugs for therapy and imaging: investigation of their mechanism of action [Groningen]: University of Groningen Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Propositions for the thesis Metallodrugs for Therapy and Imaging: Investigation of Their Mechanism of Action Sarah Spreckelmeyer 1) Bifunctional chelators as radiopharmaceuticals for imaging or therapy are useful tools in personalized medicine. 2) The milestones in cancer research could not have been achieved without the interdisciplinary work of multiple research facilities. 3) The combination of PET or SPECT with CT or MRI is an enormous progress in medicine. 4) The pharmacy study is an excellent preparation for working in an interdisciplinary environment. 5) Inorganic Chemistry offers a great toolbox for the design of molecules for therapy and diagnosis. 6) Although cisplatin is used in the clinic as anticancer agent, not much is known about its mechanism of transport. 7) Work hard, play hard in order to be successful in life. adapted from James de Koven 8) Um zu wissen, was im Leben wichtig ist, muss man die Welt gesehen haben. Marteria ( You need to have seen the world to know what is important in life. ) 9) The statement Life isn t about waiting for the storm to pass. It s about learning to dance in the rain (Vivian Greene) applies to the process of a PhD project. 1

3 Paranimphs Gerian Prins Malte Schulze 2

4 Cover design: Carlos Niermeier Layout design: Sarah Spreckelmeyer Printed by: Ipskamp Printing The research presented in this thesis was financially supported by CANDA. Printing of this thesis was supported by the University of Groningen, Faculty of Science and Engineering and the University Library. ISBN (printed version): ISBN (digital version): No parts of this thesis may be reproduced or transmitted in any form or any means, electronical or mechanical, including photocopying, recording or any information storage and retrieval system, without permission of the author 3

5 INVITATION You are cordially invited to attend the public defence of the doctoral thesis of SARAH SPRECKELMEYER entitled Metallodrugs for Therapy and Imaging Investigation of Their Mechanism of Action Friday, 23 February 2018 at 16:15 hours Reception immediately after. Address of the defence: Bestuursgebouw Oude Boteringestraat 44 Groningen Address of the reception: Academiegebouw Broerstraat 5 Groningen 4

6 Metallodrugs for Therapy and Imaging: Investigation of Their Mechanism of Action PhD thesis to obtain the joint degree of PhD at the University of Groningen and the University of British Columbia on the authority of the Rector Magnificus of the University of Groningen, Prof. E. Sterken, the Faculty of Graduate and Postdoctoral Studies (Chemistry) of the University of British Columbia and in accordance with the decision by the College of Deans of the University of Groningen This thesis will be defended in public on Friday, 23 February 2018 at hours by Sarah Spreckelmeyer born on 8 May 1989 in Osnabrück, Germany 5

7 Supervisors Prof. G. M. M. Groothuis Prof. C. Orvig Co-supervisor Prof. A. Casini Assessment Committee Prof. F. J. Dekker Prof. M. Wolf Prof. J. Reedijk 6

8 Für Opa Hubert 7

9 Table of contents Introduction Metallodrugs for therapy Pharmacology of metallodrugs for therapy Pharmacokinetics (PK) and toxicity of cisplatin Radiopharmaceuticals for therapy Bifunctional chelator Biological targets discussed in this work Mechanism of targeting of radiopharmaceuticals for therapy Metallodrugs for imaging Radiopharmaceuticals PET and SPECT technique Mechanism of accumulation of radiopharmaceuticals for cancer imaging Fluorescence imaging References The aim of the thesis Part A: Vancouver.. 36 A1: p-no 2 -Bn-H 4 neunpa and H 4 neunpa-trastuzumab: Bifunctional Chelator for Radiopharmaceuticals and 111 In Immuno-SPECT Imaging Abstract Introduction Results and Discussion Synthesis and characterization of the ligand Synthesis and characterization of non-radioactive metal complexes NMR IR Thermodynamic stability Radiolabeling experiments with unmodified chelator Stability studies with unmodified chelator Initial biodistribution studies Preparation of Bioconjugates and in vitro characterization Biodistribution and SPECT/CT imaging studies Summary Experimental

10 6. References Supporting Information A2: H 4 neunpa: A Bifunctional Acyclic Chelator with Many Faces Abstract Introduction Subchapter Results and Discussion Synthesis Radiolabeling with 111 In Stability of H 4 neunpa-psma-l in human serum Subchapter Results and Discussion Metallacage exo-functionalization La-complexation reaction Fluorescence spectroscopy Subchapter Results and Discussion Radiolabeling with 225 Ac Ac/ 213 Bi itlc chromatograms Sb-complexation Summary Experimental References Supporting Information. 127 A3: Tetrahydroxamic Acid Bearing Ligands: EDTA and DTPA Analogues Abstract Introduction Results and Discussion Synthesis and characterization Metal complexation reactions Infrared (IR) spectroscopy In vitro cell experiments Stability determination of Fe-EDT(M)HA and Fe-EDT(B)HA by UV-VIS spectroscopy Zr-radiolabeling Density Functional Theory (DFT) Conclusions

11 5. Experimental References Supporting Information. 169 A4: Overcoming the Limitations in Thrombosis Treatment: A Bifunctional Chelator as Positron Emission Tomography-Imaging Probe for Detecting Blood Clots Abstract Introduction Results and Discussion Synthesis Thiol bioconjugation of compound DTNB assay Conclusions Experimental References Supporting Information Part B: Groningen B1: Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview Beyond Cisplatin Abstract Introduction Transport processes of metal-base compounds Anticancer Pt drugs Cu transporters Organic cations transporter (OCTs) and toxin extrusion proteins (MATEs) Experimental anticancer metal compounds Ruthenium complexes Gold complexes Iridium complexes Transporter-targeted anticancer metal compounds Conclusion and Perspectives References

12 B2: Exploring the Potential of Gold(III) Cyclometallated Compounds as Cytotoxic Agents: Variations on the C^N Theme Abstract Introduction Results and Discussion Synthesis and structural characterization Antiproliferative activity PARP-1 inhibition Conclusions Experimental section References Supporting Information B3: On the Toxicity and Transport Mechanisms of Cisplatin in Kidney Tissues in Comparison to a Gold-based Cytotoxic Agent Abstract Introduction Results and discussion Toxicity evaluation ATP content determination Histomorphology Expression of kidney-injury molecule 1 (KIM-1), villin, p53 and BAX Uptake studies Metal content determination by ICP-MS Effect of temperature on uptake in PCKS Conclusions Experimental methods References B4: Investigation of the Molecular Accumulation Mechanisms of an Au(III) Cyclometallated Compound Compared to Cisplatin in vitro: Are OCT2 and CTR1 involved? Abstract Introduction Results and Discussion Synthesis and characterization Fluorescence Antiproliferative effects Studies of the mechanisms of transport

13 Competition experiments Metal content determination Passive/active mechanisms Copper accumulation Fluorescence microscopy Conclusions Experimental section References General Discussion and Future Perspectives Samenvatting Acknowledgements Curriculum Vitae