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Metallodrugs for therapy and imaging : investigation of their mechanism of action

University of British Columbia

In this thesis, the application of metallodrugs for therapy and imaging was investigated as part of the field of medicinal inorganic chemistry. In the introduction, an overview was given on the application of organic molecules, incorporating a metal or radiometal for either therapeutic or diagnostic purposes, particularly in relation to cancer. It is evident that their mechanism of action, their pharmacokinetic behaviour and biological targets are mostly not fully elucidated yet. Thus, our overall aims included: i) to synthesize new radiopharmaceuticals for either cancer therapy or imaging, and ii) to elucidate the mechanism of cellular uptake and excretion, the anti-cancer activity and the organ toxicity of some new Au containing metallodrugs in comparison to cisplatin. To investigate the toxicity and transport mechanisms of the new cytotoxic organometallic Au(III) compounds, the ex vivo model of precision cut tissue slices and human cell cultures in vitro were used. The work described in Part A was performed at the University of British Columbia in Vancouver, BC, Canada in the Department of Medicinal Inorganic Chemistry under the supervision of Prof. Chris Orvig. Different radiotracers were developed and characterized by chemical-physical methods. Radiolabeling experiments were also performed at TRIUMF (Canada’s national laboratory for particle and nuclear physics and accelerator-based science) and in vivo animal experiments were conducted at the BC Cancer Agency. In chapter A1, we report on the synthesis of H₄neunpa and its immunoconjugate H₄neunpa-trastuzumab (Figure 1) and showed that it can be efficiently radiolabeled with ¹¹¹In³⁺ at ambient temperature within 15 min or 30 min, respectively. ¹¹¹In is a gamma emitter and can thus be used for single photon emission computed tomography (SPECT). The immunoconjugate was further investigated in an in vivo model using HER2/neu positive subcutaneous SKOV-3 ovarian cancer xenografts bearing mice. Unfortunately, our results showed an unexpected lower accumulation of 111Inneunpa- trastuzumab into the tumor compared to the gold-standard ¹¹¹In-CHX-DTPA-trastuzumab, which was supported by Immuno-SPECT images taken after 1 day, 3 days and 5 day post injection. Consequently, ¹¹¹In-neunpa-trastuzumab does not seem to be suitable for clinical application, although in vitro experiments (immunoreactivity, radiolabeling efficiencies, stability in human serum) showed similar or superior properties of this chelator compared to the goldstandard. A reason for this lower accumulation might be a difference in internalization process of the chelator- HER2/neu-receptor complex. Finally, radiolabeling of H₄neunpa with ¹⁷⁷Lu, a therapeutic radiometal, was tried but appeared unsuccessful. Comparison of In³⁺ (92pm CN=8) and Lu³⁺ (103pm CN=9)¹ leads to the hypothesis that either Lu³⁺ might be too big for H₄neunpa or the preferred coordination number is not saturated because of steric hindrance.

Text

2019-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/64785

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/