Metallodrugs for therapy and imaging : investigation of their mechanism of action
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».