Project

Back to overview

Development of Biocompatible Site Specific Metal Based CO-Releasing Molecules for Medical Applications

English title Development of Biocompatible Site Specific Metal Based CO-Releasing Molecules for Medical Applications
Applicant Zobi Fabio
Number 144700
Funding scheme SNSF Professorships
Research institution Département de Chimie Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Inorganic Chemistry
Start/End 01.07.2013 - 30.06.2017
Approved amount 1'593'148.00
Show all

All Disciplines (3)

Discipline
Inorganic Chemistry
Biochemistry
Physical Chemistry

Keywords (9)

Proteins; Bioflavonoids; CO Releasing Molecules; Metal Bioconjugates; Medicinal Inorganic Chemistry; Hepatic Dysfunctions; Vitamins; Cardiovascular Diseases; Carbon Monoxide

Lay Summary (French)

Lead
Titre du projet de rechercheDéveloppement de molécules biocompatibles dérivées pour la libération spécifique de monoxyde de carbone pour des applications médicalesDevelopment of Biocompatible Site Specific Metal Based CO-Releasing Molecules for Medical Applications
Lay summary

Résumé

L'utilisation de monoxyde de carbone (CO) comme molécule protectrice a reçu une attention croissante de la médecine en raison de son efficacité thérapeutique documentée. Testé sur des modèles expérimentaux, le CO est en mesure d'améliorer les lésions cardiaques, vasculaires et pulmonaires et de protéger contre de nombreux états inflammatoires.  Malgré son évaluation sur de nouveaux traitements, l'utilisation clinique du gaz présente plusieurs problèmes liés à sa manipulation et à sa toxicité intrinsèque. Dans ce contexte, le problème est passé à l'identification de molécules capables de libérer du CO et ayant des propriétés acceptables pour un usage médical.

Contenu et objectifs du travail de recherche

Notre objectif principal est de contribuer à la conception et au développement de molécules capables de libérer du CO d'une manière contrôlée et en même temps de contribuer à une meilleure compréhension des mécanismes par lesquels ces molécules sont capables de libérer le gaz. Pour cela, nous avons l’intention de: (i) développer les procédés de synthèse à la réalisation des substances (ii) joindre les molécules à vitamines ou à autres biomolécules pour conférer spécificité aux nouveaux médicaments afin de traiter un problème particulier (iii) rendre les molécules fluorescentes afin de localiser et de visualiser le processus thérapeutique.

Contexte scientifique et social du projet de recherche

Notre travail nous permettra de recueillir de nouvelles informations sur cette nouvelle classe de composés pharmaceutiques. Des importantes implications scientifiques, académiques et médicales / technologiques seront fournies. Dans l'ensemble, les résultats de cette recherche devraient être d'intérêt pour diverses disciplines scientifiques et contribuer à une amélioration significative des perspectives de la santé publique.

Direct link to Lay Summary Last update: 02.04.2013

Lay Summary (Italian)

Lead
Titolo del progetto di ricercaSviluppo di molecole biocompatibili per il rilascio specifico di monossido di carbonio in applicazioni medicheDevelopment of Biocompatible Site Specific Metal Based CO-Releasing Molecules for Medical Applications
Lay summary

In sintesi

Nell'ultimo decennio, l'uso di monossido di carbonio (CO) come molecola protettiva ha ricevuto una crescente attenzione in medicina grazie alla sua documentata efficacia terapeutica. Testato in modelli sperimentali, il CO è in grado di migliorare lesioni cardiache, polmonari e vascolari e di proteggere contro numerosi stati infiammatori. Nonostante la sua attuale valutazione in nuove terapie, l'uso clinico del gas presenta diversi problemi legati alla sua manipolazione ed inerente tossicità. In quest’ambito il problema è ora passato all´identificazione di adeguate molecole capaci di rilasciare CO e che presentino proprietà accettabili per un uso medico.

Soggetto ed obiettivo

Il nostro obiettivo principale è quello di contribuire al design e allo sviluppo di molecole capaci di rilasciare monossido di carbonio in maniera controllata e al tempo stesso contribuire ad una migliore comprensione dei meccanismi attraverso i quali tali molecole sono capaci di rilasciare il gas. Più precisamente, (i) svilupperemo le procedure sintetiche atte al conseguimento delle sostanze (ii) accoppieremo le molecole a vitamine o altre biomolecole in modo da impartire specificità alle nuove droghe cosi da trattare una determinata disfunzione. Intendiamo inoltre (iii) rendere le molecole fluorescenti in modo da localizzarle e visualizzare il processo terapeutico.

Contesto socio-scientifico

Il nostro lavoro permetterà di raccogliere nuove informazioni su questa classe emergente di composti farmaceutici. Importanti implicazioni scientifiche, accademiche e medico/tecnologiche sono previste. Nel complesso il risultato di questa ricerca dovrebbe interessare diverse discipline scientifiche e contribuire ad un significativo miglioramento  delle prospettive di salute pubblica.

Parole chiave

Medicinal Inorganic Chemistry, Metal Bioconjugates, Carbon Monoxide, CO Releasing Molecules, Vitamins, Bioflavonoids, Proteins, Cardiovascular Diseases, Hepatic Dysfunctions

2 Aprile 2013

Direct link to Lay Summary Last update: 02.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Correlation of surface pressure and hue of planarizable push–pull chromophores at the air/water interface
Neuhaus Frederik, Zobi Fabio, Brezesinski Gerald, Dal Molin Marta, Matile Stefan, Zumbuehl Andreas (2017), Correlation of surface pressure and hue of planarizable push–pull chromophores at the air/water interface, in Beilstein Journal of Organic Chemistry, 13(1), 1099.
Heptacoordinate CoII Complex: A New Architecture for Photochemical Hydrogen Production
Lucarini Fiorella, Pastore Mariachiara, Vasylevskyi Serhii, Varisco Massimo, Solari Euro, Crochet Aurelien, Fromm Katharina M., Zobi Fabio, Ruggi Albert (2017), Heptacoordinate CoII Complex: A New Architecture for Photochemical Hydrogen Production, in Chemistry - A European Journal, 23, 6768-6771.
Modified biovectors for the tuneable activation of anti-platelet carbon monoxide release
Prieto Lucas, Rossier Jeremie, Derszniak Katarzyna, Dybas Jakub, Oetterli René M., Kottelat Emmanuel, Chlopicki Stefan, Zelder Felix, Zobi Fabio (2017), Modified biovectors for the tuneable activation of anti-platelet carbon monoxide release, in Chemical Communications, 53, 6840-6843.
Organometallic cobalamin anticancer derivatives for targeted prodrug delivery via ranscobalamin-mediated uptake
Rossier Jeremie, Hauser Daniel, Kottelat Emmanuel, Rothen-Rutishauser Barbara, Zobi Fabio (2017), Organometallic cobalamin anticancer derivatives for targeted prodrug delivery via ranscobalamin-mediated uptake, in Dalton Transactions, 46, 2159-2164.
Two-and Three-dimensional Mid-Infrared Chemical Imaging
Zobi Fabio, Obst Martin (2017), Two-and Three-dimensional Mid-Infrared Chemical Imaging, in CHIMIA, 71, 32-37.
Visible light-​activated photoCORMs
Kottelat Emmanuel, Zobi Fabio (2017), Visible light-​activated photoCORMs, in Inorganics, 5, 24.
Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes
Hagir B. Suliman, Fabio Zobi, Claude A. Piantadosi (2016), Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes, in Antioxidants & Redox Signaling, 345.
N -Nitrosamine-{cis-Re[CO]2}2+ cobalamin conjugates as mixed CO/NO-releasing molecules
Giuseppe Santoro, Ruben Beltrami, Emmanuel Kottelat, Olivier Blacque, Anna Yu. Bogdanova, Fabio Zobi (2016), N -Nitrosamine-{cis-Re[CO]2}2+ cobalamin conjugates as mixed CO/NO-releasing molecules, in Dalton Transactions, 45, 1504.
Red-light activated photoCORMs of Mn(I) species bearing electron deficient 2,2'-azopyridines.
Kottelat Emmanuel, Ruggi Albert, Zobi fabio (2016), Red-light activated photoCORMs of Mn(I) species bearing electron deficient 2,2'-azopyridines., in Dalton Transactions, 45, 6920.
Dreidimensionale Tomographie im mittleren Infrarotbereich von endogenen und exogenen Molekülen in einer einzelnen Zelle mit subzellulärer Auflösung
Quaroni Luca, Obst Martin, Nowak Marcus, Zobi Fabio (2015), Dreidimensionale Tomographie im mittleren Infrarotbereich von endogenen und exogenen Molekülen in einer einzelnen Zelle mit subzellulärer Auflösung, in Angewandte Chemie, 127, 323-327.
Quantum-CORMs: quantum dot sensitized CO releasing molecules
Ruggi Albert, Zobi Fabio (2015), Quantum-CORMs: quantum dot sensitized CO releasing molecules, in Dalton Transactionns, 44, 10928-10931.
Synthesis, characterization and cellular location of cytotoxic constitutional organometallic isomers of rhenium delivered on a cyanocobalmin scaffold
Santoro Giuseppe, Zlateva Theodora, Ruggi Albert, Quaroni Luca, Zobi Fabio (2015), Synthesis, characterization and cellular location of cytotoxic constitutional organometallic isomers of rhenium delivered on a cyanocobalmin scaffold, in Dalton Transactions, 44, 6999-7008.
Three-Dimensional Mid-Infrared Tomographic Imaging of Endogenous and Exogenous Molecules in a Single Intact Cell with Subcellular Resolution
Quaroni Luca, Obst Martin, Nowak Marcus, Zobi Fabio (2015), Three-Dimensional Mid-Infrared Tomographic Imaging of Endogenous and Exogenous Molecules in a Single Intact Cell with Subcellular Resolution, in Angewandte Chemie International Ed., 54, 318-322.
Towards Cardiolite-Inspired Carbon Monoxide Releasing Molecules – Reactivity of d4, d5 Rhenium and d6 Manganese Carbonyl Complexes with Isocyanide Ligands
Emmanuel Kottelat, Valentin Chabert, Aurélien Crochet, Katharina M. Fromm, Fabio Zobi (2015), Towards Cardiolite-Inspired Carbon Monoxide Releasing Molecules – Reactivity of d4, d5 Rhenium and d6 Manganese Carbonyl Complexes with Isocyanide Ligands, in European Journal of Inorganic Chemistry, 2015(34), 5628.
Cellular Imaging with Metal Carbonyl Complexes
Quaroni Luca and Zobi Fabio (2014), Cellular Imaging with Metal Carbonyl Complexes, in Gilles Gasser (ed.), Wiley, United Kingdom, 149-170.

Collaboration

Group / person Country
Types of collaboration
Claude Piantadosi / Duke University Medical Center, Duke University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Andreas Zumbuehl / Département de Chimie Université de Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Luca Ronconi / School of Chemistry NUI Galway Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Gilles Gasser / Chimie ParisTech France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Anna Bogdanova / Institute of Veterinary Physiology, University Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Stefan Chlopicki / Jagiellonian Center for Experimental Therapeutics Poland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Katharina Fromm / Département de Chimie Université de Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Felix Zelder / Department of Chemistry, University Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Deon Visser / Department of Chemistry, University of the Free State South Africa (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Barbara Rothen-Rutishauser / Adolphe Merkle Institute Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Infrared Beamline, Swiss Light Source, Paul Scherrer Institut Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Gregory Smith / Department of Chemistry University of Cape Town South Africa (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Bernhard Spingler / Department of Chemistry, University Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
8th Asian Biological Inorganic Chemistry Conference (AsBIC8) Talk given at a conference ORGANOMETALLIC COBALAMIN ANTICANCER DERIVATIVES FOR TARGETED PRODRUG DELIVERY VIA TRANSCOBALAMIN-MEDIATED UPTAKE 04.12.2016 Auckland, New Zealand Zobi Fabio;
SCS Fall Meeting 2016 Talk given at a conference Red-light activated photoCORMs of Mn(i) species bearing symmetric substituted 2,2’-azopyridines 15.09.2016 University of Zürich , Switzerland Kottelat Emmanuel;
SCS Fall Meeting 2016 Poster Active metal-based drugs delivery using vitamin B12 as a carrier 15.09.2016 University of Zürich , Switzerland Rossier Jérémie;
Summer School Supramolecular Chemistry Poster POTENT ANTI -TUMOR COMPLEXES CARRIED BY COBALAMIN FOR TARGETED DRUG DELIVERY 16.06.2016 Borovets, Bulgaria Rossier Jérémie;
Summer School Supramolecular Chemistry Poster RED-LIGHT ACTIVATED PHOTOC ORMS OF MN(I) SPECIES BEARING SYMMETRIC SUBSITUTED 2,2’ -AZOBIPYRIDINES 16.06.2016 Borovets, Bulgaria Kottelat Emmanuel;
Summer School Supramolecular Chemistry Talk given at a conference Silent Killers and Healing Heros: CO-Releasing Molecules in Medicine and Imaging 16.06.2016 Borovets, Bulgaria Zobi Fabio;
3rd Jena HHDP Symposium Talk given at a conference Recent developments of biocompatible group 7 metal-based CORMs: from vitamin B12 conjugates to red light activated photoCORMs 26.05.2016 Leibniz Institute of Photonic Technology (IPHT), Jena, DE, Germany Zobi Fabio;
Imaging Techniques Wokshop - SCOPES Individual talk Cellular and medical infrared spectromicroscopy imaging 26.01.2016 Fribourg, Switzerland Zobi Fabio;
Swiss Snow Symposium 2016 Poster Red-light activated photoCORMs of Mn(I) species bearing symmetric substituted 2,2'-azobipyridines 22.01.2016 Saas Fee, Switzerland Kottelat Emmanuel;
SCS Fall Meeting 2015 Poster Crystallographic structures of novel Mn- and Re-CORMs designed for medical applications 04.09.2015 Lausanne, Switzerland Kottelat Emmanuel;
29th European Crystallographic Meeting Poster Crystallographic structures of novel Mn- and Re-CORMs designed for medical applications 23.08.2015 Rovinj, Croatia Kottelat Emmanuel;
University of Fribourg and Fribourg Chemical Society Seminars Individual talk The Science and Applications of Carbon-Monoxide-Releasing Molecules: The Quest for the Therapeutic CO Delivery in Vivo. 10.03.2015 Fribourg, Switzerland Zobi Fabio;
Invited presentation/seminar. Event organized by Professor Bernhard Kräutler Individual talk The Pharmaceutical and Bio-Imaging Potentials of CORMs: from Academia to Applications. 27.11.2014 Universität Innsbruck, Austria Zobi Fabio;
SCS Fall Meeting 2014 Poster Carbonyl Isocyanide Complexes of Rhenium and Manganese: A Redox Struggle towards CORMs [IC-132] 11.09.2014 Zürich, Switzerland Kottelat Emmanuel;
SCS Fall Meeting 2014 Poster Modifications of Vitamin B12 as a Drug Delivery System for CORMs [IC-104] 11.09.2014 Zürich, Switzerland Beltrami Ruben;
12th European Biological Inorganic Chemistry Conference - EuroBIC 12 Talk given at a conference Cyanocobalamin conjugates for live-cell IR Imaging and distribution of active PhotoCORMs via synchrotron FTIR spectromicroscopy 24.08.2014 Zürich, Switzerland Zobi Fabio;
Eighth International Conference on Porphyrins and Phthalocyanines (ICPP-8) Talk given at a conference Cyanocobalamin Conjugates for Live-Cell IR Imaging and Distribution of Active PhotoCORMs via Synchrotron FTIR Spectromicroscopy 22.06.2014 Istanbul Congress Center, Turkey Zobi Fabio;
Scientific Summer Retreat organized by Prof. Roger Alberto, UZH Talk given at a conference Carbonyl Isocyanide Complexes of Rhenium and Manganese: A RedOx Struggle towards CORMs 11.06.2014 Saas-Grund, Switzerland Zobi Fabio; Kottelat Emmanuel; Beltrami Ruben;
Invited presentation. Event organized by Professor Stefan Chłopicki Individual talk The Pharmaceutical and Bio-Imaging Potentials of CORMs: from Academia to Applications. 09.05.2014 Jagiellonian Centre for Experimental Therapeutics (JCET), Kraków, Poland Zobi Fabio;
COST Action BM1005 Talk given at a conference Recent Developments of Vitamin B12 Based CO and NO Releasing Molecules: Chemistry and Biological Evaluation 24.10.2013 CEDOC (Chronic Disease Research Center), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Portugal Zobi Fabio;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Silent Killer & Healing Hero paneuropeannetworkspublications International 2016
Print (books, brochures, leaflets) Neue Methode liefert 3D-Bilder über die Chemie der Zelle International 2015
New media (web, blogs, podcasts, news feeds etc.) Nouvelle méthode pour des images 3D sur la chimie de la cellule Web/Press Release Universite' de Fribourg Western Switzerland International 2014

Awards

Title Year
Pool de Recherche - University Fribourg Equipment Fund for the project entitled: "3D Infrared Cellular Microtomography with Transition Metal Carbonyl Complexes" 2014

Associated projects

Number Title Start Funding scheme
139424 Biocompatible 17 e- Rhenium Dicarbonyl CO-Releasing Molecules on Natural Heme and Cobalamin Scaffolds 01.01.2012 Ambizione
170589 Bio-Inspired Vectors and Materials for the Targeted Delivery of CO-Releasing Molecules and Chemotherapeutic Agents 01.07.2017 SNSF Professorships

Abstract

In the last decade, the use of carbon monoxide (CO) as a cytoprotective and homeostatic molecule has received increasing attention in medicine due to its documented beneficial therapeutic effects. Both endogenous and exogenous CO ameliorates experimental cardiac, lung and vascular injuries and protect against numerous inflammatory states. Carbon monoxide was proven valuable in prolonging organ graft survival, particularly in heart and kidney transplants, and has been shown to elicit various defensive physiological effects (albeit via largely undeterminedmechanisms). Despite its current evaluation in novel therapies, the clinical use of the gas poses several problems related to safe handling and delivery to specific target sites in a controlled and measurable fashion. In this field the problem has now shifted to the design and identification of suitable CO-releasing molecules (CORMs) with acceptable properties as required for a medical drug. Transition metal carbonyl complexes havebeen predominantly evaluated as CORMs. There are numerous examples available in the literature. However, none of the complexes described so far shows the pharmaceutically desired biocompatibility and preferential accumulation at a specific target sites.Within this contest I have recently began to develop biocompatible-site specific metal based CORMs via conjugation of an active metal carbonyl complex to natural biomolecules. The underlying approach of my research is to develop clinically useful transition metal based CORMs that are not limited to the simple inorganic chemistry design. By this strategy the idea is to target the metallo “prodrug” to a specific location within the organism and thus elicit a compartmentalized homeostatic response as opposed to a systemic one that is chaotic and disordered.With this proposal I intend to develop and expand this concept to biocompatible CORMs coupled to natural substrates of proven and documented: a) non-toxicity; b) accumulation at specific organs/sites; c) efficacy at ameliorating desired conditions; d) induction (i.e. up-regulation) of the Heme Oxygensase (HO) family of enzymes. Four distinct targets are considered: 1) the heart, for treatment of cardiovascular diseases; 2) the liver, for treatment of hepatic dysfunctions; 3) sites of inflammation, formediating and assisting pain relief primarily in the acute phase; 4) HemeOxygensase-1 and -2, for promoting the intrinsic cellular defense mechanisms. Several transition metal carbonyl complexes and biological carriers will be evaluated. Preference will be given to CORMs for which no external stimuli (e.g. light) are needed to elicit CO release. Bio-compatible carriers include vitamins (e.g. E, B6 and B12, liver targeting), flavonoids and phenols (e.g. Quercetin and Curcumin, OH-1 up-regulators), NMDA receptor binders (e.g. Erythro-ifenprodil, heart targeting) and proteins (e.g.human serum albumin and lysozyme, vasodilation-mediated accumulation at sites of inflammation). CORM conjugation to bio-carriers will be archived via different synthetic methods but preference will be given to hydrolyzable linkers (e.g. amide bonds) in order to release the natural substrate after CORM decomposition. In a truly interdisciplinary fashion, the project is intended to encompasses traditional inorganic (complexsyntheses) and organic chemistry (preparations of tailor-made ligands), (bio)physical chemistry (study of interaction of complexes with targets), biological chemistry (vector-drug conjugations) and biology or medicine (in vitro and in vivo testing of the corresponding compounds).
-