Project

Back to overview

Bio-Inspired Vectors and Materials for the Targeted Delivery of CO-Releasing Molecules and Chemotherapeutic Agents

English title Bio-Inspired Vectors and Materials for the Targeted Delivery of CO-Releasing Molecules and Chemotherapeutic Agents
Applicant Zobi Fabio
Number 170589
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 01.07.2017 - 30.06.2019
Approved amount 284'038.00
Show all

All Disciplines (3)

Discipline
Inorganic Chemistry
Experimental Microbiology
Cellular Biology, Cytology

Keywords (7)

CO releasing molecules; Targeted drug delivery; Vitamin B12; Diatoms; Bio-inspired vectors and materials ; IR imaging; Chemotherapeutic drugs

Lay Summary (French)

Lead
Un objectif clé de la chimie pharmaceutique est de trouver des solutions pour traiter sélectivement une population de cellules malades, laissant les tissus sains non affectés. Cet objectif est particulièrement strict pour les agents thérapeutiques anti-tumoraux, mais il est également important pour d'autres médicaments, tels que des molécules capables de libérer du monoxyde de carbone (CO). Actuellement, Ces derniers sont des composés pharmaceutiques largement étudiés sur la base des effets thérapeutiques bénéfiques documentés du monoxyde de carbone. Des efforts importants de recherche scientifique sont consacrés à la modification de ces molécules dans le but de les rendre biocompatibles et sélectives (pour le traitement d'une maladie donnée), afin d'obtenir les propriétés nécessaires à l'administration de ces médicaments.
Lay summary
Contenu et objectifs du travail de recherche

Dans le contexte ci-dessus, nous allons développer des agents anticancéreux thérapeutiques et CORMs sélectifs et biocompatibles par conjugaison de molécules actives avec la vitamine B12 ainsi que des matériaux bio-inspirés avec un accent sur les diatomées. Plus précisément, les objectifs de ce projet sont: (i) développer des agents thérapeutiques inorganiques (i.e. contenant des métaux) qui fonctionnent comme des régulateurs "pro-drogue" des réseaux biologiques (d'où notre intérêt pour des molécules capables de libérer du monoxyde de carbone); (ii) élargir la bibliothèque actuelle de vecteurs à base de vitamine B12 pour la conjugaison des CORMs et de médicaments de chimiothérapie; (iii) développer des matériaux bio-inspirés sur la base de frustules de diatomées pour la délivrance ciblé de médicaments. Un autre objectif de cette recherche est d'acquérir une meilleure compréhension de l'interaction des molécules et des matériaux décrits avec des populations de cellules malades. A cet effet, des techniques de tomographie tridimensionnelle seront appliquée.

Contexte scientifique et social du projet de recherche

Grâce à une approche modulaire qui utilise des substrats naturels, notre travail permettra d'améliorer les propriétés pharmacologiques des composés anti-tumoraux connus dans le but d'améliorer leur efficacité, mais aussi de découvrir de nouveaux types de médicaments. En outre, les matériaux bio-inspirés pourront être utilisés sous forme de capsules pour l'administration ciblée de médicaments dans le corps et provoquer ainsi une réponse homéostatique spécifique plutôt qu’une réponse systémique désordonnée.

Keywords

CO releasing molecules, chemotherapeutic drugs, vitamin B12, targeted drug delivery, diatoms, bio-inspired vectors and materials, IR imaging.

Direct link to Lay Summary Last update: 23.08.2016

Lay Summary (Italian)

Lead
Uno degli obiettivi fondamentali della chimica farmaceutica è quello di trovare soluzioni per curare selettivamente popolazioni di cellule malate lasciando inalterati i tessuti sani. Questo obiettivo è particolarmente stringente per gli agenti terapeutici antitumorali, ma è importante anche per altri farmaci, come ad esempio molecole capaci di rilasciare monossido di carbonio (CORMs). Queste ultime sono composti farmaceutici attualmente ampiamente studiati sulla base degli effetti terapeutici benefici documentati del monossido di carbonio. Significativi sforzi di ricerca intellettuale e chimica sono dedicati alla modifica di tali molecole con l'obiettivo di renderle biocompatibili e selettive (per la cura di una data malattia) cosi da realizzare le proprietà necessarie per la somministrazione di questi farmaci.
Lay summary

Soggetto e obiettivo

Nel contesto di cui sopra, lavoreremo allo sviluppo di agenti terapeutici antitumorali e CORMs selettivi e biocompatibili tramite coniugazione di molecole attive con la vitamina B12 e materilai bio-ispirati con particolare attenzione a diatomee. Nello specifico gli obbiettivi di questo progetto sono: (i) sviluppare ulteriormente agenti terapeutici inorganici (cioè conteneti metalli) che funzionino come regolatori "pro-farmaco" di reti biologiche (da qui il nostro interesse molecole capaci di rilasciare monossido di carbonio); (ii) espandere l'attuale libreria di vettori basati sulla vitamina B12 per la coniugazione di CORMs e farmaci chemioterapici; (iii) sviluppare materiali bio-ispirati basati su frustoli di diatomee per la somministrazione mirata dei farmaci. Altro obbiettivo di questa ricerca è ottenere una migliore comprensione dell'interazione delle molecole e materiali descritti con popolazioni di cellule malate. A tale scopo, dove possibile, tecniche di tomografia tridimensionale saranno applicate.

Contesto socio-scientifico

Tramite un approccio modulare che fa uso di substrati naturali, il nostro lavoro permetterà di migliorare le proprietà farmacologiche di composti antitumorali noti nel tentativo di migliorare la loro efficacia, ma anche per scoprire nuovi tipi di farmaci. Inoltre si prevede l'utilizzo di materiali bio-ispirati che possono essere utilizzati come capsule per la somministrazione mirata di farmaci all'interno dell'organismo e quindi provocare una risposta omeostatica specifica rispetto a una sistemica e quindi disordinata.

Parole chiave

CO releasing molecules, chemotherapeutic drugs, vitamin B12, targeted drug delivery, diatoms, bio-inspired vectors and materials, IR imaging.

Direct link to Lay Summary Last update: 23.08.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Design, synthesis and in vivo evaluation of 3-arylcoumarin derivatives of rhenium(I) tricarbonyl complexes as potent antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)
Sovari Sara Nasiri, Vojnovic Sandra, Bogojevic Sanja Skaro, Crochet Aurelien, Pavic Aleksandar, Nikodinovic-Runic Jasmina, Zobi Fabio (2020), Design, synthesis and in vivo evaluation of 3-arylcoumarin derivatives of rhenium(I) tricarbonyl complexes as potent antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA), in European Journal of Medicinal Chemistry, 205, 112533.
Cytotoxicity of Mn-based photoCORMs of ethynyl-α-diimine ligands against different cancer cell lines: The key role of CO-depleted metal fragments
Rossier Jeremie, Delasoie Joachim, Haeni Laetitia, Hauser Daniel, Rothen-Rutishauser Barbara, Zobi Fabio (2020), Cytotoxicity of Mn-based photoCORMs of ethynyl-α-diimine ligands against different cancer cell lines: The key role of CO-depleted metal fragments, in Journal of Inorganic Biochemistry, 209, 111122.
Recent Studies on the Antimicrobial Activity of Transition Metal Complexes of Groups 6–12
Nasiri Sovari Sara, Zobi Fabio (2020), Recent Studies on the Antimicrobial Activity of Transition Metal Complexes of Groups 6–12, in Chemistry, 2(2), 418-452.
Photoactivatable Surface-Functionalized Diatom Microalgae for Colorectal Cancer Targeted Delivery and Enhanced Cytotoxicity of Anticancer Complexes
Delasoie Joachim, Schiel Philippe, Vojnovic Sandra, Nikodinovic-RunicJasmina, ZobiFabio (2020), Photoactivatable Surface-Functionalized Diatom Microalgae for Colorectal Cancer Targeted Delivery and Enhanced Cytotoxicity of Anticancer Complexes, in Pharmaceutics, 1-23.
Natural Diatom Biosilica as Microshuttles in Drug Delivery Systems
Delasoie Joachim, ZobiFabio (2019), Natural Diatom Biosilica as Microshuttles in Drug Delivery Systems, in Pharmaceutics, 1.
Antiplasmodial Activity and In Vivo Bio-Distribution of Chloroquine Molecules Released with a 4-(4-Ethynylphenyl)-Triazole Moiety from Organometallo-Cobalamins
Rossier Jeremie, Nasiri Sovari Sara, Pavic Aleksandar, Vojnovic Sandra, Stringer Tameryn, Bättig Sarah, Smith Gregory S., Nikodinovic-Runic Jasmina, Zobi Fabio (2019), Antiplasmodial Activity and In Vivo Bio-Distribution of Chloroquine Molecules Released with a 4-(4-Ethynylphenyl)-Triazole Moiety from Organometallo-Cobalamins, in Molecules, 24(12), 2310-2310.
Slow-targeted release of a ruthenium anticancer agent from vitamin B 12 functionalized marine diatom microalgae
Delasoie Joachim, Rossier Jérémie, Haeni Laetitia, Rothen-Rutishauser Barbara, Zobi Fabio (2018), Slow-targeted release of a ruthenium anticancer agent from vitamin B 12 functionalized marine diatom microalgae, in Dalton Transactions, 47(48), 17221-17232.
Evaluation of the Potential of Cobalamin Derivatives Bearing Ru(II) Polypyridyl Complexes as Photosensitisers for Photodynamic Therapy
Marta Jakubaszek, Jeremie Rossier, Johannes Karges, Joachim Delasoie, Bruno Goud, Gilles Gasser, Zobi Fabio, Evaluation of the Potential of Cobalamin Derivatives Bearing Ru(II) Polypyridyl Complexes as Photosensitisers for Photodynamic Therapy, in Helvetica Chimica Acta, 1.

Collaboration

Group / person Country
Types of collaboration
Department of Chemistry, University Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Department of Chemistry, University of Cape Town South Africa (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institute of Nuclear Physics, Polish Academy of Sciences Poland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institute of Veterinary Physiology, University Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Adolphe Merkle Institute, University of Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
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
Institute of Pharmacology and Toxicology, University Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Department of Chemistry, University Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Department of Chemistry, University Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade Serbien (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Jagiellonian Centre for Experimental Therapeutics Poland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Department of Chemistry, University Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Department of Chemistry, University Fribourg 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
9th International Symposium on Bioorganometallic Chemistry Talk given at a conference Comparison of dark and light-induced cytotoxicity of Mn-based photoCORMs against different cancer cell lines reveals an apparent lack of CORM-derived carbon monoxide effect on cell viability 28.07.2019 York, Great Britain and Northern Ireland Zobi Fabio;
SCOPES Meeting - Supramolecular Chemistry in Medicine and in Technology: Advances and Challenges Poster Synthesis and characterization of organometallic antimalaial agents 30.08.2018 Albena, Bulgaria Nasiri Sovari Sara;
SCOPES Meeting - Supramolecular Chemistry in Medicine and in Technology: Advances and Challenges Talk given at a conference Vitamin B12 functionalized diatoms as micro-shuttles for the targeted delivery of anticancer agents 30.08.2018 Albena, Bulgaria Zobi Fabio;
European Biological Inorganic Chemistry Conference (EuroBIC14) Talk given at a conference Vitamin B12 functionalized diatoms as micro-shuttle for targeted delivery of anticancer agents 26.08.2018 Birmingham, Great Britain and Northern Ireland Zobi Fabio;
European Biological Inorganic Chemistry Conference (EuroBIC14) Poster Organometallic Cobalamin photoCORMs to Help Evaluating the Impact and Role of CO in Anticancer Therapy 26.08.2018 Birmingham, Great Britain and Northern Ireland Rossier Jérémie;
International Conference on Porphyrins and Phthalocyanines (ICPP) Talk given at a conference Organometallic cobalamin photoCORMs to evaluate the impact and role of CO in their anticancer activity 01.07.2018 Munich, Germany Zobi Fabio;
Caribbean Conference on Functional Materials (CARIBMAT 2018) Talk given at a conference Vitamin B12 functionalized diatoms as micro-shuttles for the targeted delivery of anticancer agents 07.02.2018 Cartagena de Indias, Colombia Rossier Jérémie;
Invited Seminar Individual talk Carbon monoxide and its controlled release: development, detection and therapeutic application of carbon monoxide-releasing molecules (CORMs 30.10.2017 University of Kragujevac, Serbien Zobi Fabio;
Invited Seminar Individual talk Carbon monoxide and its controlled release: development and therapeutic application of Vitamin B12-based carbon monoxide-releasing molecules (CORMs) 20.10.2017 Polish Academy of Sciences, Poland Zobi Fabio;
SCOPES Meeting - Medicinal Chemistry, State of Art and Perspectives Talk given at a conference Carbon monoxide and its controlled release: development, detection and therapeutic application of carbon monoxide-releasing molecules (CORMs) 26.08.2017 Vrnjačka Banja, Serbien Zobi Fabio;
SCOPES Meeting - Medicinal Chemistry, State of Art and Perspectives Talk given at a conference Cobalamin scaffold as a vector for biologically active compounds 26.08.2017 Vrnjačka Banja, Serbien Rossier Jérémie;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Annual meeting / General Assembly of University of Fribourg Alumni Talk 04.05.2019 Fribourg, Switzerland Zobi Fabio;


Awards

Title Year
SCOPES Meeting - Medicinal Chemistry, State of Art and Perspectives Best PhD presentation award for contribution entitled: "Cobalamin scaffold as a vector for biologically active compounds" 2017

Associated projects

Number Title Start Funding scheme
144700 Development of Biocompatible Site Specific Metal Based CO-Releasing Molecules for Medical Applications 01.07.2013 SNSF Professorships
139424 Biocompatible 17 e- Rhenium Dicarbonyl CO-Releasing Molecules on Natural Heme and Cobalamin Scaffolds 01.01.2012 Ambizione
183293 Single Crystal Diffraction: Dual System 01.09.2019 R'EQUIP

Abstract

In this SNFS application an approach to the synthetic preparation of cobalamin-based biocompatible scaffolds for CO-releasing molecules (CORMs) and chemotherapeutic drugs delivery and the development of surface functionalized diatom frustules as bio-inspired drug delivery materials and CO-releasing materials is described. Context: A key objective of medicinal chemistry is that of selectively addressing diseased or injured cell populations while leaving healthy tissues unaffected. This goal is particularly stringent for anticancer therapeutic agents but also important for other drugs as (e.g.) CORMs. The latter are a class of pharmaceutical compounds currently widely investigated due to the documented beneficial therapeutic effects of carbon monoxide (CO). Indeed, endogenous and exogenous CO ameliorates (e.g.) experimental cardiac, lung and vascular injuries and protect against numerous inflammatory states. In these fields transition metal complexes continue to play a major role. Alongside the design and identification of new pharmacologically suitable anticancer agents and CORMs, significant intellectual and chemical research efforts are also devoted to the modification of the same with tailor-made biocompatible ligands (or scaffolds) with the aim of addressing properties required for a medical drug. Often vitamins, sugars or peptides are appended to the metal complexes, but in recent years materials such as (e.g.) mesoporous silica nanoparticles or nanoporous fibers have investigated for this purpose. Approach: Within the above-mentioned context, we have been working on the development of biocompatible-site specific metal based CORMs via conjugation of active metal carbonyl complexes to natural biomolecules with a focus on vitamin B12. Recently the same strategy was extended in our group to anticancer drugs. The validity of our approach was confirmed by very promising biological and medical data. With this prolongation proposal I intend to develop and expand the concepts above to bio-inspired vectors and materials for the targeted delivery of CO-releasing molecules and chemotherapeutic agents. In order to realize the goals of this project, the proposed research will be divided into two subprojects. These are strongly interconnected and the responsible students will work synergistically towards the common greater objective.Aims: The fundamental objectives of this research may be summarized as follows:Subproject Aa) Further develop site-specific metal-based therapeutic agents which will function as “prodrug” regulators of biological networks (hence our interest in CORMs as CO delivery prodrugs). b) Expand our current library of vitamin B12 vectors for ligand-supported CORM and chemotherapeutic drugs conjugation and delivery. Subproject Bc) Develop diatom frustules-based bio-inspired materials for targeted drug delivery. d) Improve and establish methods and protocols for the 3D tomographic reconstruction of fluorescent and IR imaging studies of drug distribution on frustules and live cells.
-