Description du sujet de thèse

PhD project on the chemical multifunctionalization of iron carbide nanoparticles and assessment of their enzymatic biodegradability, with the following objectives:
1) Covalent chemical functionalization of iron carbide nanoparticles (NPs) coated with different shells (e.g., graphitic carbon);
2) Characterization of the functionalized iron carbide NPs by different microscopic and spectroscopic techniques, and by thermogravimetric analysis;
3) Evaluation of the biodegradation of the nanoparticles.

Methodology
The aim of this PhD project is to design and develop chemical strategies to covalently functionalize carbon graphitic-coated iron carbide NPs with molecules (or short polymers) to increase the water dispersibility, ligands (or antibodies) to target cancer cells and other cells in the tumor microenvironment (stroma cells, tumor-associated macrophages), and with imaging contrast agents to track the NPs in vitro and in vivo. Mild conditions will be used to preserve the structural integrity of the NPs. The NPs will be functionalized by exploiting the graphitic carbon layer, for example by an arylation reaction using a mixture of different aryl diazonium salts bearing amines blocked by orthogonal protecting groups, a strategy we developed on carbon nanomaterials (carbon nanotubes, graphene). Each of the protecting groups will be removed sequentially using specific conditions that do not induce the cleavage of the other groups, allowing to control the sequential derivatization of the amines with the desired molecules. The functionalized NPs will be characterized by different microscopic and spectroscopic techniques, and by thermogravimetric analysis to assess the level of functionalization. We will also investigate the degradation of the NPs in biological fluids and by human peroxidases. The degradation will be monitored by transmission electron microscopy and Raman spectroscopy to obtain information on the morphology of the NPs and the introduction of defects, respectively. We will assess the cell viability and the impact of the degradation products on different cell types, (e.g., lymphocytes, macrophages) (collaboration avec des biologistes). We will check that the degradation products do not induce any inflammatory response in mouse & human primary immune cells by measuring the release of cytokines by ELISA.

Expected results:
1) Covalent multifunctionalization of the graphitic carbon coated-iron carbide NPs with orthogonally protected amines;
2) Derivatization of the NPs with targeting ligands, bioactive molecules and/or imaging probes;
3) Assessment of the biodegradability of the NPs.

Supervisors and host organisations:
a) Main supervisors and recruiting organisation:
Cécilia MENARD-MOYON
CNRS, Laboratory of Immunology, Immunopathology and Therapeutic Chemistry, Strasbourg, France
b) Co-supervisor (academic partner):
Davide BONIFAZI
University of Vienna, Department of Chemistry, Institute of Organic Chemistry, Vienna, Austria
c) Co-supervisor (non-academic partner):
Antreas AFANTITIS
NovaMechanics Ltd, Cyprus

Planned mobility track and secondments:
1) NovaMechanics Ltd (3 months, M16-M18): In silico evaluation of the correlation between the functionalization degree of the NPs and their interactions with biomolecules (e.g., formation of a protein corona);
2) University of Vienna (4 months, M22-M25): Synthesis of NPs with variable shell thickness and influence on their magneto- and photothermal properties;
3) ICN2 (Fundació Institut Català de Nanociència i Nanotecnologia, Barcelona, Spain) - Electron Microscopy Unit led by Dr. Belén Ballesteros (3 months, M34-M36): Characterization of the NPs degraded by biological fluids and human enzymes by advanced electron microscopy.

THE CANDIDATE PROFILE
Academic prerequisite
We are looking for a student with a 5-years degree (Master) with a strong background in chemistry, in particular in organic chemistry and materials chemistry, or related fields.

Technical skills and knowledge required
- Synthesis of organic molecules;
- Chemical functionalization of nanoparticles;
- Characterization of organic molecules and nanoparticles by spectroscopic techniques (e.g., NMR, FT-IR, UV-Vis-NIR spectroscopy).

Soft skills
- Great sense of thoroughness, rigor and organization;
- Dynamism, high motivation, reactivity and autonomy;
- Writing skills in English and ability to summarize are essential;
- Provide ideas for the research projects;
- Carry out scientific bibliography;
- Compile results for publication in peer-reviewed journals;
- Capacity to present results orally.

Contexte de travail

This project will be developed in the Laboratory of Immunology, Immunopathology and Therapeutic Chemistry (CNRS UPR 3572, I2CT), which belongs to the CNRS and is located at the Institute of Molecular and Cellular Biology in Strasbourg (France), in particular in the group Therapeutic multifunctional carbon and 2D nanomaterials (led by Dr. Alberto Bianco) and under the supervision of Dr. Cécilia Ménard-Moyon. The research unit has a unique and internationally recognized expertise in autoimmune diseases and nanomedicine, in particular the development of carbon nanomaterials and nanoparticles, for biomedical applications and the assessment of their potential toxicity.

What we offer:
- An enrolment in a PhD program at the University of Strasbourg (France);
- An international work environment, in which doctoral researchers can develop their skills and innovate within a competent team;
- An attractive 36 months' salary;
- An individual and well-structured scientific and transferable training (open science, responsible research and innovation, circular economy, ethics, data management, entrepreneurship, creativity, communication, career plans and gender balance in science) within the Melomanes network.

This PhD project is funded by the HORIZON EUROPE MSCA DOCTORAL NETWORK “Melomanes” project on the combination therapy for the treatment of metastatic melanoma using magnetic nanoparticles.
Metastatic melanoma is a hard-to-treat disease and it remains as one of the most worrisome cancer. There is an urgent need to improve the current therapies (chemotherapy, radiotherapy) that have a limited efficacy. A single therapy is not efficient to tackle metastatic melanoma and a combination of therapies is thus emerging as a necessity to efficiently eradicate all cancer cells. Recently, the development of immunotherapies has shown promises, in particular chimeric antigen receptor (CAR)-T cells. Nevertheless, the physical barriers represented by cellular and non-cellular components of the tumor microenvironment combined to the abnormal tumor vasculature and high interstitial fluid pressure, hamper an efficient tumor infiltration of CAR-T cells. In this context, thanks to a network of 18 partners (including 10 non-academic partners), MELOMANES aims to train 12 doctoral researchers for the development of a combined therapy exploiting the properties of magnetic nanoparticles to induce damage on the tumor microenvironment by magnetic and optic hyperthermia in order to facilitate the infiltration of CAR-T cells. Research and transferable training of the doctoral researchers will be performed in a highly interdisciplinary, intersectoral, and international environment. In addition to acquiring skills related to the research project, they will be trained also in open science, communication and dissemination, responsible research and innovation, circular economy, ethics, data management, entrepreneurship, marketing, intellectual property, and gender dimension in research. Their competences will be validated through certification and qualification examination, allowing a new generation of highly skilled doctoral researchers to emerge with a high-level training in particular in the multidisciplinary field of nanomedicine.

Contraintes et risques

There are no constraints.
Biological and chemical risks.

Informations complémentaires

APPLICATION PROCEDURE
- Motivation letter (max. 2 pages);
- CV including the details of education/qualifications, work experience, language skills and other relevant skills; indication of at least two Scientists for reference letters (academic and/or non-academic);
- Certified/signed copy of a recent transcript of exams taken with relative mark. A certified/signed copy of Master of Science certificate or a letter from the Head of the degree course stating that the Student is going to finish before September 2023;
- A summary of your research projects (max. 5 pages).
Applicants can apply for up to 3 projects within the consortium, indicating the order of preference.
All applications will be checked for eligibility (in particular, the adherence to the mobility rule). Incomplete applications will be ignored. Shortlisted candidates will be invited for an interview. Candidates will be notified of the outcome. Start of employment is foreseen September 2023.