Description du sujet de thèse

Title: Prodrug formulation of boron-containing API for BNCT

Context and objectives:
Some cancers cannot be cured with current treatments. This project explores a promising new approach, Boron Neutron Capture Therapy (BNCT), to offer novel options for hard-to-treat cancers, especially those that have recurred after prior X-ray radiation. The goal is to develop a therapeutic vector - a carrier - using specially designed polymers to deliver boron directly into tumour cells. After exposing the tumour to neutrons, it becomes possible to selectively destroy the cancerous cells that have accumulated the carrier, without damaging the surrounding healthy tissue. This targeted approach could allow for more precise treatments in just one or two sessions, particularly in cases of recurrence. If successful, BNCT could open up new therapeutic possibilities and offer hope to those who currently have no viable options.
We (via the ANR JCJ BORE funding) and others have demonstrated that boron can be encapsulated into polymeric nanoparticles. However, this first generation of nanocarriers requires multiple synthetic steps, which prevents any future clinical development. The main objective of this PhD thesis is therefore to develop and characterise polymeric formulations containing boron compounds, suitable for clinical development, in order to promote the targeting of the active compound to tumour cells. These drug delivery systems will then be evaluated - in vitro then in vivo - without and with neutron irradiation before their potential progression to clinical trials.

Expected results:
The first objective aims at designing and synthesising nanoparticles rich in 10-B, non toxic without irradiation, for all cell types. We expect these drug delivery systems to be administered intravenously on rodents, thereby allowing for a preferential accumulation in the tumour tissues compared to healthy adjacent tissues. The accumulation kinetic will be evaluated and a ratio of the boron content in tumour tissues over healthy tissues greater than three will be targeted, which is a prerequisite before any neutron irradiation. Moreover, via in vitro (2D and 3D models) and in vivo evaluation of the toxicity and internalisation of these nanoparticles and of boron, and the determination of the pharmacokinetics and pharmacodynamics of these nano-formulations, we will gain an in-depth understanding of the relationship between the structure and and organisation of these drug delivery systems and their accumulation potential at the tumour location.

Most of the planned experiments and analyses will be carried out at the Institut Galien Paris-Saclay (Université Paris-Saclay, Orsay) but research stays at the Institute for Advanced Biosciences (Université Grenoble Alpes, Grenoble) are expected for 6 to 12 months.

Expected skills:
- MChem, MSci, Master 2 or equivalent degree in polymer chemistry, synthetic chemistry or a related discipline
- Experience of working in a lab is essential
- A keen interest in formulation and cell biology (in vitro and in ovo)
- A level of English equivalent to level B1 on the Common European Framework of Reference (CEFR), both oral and written.

Application:
Applications must be written in English and include a Curriculum Vitae (CV), a cover letter indicating the motivation for the project, copies of transcripts of degrees obtained (including first semester of the current academic year) as well as the contact details of two references (names and emails). Applications must be submitted via the CNRS job portal (CNRS emploi).

Contexte de travail

The doctoral thesis will be primarily carried out at the Institut Galien Paris-Saclay (Orsay, Moulon campus, https://www.institut-galien.universite-paris-saclay.fr/), located on the new Université Paris-Saclay campus in the recently inaugurated Henri Moissan building. The project will benefit from state-of-the-art academic and research infrastructure, within a rich and stimulating scientific environment. This PhD is funded through a CNRS 80PRIME project that has already been secured.

IGPS is a joint research unit (UMR 8612) of the CNRS and Université Paris-Saclay, conducting original and innovative research in the field of micro- and nanotechnologies applied to drug development and diagnostics in healthcare. Biological analyses will be conducted at the Institute for Advanced Biosciences (Grenoble, https://iab-grenoble.fr/, UMR 5309 CNRS, INSERM, and Université Grenoble-Alpes), whose aim is to improve human health by better understanding how the environment—from the molecular to the population scale—shapes the development and fate of biological systems.

The thesis will be co-supervised by Anaïs Pitto-Barry (CNRS Research Scientist, IGPS) and Lucie Sancey (CNRS Research Director, IAB).
This position falls under the scope of regulations related to the protection of scientific and technical potential (PPST), and as such, your appointment must be authorised by the competent authority of the Ministry of Higher Education and Research (MESR).

Le poste se situe dans un secteur relevant de la protection du potentiel scientifique et technique (PPST), et nécessite donc, conformément à la réglementation, que votre arrivée soit autorisée par l'autorité compétente du MESR.

Contraintes et risques

Experimental work will take place in chemistry and biology laboratories.