Description du sujet de thèse

Triple-negative breast cancer (TNBC) is a very aggressive disease that fails to respond to estrogen receptor- or Human Epidermal Growth Factor Receptor 2-targeted drugs (ESR- or HER2-targeted drugs) (doi: 10.3389/fmolb.2022.836417). There is therefore an urgent need to develop new treatments. Photodynamic therapy (PDT) is a minimally invasive treatment for cancer using light and photoactivatable molecules known as photosensitizers (PSs) to generate reactive oxygen species (ROS) when oxygen is present. The generation of ROS enables oxidative damages in cancer cells and tumours. PDT proven effective in much preclinical cancer research, notably thanks to absence of dark toxicity and treatment resistance (doi: 10.3390/cancers15030585). Thus, PDT could be proposed to treat TNBC, however, hypoxia is a known hallmark of many aggressive cancer cell phenotypes. These tumours have impaired vasculature and rapid metabolic oxygen uptake by cancer cells leading to limited oxygen diffusion and the efficacy of PDT is significantly compromised in hypoxic tumors due to low oxygen levels and altered gene expression (doi: 10.1038/nrc1367). Since cancer cells upregulate hypoxia-inducible factors (HIFs) and initiate downstream biological responses including intracellular reductase overexpression under hypoxic stress, tumour hypoxia is potentially reversible (doi: 10.3390/biom9080339). We therefore proposed a novel approach to overcome these challenges by employing lipid nanoparticles (LNPs) to co-deliver an amphiphilic PS and a small interfering RNA encoded for HIF-1α (siHIF). A peptide-targeting receptors overexpressed in TBNC cells will be attached to the surface of the LNPs for a selective delivery. With the delivery of siHIF to cancer cells intended to silence the HIF expression and normalize the tumor vasculature. The improved vasculature enabling better oxygen delivery to the tumor, can potentially enhancing PDT outcomes in hypoxic tumor environments.

Contexte de travail

This thesis is in collaboration with The University of British Columbia | Vancouver, Canada. The candidate will synthesize analogues of amphiphilic porphyrins and targeting peptide lipids. Different types of amphiphilic PS will be developed and synthesized. For example, cationic pyridium porphyrins (doi: 10.1007/s12551-017-0257-7) and amphiphilic protoporphyrin IX (PpIX) derivatives (doi: 10.3390/biomedecines10020423). Peptide-lipid conjugates targeting TNBC will also be developed. 4T1 cells are widely used to specifically study TNBC (doi: 10.1016/j.neo.2015.02.003). For example, some peptides that target 4T1 tumors will be synthesized in solid phase using Fmoc/t-Bu chemistry and then attached to the surface of LNPs. The photophysical properties of the synthesized compounds will be investigated. Encapsulation in nanoparticles and biological studies will then be carried out in Canada.

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

As part of the collaboration, the candidate will be required to spend time in Canada.