PhD offer
Innovative GOLD Nanostructures to Overcome Phototherapy Resistance in Lung Cancer: A Multifaceted Approach Targeting Heat Shock Response
Description of the project:
Non–small‐cell lung cancer (NSCLC) is the most common cause of death from cancer worldwide. Since conventional cancer therapies such as chemotherapy and radiotherapy have side effects and high reappearance rate, alternative modalities with lower negative impacts have been developed. In this regard, combined therapies based on photodynamic and photothermal therapies (PDT and PTT) have emerged as a local and noninvasive treatment for lung cancer. The photo-agents absorb light energy to generate heat as PTT for thermal erosion of tumour cells or reactive oxygen species (ROS) as PDT, which can promote the apoptosis or necrosis of cancer cells. PTT is increasingly recognized to be a promising strategy for cancer treatment, which shows high selectivity and effectivity with reduced side effect.
However, the efficacy of PTT treatment is hampered by cellular defence mechanism as heat shock response (HSR) which leads to therapeutic resistance of cancer cells due to their cytoprotective and antiapoptotic effects. Several families of heat shock proteins (such as HSP70) induced by the HSR as well as the transcription factor 1 (HSF1) play a major role in the thermoresistance. The application of small-interfering RNA (siRNA) could be an interesting therapeutic modality to prevent
thermoresistance by interfering with the expression of genes involved in the HSR.
Nanoparticles called gold nanoclusters (AuNCs) are emerging luminescent carriers and photo/radiosensitizers that have been explored for enhanced therapeutic efficiency in cancer. Depending on the nature of their functionalization, AuNCs are able to protect and deliver biomolecules such as siRNA in cells and to be tracked by non-invasive near infrared (NIR) fluorescent imaging in vitro and in vivo. We are interested in AuNCs that present also promising PTT and PDT features by inducing an increase of temperature as well as the production of ROS in cells under NIR irradiation.
This transdisciplinary project proposes to establish a multifunctional delivery system that not only delivers siRNA targeting HSP70 or HSF1 to counterbalance the HSR defence mechanism activated in lung cancer treated by phototherapy, but also acts as a synergistic enhancer of PTT and PDT therapy. It is divided in 4 axes:
1/ Characterization of phototherapeutic positively charged AuNCs-siRNA.
2/ Cytotoxicity, cellular uptake of nanoconjugates and their ability to inhibit Hsp70 or HSF1 expression in vitro.
3/ Phototherapeutic activity of nanoconjugates on cellular temperature, ROS production, HSR and cellular proliferation after NIR irradiation in vitro.
4/ Investigation of proteome dynamics, cell structure variations and death due to the thermal change
intracellularly induced by the nanoconjugates under NIR light in lung cancer.
Duration: 3 years Starting date: January 2025 Location: Grenoble, France
Figure 1: Schematic representation of the 4 axes of the GOLDEN-HEART project.
Project supervisors:
Dr Virginie Faure from the Institute of Advanced Biosciences (https://iab.univ-grenoble-alpes.fr/)
Dr Judith Peters from the Interdisciplinary Laboratory of Physics (https://liphy.univ-grenoble-alpes.fr/)
Applicant profile:
Applicants should hold a Master of Sciences in Biology or Nanotechnology Sciences with knowledge in cellular biology and in biochemistry. He/she should have a strong interest in working in a cross-disciplinary environment at biology-chemistry and physical interface with biologists, physicists and chemists. A good English level is required.
Applicant skills:
The PhD student is expected to actively drive forward a cross-disciplinary project on theranostic approach targeting heat shock response in lung cancer cells treated by phototherapy. She/he will be in charge of most of a part of the experiments of the project and set up experimental protocols with the advice and assistance of the 2 co-directors of thesis (Dr Virginie Faure and Pr Judith Peters). She/he will use diverse techniques such as nanoparticles’ assembly,
functionalization and characterization, 2D and 3D cell cultures, western blot analysis, RT- qPCR, immunofluorescence combined with microscopy and FACS analysis. He/she will work in three different laboratories located all in Grenoble: the Institute for Advanced Biosciences, the Interdisciplinary Laboratory of Physics and the Institute Laue Langevin. The student must therefore be able to tackle a diversity of methods and approaches. Along with performing experiments and analysing data, the candidate will also be responsible for communicating clearly and regularly the progress of the work using numeric lab books, carry out bibliographic work, contributing to relevant national and international conferences on nanotechnology, heat shock response and cancer, and writing high-quality scientific papers. She/he will also participate in collective laboratory tasks and in scientific and federating animations of the Institute. The student will have to follow courses as part of the education.
Application:
Candidates should send a Cover Letter, a CV, recommendation letters, and grade transcripts, only by email to virginie.faure@univ-grenoble-alpes.fr and judith.peters@univ-grenoble-alpes.fr.
deadline: 20th of September 2024
An interview should be organized at the beginning of October 2024 for this PhD position.
