• 36 months doctoral funding (October 2021 to September 2024)
• Keywords

liposome, metformin, doxorubicin, antibody fragment (scFv), triple negative breast cancer, treatment combination

• Profile and skills required

The student must have a good knowledge on nanoformulation and analytical methods allowing the characterization of the formulated nano-objects. Expertise in surface functionalization of nanosystems would be a plus. Theoretical notions on therapeutic antibodies would be interesting, and a first experience on cell culture (work in sterile environment). The student profile is rather a pharmacist or a chemist profile with a specialization in nanomedicine.

Level of French required: Pre-Intermediate: You can communicate and make yourself understood with simple messages in certain everyday contexts.

Level of English required: Pre-Intermediate: You can communicate and make yourself understood with simple messages in some everyday contexts.

• Project description

The anti-diabetic drug metformin (MET) has been described for several years as a multifaceted adjuvant for cancer therapy. Numerous clinical studies demonstrate a protective effect of MET on the incidence of cancers of various organs (Farmer RE, Int J Epidemiol. 2017). A dose-dependent antiproliferative effect has been demonstrated in numerous cell cultures as well as in animal models (Peng M, Cancer Treat Rev. 2017). A synergistic effect is known between MET and chemotherapy, mainly linked to the tumor re-oxygenation properties induced by MET via the decrease in mitochondrial metabolism. MET also increases the anti-tumor functionality of T cells, by neutralizing populations of immuno-inhibitory cells residing in the tumor microenvironment or by down-regulating PDL1 expression in cancer cells (Verdura S et al. Oncoimmunol. 2019). Thus, MET could potentiate the action of monoclonal antibodies (MAbs) and sensitize breast tumors to immune checkpoint inhibitors (anti-PD1, anti-PDL-1).

Although MET is a well tolerated drug, its application in cancer treatment is limited by its poor bioavailability (50-60%) and rapid renal clearance. Because MET is highly soluble in water and and could not enter the cells by passive diffusion, this molecule is a good candidate for vectorization. Among the existing nanovectors, liposomes appear promising for carrying this molecule thanks to the presence of an internal aqueous cavity. In addition, it is also possible to co-encapsulate other active compounds in their lipid bilayers as well as functionalize their surface with biological ligands to target the cells of interest.

This phD project proposes to formulate, characterize and test the biological relevance of such a nanosystem called immunoliposome (IL) in the context of triple negative breast cancer (CSTN). This cancer is the most aggressive form of breast cancer with a weak therapeutic arsenal and major resistance problems. The thesis has three main part: i) the significant co-encapsulation of MET and doxorubicin (DOX) in injectable ILs, ii) the grafting of scFv targeting ligands on the IL surface in order to target the CSTN cells or their microenvironment, iii) the study of antineoplastic, metabolic and immunogenic effects of this association on 2D and 3D in vitro models of CSTN. The scFv grafted onto these ILs will target two relevant proteins in CSTN: i) a membrane target overexpressed in CSTN cells, the TROP 2 antigen (Goldenberg DM et al, Oncotarget. 2018 - collaboration with N. Joubert and N. Aubrey, Tours), ii) a soluble and extracellularly secreted target, cathepsin D (Ashraf Y, et al J Immunother Cancer - collaboration with E. Liaudet-Coopman, Montpellier).

• References

- Farmer RE et al, Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation., Int J Epidemiol. 2017 Apr 1;46(2):728-744.

- Peng M, et al, Combination of metformin with chemotherapeutic drugs via different molecular mechanisms. Cancer Treat Rev. 2017 Mar;54:24-33.

- Verdura S, et al, Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy. Oncoimmunology. 2019 Jun 25;8(10):e1633235.

- Goldenberg DM, et al, The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018 Jun 22;9(48):28989-29006.

- Ashraf Y, et al, Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies. J Immunother Cancer. 2019 Feb 4;7(1):29.

- Alric C, et al, Covalent conjugation of cysteine-engineered scFv to PEGylated magnetic nanoprobes for immunotargeting of breast cancer cells, RSC advances, 2016, 6, 37099

- Hervé-Aubert K, et al. Impact of Site-Specific Conjugation of ScFv to Multifunctional Nanomedicines Using Second Generation Maleimide. Bioconjug Chem. 2018 May 16;29(5):1553-1559.

- Nguyen PV, et al, Targeted nanomedicine with anti-EGFR scFv for siRNA delivery into triple negative breast cancer cells. Eur J Pharm Biopharm. 2020 Dec;157:74-84.

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