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Author
Charles, Inés
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Abstract
Breast cancer is the most commonly occurring cancer in women. Triple negative breast cancer (TNBC), one subtype of breast cancer, is characterized by its unique molecular profile, aggressive behavior, clear patterns of metastasis, and lack of targeted therapy, making it one of the more challenging breast cancers to treat. Lately, only chemotherapy is used as standard of care treatment in patients with TNBC and if metastasis is present, the treatment is unlikely to be successful. Tumor stem cells are the main cause of resistance to immunotherapy in this subtype of breast cancer because they are "invisible" to the immune system, and this makes immunotherapy ineffective.
LCOR (Ligand-dependent corepressor) activates transcription of the antigen presenting machinery (APM) independently of interferon (IFN), rendering cancer stem cells (CSCs) visible and vulnerable to immune attack during ICB. Therefore, in the case of CSC, their low presence of this LCOR factor makes them invisible and resistant to the body's defences. Thus, this factor plays a central role in modulation of tumor immunogenicity and responsiveness to immunotherapy. The idea is to use a strategy similar to the design of messenger RNA vaccines against Covid-19 to transport and introduce the LCOR gene RNA into tumor cells and reactivate its function, so that the cells become visible for recognition of the virus. immune system and its subsequent elimination.
Various nanoparticles composed of poly(β-aminoesters) (pBAEs) were formulated to deliver mRNA efficiently to cancer cells. LCOR mRNA could not be synthesized and further investigation regarding plasmid S1pcDNA3.1 needs to be done. Therefore, OM-PBAE:mRNA nanoparticles were synthesized with model mRNA/plasmids, as a first proof of concept of the therapy. Therefore, this TFG focused on the selection of the best polymers, with targeting molecules, to use in TNBC therapies.
Physicochemical characterization of various nanoparticle formulations containing other forms of gene therapy was performed. The kinetics of two breast cancer cell lines was characterized and the toxicity of the polymer was evaluated for its subsequent transfection with OM-PBAE:pDNA nanoparticles. Anisamide-functionalized nanoparticles and born derivatives, as tumor-directing moieties, have shown good physicochemical characteristics and promising transfection efficiencies.
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