Preclinical evaluation of senescence-based strategies to improve cancer therapydissertation
Аннотация: preclinical model, the combined treatment of palbociclib with NP(nav)-Gal decreased endothelial senescence in veins as well as in metastatic nodules in the lungs.Based on the results obtained in the first chapter, chapter two describes a similar one-two punch therapeutic strategy for triple-negative breast cancer patients.In this case, a human xenograft mice model was employed to evaluate the effect of combined therapy of palbociclib plus navitoclax.In order to overcome the side effects of navitoclax treatment (mainly thrombocytopenia), we evaluated the effect of the prodrug nav-Gal, synthetized by the galactose-conjugation of navitoclax.Palbociclib therapy-induced senescence (TIS) followed by adjuvant therapy with navitoclax or nav-Gal caused a synergistic elimination of senescent tumor cells and reduction of tumor growth and lung metastasis in a xenograft mice model of aggressive human TNBC (hTNBC).Chapter three focuses on the design and development of a new stigmergy nanoparticle communication system to improve tumor therapy in breast cancer.The communication of nanoparticles by stigmergy consists of a sequential system of two nanoparticles in which the first modifies the environment allowing the second nanoparticle to act.To do this, we again rely on a two-step therapy.The first step is the induction of senescence with palbociclib, and the second is the subsequent elimination of senescent tumor cells with navitoclax.For this purpose, two nanodevices based on gated MSNs were prepared.The first nanodevice (NP(palbo)PEG-MUC1) was loaded with palbociclib and functionalized, through disulfide bonds, with a poly(ethylene glycol) that binds to an aptamer cap that targets the MUC1 surface protein, which is overexpressed in breast tumor cells.The second nanodevice was the senolytic NP(nav)-Gal already described in the third chapter.A synergistic effect was achieved when both nanoparticles were sequentially administered, delaying tumor growth and reducing metastases in a xenograft hTNBC mice model.In the fourth chapter, we identify a novel senolytic agent (H14) that can target malignant tumoral melanoma senescent cells with optimal in vivo efficacy and safety.To Abstract xxv do so, a combinatorial library of D-amino acid hexapeptides was screened in senescent SK-Mel-103 melanoma cells in which the induction of senescence was achieved by treatment with palbociclib.The combined therapy of palbociclib and H14-hexapeptide improved the elimination of senescent tumor cells and reduced tumor growth, reaching effects similar to the combined treatment of palbociclib with navitoclax.Finally, the main conclusions derived from the presented experimental work, as well as the general conclusions of this Ph.D. thesis, are addressed.Future breakthroughs in the field of cellular senescence treatment are expected.We hope that the results achieved in this PhD thesis will open new research opportunities and inspire the development of advanced strategies with smart nanodevices and prodrugs for their application in the field of cellular senescence and other different biomedical areas and in sensing and communication technologies to solve patient needs.
Год издания: 2022
Авторы: Alejandra Estepa‐Fernández
Ключевые слова: Graphene and Nanomaterials Applications, Advanced Breast Cancer Therapies, Advanced biosensing and bioanalysis techniques
Открытый доступ: hybrid