Dipartimento di Farmacia e Scienze della Salute e della Nutrizione - Tesi di Dottorato
Permanent URI for this collectionhttps://lisa.unical.it/handle/10955/33
Questa collezione raccoglie le Tesi di Dottorato afferenti al Dipartimento di Farmacia e Scienze della Salute e della Nutrizione dell'Università della Calabria.
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Item Tamoxifen resistance in breast tumors relays on increased translation of lipid metabolism genes(Università della Calabria, 2024-05-16) La Padula, Davide; Catalano, Stefania; Sirianni, RosaItem INNOVATIVE MASS SPECTROMETRY TECHNIQUES FOR FOOD QUALITY AND AUTHENTICIY(Università della Calabria, 2024-03-05) Talarico, Ines Rosita; Catalano, Stefania; Di Donna, LeonardoItem Next-Generation vesicular systems in Nanomedicine: building blocks for personalized therapeutics(Università della Calabria, 2024-05-21) Romeo, Martina; Catalano, Stefania; Muzzalupo, RitaThe emergence of nanotechnology has not only revolutionized the field of drug formulation but has also ushered in a new era of personalized therapeutic interventions. Over the past few years, nanoscale-controlled release systems have emerged as gamechangers, exhibiting extraordinary potential in augmenting therapeutic effectiveness while concurrently mitigating the adverse effects associated with traditional medications. This novel cohort of nanocarriers, comprising a rich array of materials including lipids, polymers, and non-ionic surfactants, stands as a testament to the versatility and ingenuity of nanotechnological advancements. By harnessing their unique properties, nanovehicles offer a precision-targeted approach to drug delivery, homing in on specific pathological sites with unprecedented accuracy. Moreover, the inherent adaptability of nanocarriers allows for bespoke modifications tailored to individual therapeutic needs, whether it be bolstering drug stability, facilitating permeation across biological barriers, or orchestrating sophisticated "intelligent" systems for targeted cancer therapy. Not only does this approach promise to enhance therapeutic outcomes, but it also presents a more efficient and cost-effective alternative to the traditional pursuit of novel pharmacologically active compounds. As such, the convergence of nanotechnology and drug delivery represents a compelling frontier in the quest for optimized therapeutic interventions, holding profound implications for the future of medicine.Item Modulatory role of adiponectin on endocrine resistance in breast cancer(Università della Calabria, 2024-05-22) Forestiero, Martina; Catalano, Stefania; Mauro, LoredanaEstrogenReceptor (ER) represents a breast cancer positive prognostic factor and the main molecular target of endocrine therapy, although de novo and acquired resistance to this treatment remains a major challenge. Breast Cancer Stem Cells (BCSCs) are blamed to be the driving force behind breast tumor initiation, progression, metastasis, endocrine resistance, and recurrence, due to their strong selfrenewal and multilineage differentiation properties. Notably, it has been evidenced that tumor microenvironment (TME) influences BCSCs behavior, regulating the complex interaction between stromal and breast epithelial cells, through the secretion of different cytokines and growth factors. The most abundant cellular component of TME is represented by adipocytes which became dysfunctional in obesity, leading to an unbalanced adipokines secretion. Particularly, plasma levels of adiponectin, the main adipocytederived factor, are reduced in obese compared to normal weight subjects, promoting growth and progression in ERαpositive breast cancer. This let us to wonder if the induced proliferative effect of low level of adiponectin on ERαpositive breast cancer cells could be related to specific stimulatory effects on breast cancer stemness. In tamoxifenresistant MCF7 (TR MCF7) mammospheres adiponectin increased Mammospheres Forming Efficiency (MFE) and selfrenewal capacity concomitant with an enrichment in CD44+/CD24/ ALDH1+ subpopulation, identifying a typical stemlike phenotype. This was not observed in hormoneresponsive MCF7 (WT MCF7) cells. An increase in mRNA levels of stemness and EpithelialMesenchymal Transition (EMT) markers corroborated the increased percentage of BCSCs in TR compared to WT MCF7 mammospheres. Consistent with these data hormoneresistant cells showed a G0/G1 arrest and an apoptosis reduction compared to WT cells, as evidenced by cell cycle and Annexin V assay, Western Blotting and proteomic analysis. Interestingly, in adiponectintreated TR MCF7 mammospheres, it has been observed a reduced ROS production, concomitant with a slight enhance of mitochondrial membrane potential, confirming the antiapoptotic features of BCSCs. Finally, TR MCF7 cells, obtained from secondary generation mammospheres, exhibited a reduced proliferation rate, Ki67 level and cell motility, suggesting a cellular state of quiescence in TR MCF7 cells. Overall, we demonstrated that low levels of adiponectin promote stemlike features in TR MCF7 cells, that may contribute to relapse. Thus, the study of the molecular mechanisms involved in the regulation of cell death and in the entry of a quiescent state, could pave the way for the development of successful therapies for the treatment of hormoneresistant obese breast cancer patients.Item DESIGN AND SYNTHESIS OF SMART MESOPOROUS SILICA-BASED NANODEVICES FUNCTIONALIZED WITH SMALL MOLECULES AND PEPTIDES FOR TARGETED CANCER THERAPY(Università della Calabria, 2024-07-19) De Santo, Marzia; Catalano, Stefania; Leggio, AntonellaMy PhD research project focused on the design and synthesis of mesoporous silica-based nanoframworks for the targeted delivery of anticancer drugs. The use of nanomaterials for cancer treatment has revolutionized chemotherapy, improving drug efficacy and safety while reducing side effects. Mesoporous silica nanoparticles (MSNs) offer unique advantages, including tunable pore size and shape, easy surface functionalization, high loading capacity, and excellent biocompatibility, making them a promising platform for cancer therapy. Initially, my PhD research activity was concentrated on developing highly selective MSN-based nanosystems for the smart administration of bortezomib (BTZ), a first-line treatment for multiple myeloma. A novel bortezomib (BTZ) delivery system, named FOL-MSN-BTZ, was developed using NanoSiliCal Devices' proprietary MSN technology. NanoSiliCal Devices, an innovative PMI and spin-off from the University of Calabria, hosted me for an 18-month internship during my doctoral studies. The engineered FOL-MSN-BTZ nanodevices consists of MSU-type mesoporous silica nanoparticles able to selectively delivery bortezomib to folate receptor overexpressing multiple myeloma (FR+ MM) cells. The receptor-specific ligand, folic acid (FOL), grafted on the external surface of MSNs, allows tumor recognition and cell internalization, while BTZ linked to the pore internal surface by a pH-responsive bond, is released in a slightly acidic tumor microenvironment. By carefully balancing the different functionalities on the external and internal surface of MSNs we identified an optimized nanostructure that selectively induces death in FR+ tumor cells while sparing BTZ suspensions showed a significantly higher in vivo anticancer efficacy, and a better safety profile compared to conventional BTZ administration. Building on the remarkable in vitro and in vivo results of FOL-MSN-BTZ, we developed a new MSN-based nanodevice for the selective delivery of doxorubicin (DOXO). DOXO is a potent chemotherapeutic agent effective against a wide range of cancers but is associated with serious side effects, such as cardiotoxicity and myelosuppression. To mitigate these toxicities and enhance therapeutic performance through site-specific targeting and controlled release, we created the FOL-MSN-DOXO nanodevice. In this system, folic acid is again used as the targeting molecule on the external surface of the mesoporous silica nanoparticles (MSNs), while doxorubicin is conjugated to the internal pore walls through an acid-labile hydrazone bond. The FOL-MSN-DOXO nanosystem selectively targets FR-overexpressing cancer cells, while sparing the FR-low normal cells. Furthermore, FOL-MSN-DOXO uptake occurred via FR-mediated endocytosis. Additionally, a more specific DOXO-loaded prototype, HER2PEP-MSN-DOXO, featuring a peptide ligand on its external surface that can recognize the HER2 receptor, was designed and developed. This receptor is a crucial therapeutic target in treating HER2-overexpressing (HER2+) breast cancer. In this innovative design, the folic acid previously used on the MSNs' external surface was replaced with a peptide ligand specifically engineered to target the HER2 receptor. The interactions of the designed peptides with the HER2 receptor were studied and evaluated through computational analysis. After identifying the optimal amino acid sequence for interacting with HER2, we synthesized the sequence using solid-phase methodologies and anchored it to the external surface of the silica nanoparticles. The obtained nanosystem significantly inhibited the proliferation of HER2-positive cancer cells, without affecting the growth of HER2-negative healthy cells. The uptake of HER2PEP-MSN-DOX in HER2+ cancer cells occurred though HER2-mediated endocytosis. During a six-month period at the Institute Charles Gerhardt Montpellier (ICGM) in France, under the supervision of Prof. Colacino, my PhD research focused on preparing hybrid mesoporous silica-based materials using innovative, eco-friendly mechanochemical methodologies. The aim was to functionalize mesoporous silica nanoparticles (MSNs) with appropriate linkers and targeting molecules. By employing mechanochemical synthetic approaches, we selectively functionalized MSU-type starting materials on both their external and internal surfaces, creating nanodevices suitable for potential drug delivery applications. The primary goal was to optimize the traditional solvent-based process by minimizing solvent usage, waste generation, and reaction times, thereby enhancing overall process efficiency and eco-friendliness. Targeting molecules, such as small peptides, were effectively grafted onto the external surfaces of the MSNs. Additionally, the internal surfaces were successfully modified with organosilanes to develop stimuli-responsive linkers. Mechanochemical methods were also employed to improve the extraction of surfactants from within the pores of the MSNs, significantly reducing water consumption during the process. In conclusion, my PhD research on mesoporous silica-based systems for controlled release and targeted delivery of anticancer drugs has highlighted significant advancements in the field of targeted therapies and the strategic shift toward molecular multi-targeted approaches. While traditional methods like molecular recognition and pH sensitivity are still effective, the future of cancer treatment lies in molecular multi-targeted therapies, with nanotechnology playing a pivotal role in drug design. To address the complex nature of cancer and improve therapeutic outcomes in terms of both efficacy and reduced toxicity, a polypharmacology approach utilizing Molecular Multi-Targeted Nanostructured (MMTN) cancer therapeutics is proposed in perspective. The hypothesized MMTN device consists of mesoporous silica nanoparticles with an antibody-mimicking peptide on the external surface, connected via an uncleavable bond, and two small molecules inside the silica pores linked with a pH-sensitive bond that hydrolyses in the acidic tumor microenvironment. This design allows the antibody-mimicking peptide to inhibit extracellular target proteins, while the small molecules penetrate the cell to target intracellular proteins, resulting in a synergistic attack on cancer cells. This thesis encompasses published work (papers), completed studies awaiting publication, and ongoing research. Peptide sequences and part of experimental data of the synthesized systems have been omitted for confidentiality reasons, as patent applications are currently in progress.Item Deep Eutectic Solvents as Sustainable Media for Pharmaceutical Purposes(Università della Calabria, 2024-07-25) Procopio, Debora; Di Gioia, Maria Luisa; Ramòn, Diego J.; Catalano, StefaniaItem Diagnostic challenges for genetic approaches in Amyotrophic Lateral Sclerosis(Università della Calabria, 2023-02-28) Perrone, Benedetta; Catalano, Stefania; Conforti, Francesca LuisaOver the past years, our understanding of the genetic mechanisms involved in complex diseases, such as Amyotrophic Lateral Sclerosis, has increased dramatically. ALS is a fatal and devastating motor neuron disease for which there is no truly effective cure. In 1993, the first gene associated with ALS was identified (1). Since then, our knowledge of the genetic mechanisms of disease has expanded significantly. Diagnostic tools have followed these research insights and Sanger DNA sequencing has been routinely used for many years. The emergence of next-generation DNA sequencing (NGS) approaches in the same decade allowed high throughput approaches to DNA sequencing, enabling the identification of new genes and pathways that highlight the heterogeneity of ALS disease, providing exciting opportunities for the identification of biomarkers useful for patient stratification and helping the development of targeted therapies. Despite our increased understanding of the mechanisms of this disease, the majority of patients remain undiagnosed, and the remaining cases have no successful treatments. The absence of an effective cure can be well explained by the complex and heterogeneous nature of ALS, with patients displaying distinct clinical characteristics and distinct molecular mechanisms. In this context, the molecular profiling of patients into clinically meaningful subgroups can be extremely valuable for the development of new precision diagnostics. In this thesis project, we provide an overview on the genetic investigation of ALS patients using different diagnostic approaches highlighting the importance of each methodology and their integrative use for the study of the disease, with the aim of providing a more comprehensive characterization of patients useful for the development of new-targeted strategies in clinical practice and personalized medicine.Item Breast tumor microenvironment and endocrine resistance: dissecting the molecular link(Università della Calabria, 2023-07-04) Caruso, Amanda; Catalano, Stefania; Andò, SebastianoItem Small molecules from cycloaddition reactions: synthesis, theoretical perspectives, and biological evaluation(Università della Calabria, 2023-02-07) Tallarida, Matteo Antonio; Maiuolo, Loredana; Catalano, Stefania; Breugst, Martin; Rutjes, FlorisThe research work is related to a Ph.D. course in Translational Medicine of the Department of Pharmacy, Health, and Nutritional Sciences, University of Calabria. The project was carried out at the Department of Chemistry and Chemical Technologies of the same institution under the supervision of Prof. Loredana Maiuolo in the Laboratory of Organic Synthesis and Chemical Preparations (LabOrSy) headed by Prof. Antonio De Nino. The main subject of this research regards the use of cycloaddition reactions for the synthesis of small molecules with potential biological activity in diverse contexts. Alongside the prominent synthetic part, a series of QM computational studies were conducted to clarify some reaction mechanisms. In addition, molecular docking studies were performed to propose potential targets for some of the prepared compounds. The work is subdivided into four main parts. The first chapter is dedicated to the synthesis of 1,5-disubstituted 1,2,3-triazoles, to a series of molecular docking simulations, and to the biological evaluation of two compounds as inhibitors of the permeability transition pore opening event. The second part is about the microwave-assisted synthesis of isoxazolidine bisphosphonates as potential farnesyl pyrophosphate synthase (hFPPS) inhibitors. The third chapter focuses on the use of pyridinium ylides as building blocks for the multicomponent synthesis of indolizines and spirocyclopropyl oxindoles. The reaction mechanism regarding these latter was computationally investigated. The fourth – and last – chapter regards the synthesis and the radical expansion reaction of norbornane derivatives. A computational assessment of the mechanism is reported also in this case. All the computational studies reported in chapters 1, 3, and 4 were conducted in the frame of an abroad research stay spent in the Computational Chemistry Group headed by Dr. Gonzalo Jiménez Osés of the Center for Cooperative Research in Biosciences (CIC bioGUNE).Item New strategies in the design of functional and bioinspired materials for therapeutic applications(Università della Calabria, 2022-01-27) Servidio, Camilla; Andò, Sebastiano; Cassano, Roberta; Iemma, Francesca; Stellacci, Francesco