Progetti di ricerca

Pancreatic Ductal Adenocarcinoma (PDAC) is a common type of pancreatic cancer with dismal mortality rates. To date, complete surgical resection is the one and only cure for advanced PDAC. However, less than 20% of all PDAC patients are eligible for… Leggi tutto surgery. Peculiar features of the tumor microenvironment (TME), such as immunosuppressive leukocytes, cancer-associated fibroblasts, and a highly fibrotic stroma causing tumor hypo-vascularization and vessel abnormalities, have undermined previous attempts at developing effective therapies. In addition, the complexity of TME makes studying PDAC cells in isolation of limited translational relevance. Hence, finding more effective treatment options that target the TME in advanced PDAC is an unmet medical need that must be urgently addressed. Targeting the TME with selective nanocarriers is now considered a hot topic in cancer research. The delivery of nucleic acids is attracting increasing interest with the aim to activate antitumor action, including TME remodulation, stimulation of the immune response and activation of specific apoptotic processes. Yet, a major hurdle in studying novel PDAC therapeutic strategies resides in the lack of reliable in vitro systems recapitulating the complexity of the TME. In this project, we capitalize on a mutant of semaphorin (Sema3A) with proven abilities to activate anti-tumor immune response and to normalize the microvasculature in PDAC mouse models. We rely on lipid nanoparticles (LNPs) co-administered with a tumor penetrating peptide to efficiently deliver mut-Sema3A mRNA into the TME and achieve local Sema3A translation thereby transforming the “cold” PDAC into an immunologically “hot” tumor. We aim to develop an innovative in vitro microfluidic-based model of vascularized PDAC suitable for the investigation of its interaction with exogenous T cells, which provides a pathologically relevant platform for the study of the TME complexity. We plan: 1) To design and characterize mut-Sema3A mRNA-LNPs 2) To develop an in vitro T cell-endowed vascularized PDAC model to assess the transcytosis of the LNPs across the endothelial barrier and its release into the TME 3) To assess the anti-cancer and endothelium-normalizing effects of mut-Sema3A mRNA-LNPs in the in vitro T cell-endowed vascularized PDAC model 4) To evaluate the ability of mut-Sema3A mRNA-LNPs to reach tumor in mouse models of PDAC and the induction of cytotoxic CD8+ T-cells 5) To study the potential synergistic effect of mut-Sema3A mRNA-LNPs combined with immune-checkpoint inhibitors in hampering PDAC growth in vivo. By combining a PDAC mouse model with the implementation of a CD8+ T cell-endowed vascularized in vitro system, the mut-Sema3A mRNA-LNPs proposed in this project will shed new light into the patho-mechanisms underlying PDAC onset and progression, opening new opportunities for more effective treatments for PDAC.

Addressing the grand-challenges that the world is facing nowadays in connection with ‘energy’, ‘information’ and ‘health’ requires the development of unconventional methods for unprecedented visualization of matter. SMARTelectron aims at developing an innovative technological platform for designing, realizing and operating all-optical rapidly-programmable phase… Leggi tutto masks for electrons. By introducing a new paradigm where properly synthesized ultrafast electromagnetic fields will be used for engineering the phase space of a free-electron wave function, we will be able to achieve unprecedented space/time/energy/momentum shaping of electron matter waves, surpassing conventional passive monolithic schemes and revolutionizing the way materials are investigated in electron microscopy. Such unique high-speed, flexible and precise full-phase multidimensional control, will enable novel advanced imaging approaches in electron microscopy with enhanced features, such as higher image-resolution, lower electron dose, faster acquisition rate, higher signal-to-noise ratio, and three-dimensional image reconstruction, together with higher temporal resolution and high energy-momentum sensitivity. In SMART-electron, we will make such potential a reality by implementing for the first time three beyond-the-state-of-the-art imaging techniques enabled by our photonicbased electron modulators, namely: (1) Ramsey-type Holography, (2) Electron Single-Pixel Imaging, and (3) Quantum Cathodoluminescence. Such new approaches will lead to unprecedented visualization of many-body states in quantum materials, real-time electrochemical reactions, and spatio-temporal localization of biomimetic nanoparticles in cells for drug delivery. By surpassing the current paradigms in terms of electron manipulation, the project has the potential to drive electron microscopy into a new and exciting age where scientists will benefit from new tools with unprecedented performances that were unimaginable until now.