Responsabile scientifico

• LALLI Daniela

Partecipanti al progetto

• ROBOTTI Elisa

Titolo del progetto

• A multidisciplinary approach to develop targeted nanotherapy of Pancreatic Adenocarcinoma and improve tumor phenotyping

Ente finanziatore

• MUR - Ministero dell'Università e Ricerca

Programma di finanziamento

• PRIN - Progetti di Ricerca di Rilevante Interesse Nazionale (dal 2020)

Bando di riferimento

• PRIN 2022

Anno di presentazione del progetto

• 2022

Anno di approvazione del progetto

• 2024

Project ID / numero contratto

• 20222HY5TF_002

Durata del progetto

• 24 mesi

Inizio del progetto

• 02/04/2025

Fine del progetto

• 02/03/2027

Ente capofila

• UNITO - Università degli studi di Torino

Altri partner del progetto

• UNIUPO - Universita Degli Studi del Università del Piemonte Orientale "Amedeo Avogadro"

Progetto approvato - Contributo unità di ricerca del Dipartimento

• €80.880,00

Sustainable Development Goals - Agenda 2030

Keyword

• Metabolomics
• Nanomedicine
• Pancreatic Adenocarcinoma
• NMR
• Targeting
• Magnetic resonance imaging (MRI)

Stato del progetto

• Approvato

Abstract

• Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the deadliest cancers worldwide. It is aggressive, and difficult to diagnose early, as featured by the absence of symptoms and biomarkers. The available treatments are not effective, since the poor vascularization, the hypoxia and the fibroblasts-rich stroma surrounding PDAC hinder drugs delivery and block radiotherapy. The high heterogeneity and the poor knowledge of PDAC biochemistry prevented the development of effective therapies. To fill this gap, we aim to develop a novel nanotherapy in which drugs acting on different pathways are delivered by biocompatible targeted nanocarriers in tumor cells. To achieve this goal, a deeper knowledge of molecular signatures of cancer is needed, so the second goal of the project relies on designing a multidisciplinary core study to characterize tumor microenvironments and stroma. This has the double function of i) improving the identification of biomolecular and cellular signatures of PDAC (tumor phenotyping) and ii) assessing the outcome of the nanotherapy. As animal models we adopt genetically engineered murine PDAC models with pancreatitis, mimicking human PDAC. Mice will be treated with the drugs-loaded nanoparticles (NPs), based on PLGA copolymer (FDA-approved). They will deliver two anticancer drugs with synergistic effects, i.e. a cytotoxic drug and an inhibitor of tumor associated macrophages, TAMs. To accumulate in the tumor region and reduce side effects to organs, NPs will be equipped with a moiety targeting overexpressed integrins. To increase penetration into the tumor overcoming the fibrotic tissue, NPs will be externally decorated with fibroblast inhibitors, through a Matrix Metalloproteinases 2 (MMP-2)- cleavable linker. The latter is recognized and cleaved by MMP-2 overexpressed on PDAC, triggering the release and action of the antifibrotic drug. To image the NPs accumulation in the tumor and evaluate the efficacy of antifibrotic drugs in degrading stroma, NPs will be loaded with Gd-probes for Magnetic Resonance Imaging (MRI). The nanotherapy has several advantages over conventional chemotherapy, i.e.: -simultaneous action against different biomolecular pathways underlying PDAC aggressiveness -specific accumulation of the targeted NP on tumor cells, so reducing side effects to other organs -enhancement of drug penetration in the tumor. The second goal of the proposal is the in vivo and ex vivo molecular characterization of the cancer phenotypes both in absence of treatment (to gain insights into PDAC biochemistry) and after treatment with drug-loaded NPs, empty NPs or free drugs (to evaluate the effect of nanotherapy).