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

Progetto: Research

Dettagli progetto

Description

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).
StatoNon avviato
Data di inizio/fine effettiva2/04/252/03/27

Funding

  • MUR - Ministero dell'Università e Ricerca

Obiettivi di sviluppo sostenibile dell’ONU

Nel 2015, gli Stati membri dell'ONU hanno sottoscritto 17 obiettivi globali di sviluppo sostenibile (OSS) per porre fine alla povertà, salvaguardare il pianeta e assicurare prosperità a tutti. Il presente lavoro contribuisce al raggiungimento dei seguenti OSS:

  • SDG 3 - Salute e benessere

Keywords

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

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