Hacking pancreatic adenocarcinoma drug resistance with novel NO-GEM prodrugs targeting mitochondria and encapsulated in decorated liposomes

Starting date
July 1, 2018
Duration (months)
36
Departments
Neurosciences, Biomedicine and Movement Sciences
Managers or local contacts
Donadelli Massimo

Cancer deaths are the second leading cause of death, after cardiovascular disease, in industrialized countries and hit millions of people every year. Among cancers, pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive cancer types, with a high incidence of distant metastasis and mortality. The main issue against successful therapy for PDAC is represented by the absence of early diagnostic markers, as well as the resistance to radiation and chemotherapies. Chemotherapy still remains the mainstay of treatment for advanced PDAC and the drug gemcitabine (GEM), used in monotherapy or in combination with other pharmacologic therapies, is the standard first-line therapeutic agent since 15 years also for its low toxicity. However, many mechanisms of cancer cell resistance to GEM, as the inefficient cellular uptake, its intracellular enzymatic inactivation, or the reduced expression of intracellular activating enzymes can compromise its anti-cancer effects.
Through the synergistic collaboration with the main partner ISALIT (spin-off at the Piemonte Orientale University) and the University of Torino this project aims to synthesize a library of nitric oxide-releasing gemcitabine conjugates (NO-GEMs) targeting mitochondria of cancer cells in order to improve the antiproliferative efficiency of GEM in PDAC cells. Our purpose is to strongly affect pancreas cancer resistant cells through the mitochondrial production of peroxynitrite (ONOO−), a highly cytotoxic oxidant and nitrating ion, derived by the spontaneous reaction of endogenous mitochondrial superoxide generated by GEM treatment with the mitochondrial release of NO. To minimize eventual side effects these NO-GEM compounds will be encapsulated in liposomes, decorated with recognition molecules, and tested in cancer cells. The effect of these nanoparticles will be tested in vitro and in mice models of pancreas cancer and the overall molecular alterations associated to cancer cell death will be also investigated by the collaboration with the entrepreneurial society ISALIT through proteomic and metabolomic high-resolution mass spectrometry (HR-MS) analyses of intracellular extracts.

Sponsors:

ISALIT Srl
Funds: assigned and managed by the department
Syllabus: JOINT PROJECTS

Project participants

Massimo Donadelli
Associate Professor

Collaboratori esterni

Marcello Manfredi
Isalit Srl

Activities

Research facilities