Nanoparticles for combinatorial treatment of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in Europe and in the US. Its detection is difficult because of the lack of clinical signs and disease-specific biomarkers. As a result, most patients remain asymptomatic and the disease results incurable when it is diagnosed. The PDAC microenvironment is characterized by a thick desmoplastic stroma and disorganized blood vessels that impedes an efficient drug delivery, the accumulation of the drug in the specific site and makes this tumour extremely hard-to-treat with traditional chemotherapy. The progression from normal cells to invasive PDAC requires the accumulation of multiple inherited or acquired mutations. Several signalling pathways, such as RAS, PI3K, and Hedgehog (Hh) are known to play a role in supporting tumorigenesis and tumour progression. Treatment options for PDAC are limited and depend on the disease’s stage. The tumour can be classified in four main categories depending on tumour extension: resectable, borderline resectable, locally advanced and metastatic. The main treatment for pancreatic cancer is the surgical procedure, however it is restricted to earlier disease stages. Chemotherapy, radiotherapy, and new techniques based on the combination of hyperthermia with nanoparticles remain the main treatments for metastatic tumour. Nanomedicine has great potential in PDAC because of the ability of nanoconstructs to overcome biological barriers ant to release the drug in the specific site. A lot of organic and inorganic nanomaterials have been successfully explored as smart functional materials in nanomedicine. Zinc oxide (ZnO) nanoparticles show some interesting properties, such as semicondictive, piezoelectric and antimicrobial behaviours, as well as ease of synthesis in reduced size nanoparticles, that make them easily addressing in the human body and facilitate the cellular uptake. However, the use of ZnO nanomaterials in nanomedicine is still limited because of the intrinsic limitations such as low stability of the ZnO particles in biological fluids and the non-controllable release of Zn2+ cytotoxic species. For this purpose, the doping of ZnO served as a powerful approach to confer to ZnO new functionalities. We decided to synthetize ZnO nanoparticles and ZnO nanoparticles doped with Gadolinium which induces a magnetic behaviour in the nanoparticles, useful for further use as contrast agent in magnetic resonance imaging. Polymeric materials result a powerful tool thanks to their biological stability, reduced renal clearance and ability to co-host multiple drugs. So, many researchers have developed new systems that combine the properties of inorganic nanoparticles with the properties of the polymeric coating. In my Master Thesis work, I have coated the ZnO and the Gd-doped ZnO nanoparticles with a polymer (a proprietary polyurethane) and I have stabilized the system with a lipid bilayer made of L-α-phosphatidylglycerol (EGG-PG) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino(polyethyleneglycol)-2000] (DSPE-PEG). The aim was to characterize these nanoparticles and to evaluate their cytotoxicity against pancreatic cancer cells in vitro. Drug-encapsulated nanoparticles (containing Gemcitabine) were also prepared and characterized, in terms of therapeutic effect on pancreatic cancer cells.