A Novel Combinatorial Nanotechnology-based Oral Chemopreventive Regimen Demonstrates Significant Suppression of Pancreatic Cancer Neoplastic Lesions

摘要

Pancreatic cancer is a deadly disease killing 37,000 Americans each year. Despite two decades of research on treatment options, the chances of survival are still <5% upon diagnosis. Recently, chemopreventive strategies have gained considerable attention as an alternative to treatment. We have previously shown significant in vitro chemopreventive effects with low dose combinations of aspirin (ASP), curcumin (CUR) and sulforaphane (SFN) (ACS) on pancreatic cancer cell lines. Here, we report the results of 24-week chemopreventive study with the oral administration of ACS combinations on the N-nitrosobis (2-oxopropyl) amine (BOP)-treated Syrian golden hamster model to suppress the progression of pancreatic intraepithelial neoplasms (PanINs) using (1) unmodified (free drug) combinations of ACS, and (2) nanoencapsulated (solid-lipid nanoparticles; SLN) combinations of ASP, CUR and free SFN. The use of three different doses (low, medium and high) of unmodified ACS combinations exhibited reduction in tumor incidence by 18%, 50% and 68.7% respectively; whereas the modified nano-encapsulated ACS regimens reduced tumor incidence by 33%, 67% and 75%, respectively, at 10X lower dose compared to the free drug combinations. Similarly, while the unmodified free ACS demonstrated a notable reduction in cell proliferation, the SLN encapsulated ACS regimens, showed significant reduction in cell proliferation at 6.3%, 58.6 % and 72.8 % as evidenced by PCNA expression. Cell apoptotic indices were also up regulated by 1.5X, 2.8X and 3.2X respectively, compared to BOP control. These studies provide a proof-of-concept for the use of an oral, low dose, nanotechnology-based combinatorial regimen for the long term chemoprevention of pancreatic cancer.