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

Abstract

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 less than 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, curcumin, and sulforaphane (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 (PanIN) using unmodified (free drug) combinations of ACS, and nanoencapsulated (solid lipid nanoparticles; SLN) combinations of aspirin, curcumin, and free sulforaphane. 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 nanoencapsulated ACS regimens reduced tumor incidence by 33%, 67%, and 75%, respectively, at 10 times lower dose compared with the free drug combinations. Similarly, although the unmodified free ACS showed 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 proliferating cell nuclear antigen expression. Cell apoptotic indices were also upregulated by 1.5, 2.8, and 3.2 times, respectively, compared with 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.