Abstract 3706: A novel nanoengineering approach to target pancreatic cancer

Abstract

Abstract Pancreatic cancer kills 37,680 Americans per year, with a mortality rate of 91%, making it the deadliest of all cancers, with a median survival of only 6 months. It is also one of the hardest to treat, mainly due to its initially symptomatic nature, hidden location and extremely high metastatic potential. Unfortunately the treatment options have remained stagnant over the past 30 years. Thus far in clinical settings, the nucleoside analog Gemcitabine remains the drug of choice. However, Gemcitabine only marginally improves life-span, mainly due to its chemical instability, thus necessitating frequent systemic administration at high doses. This translates to extreme toxicities and malaise for the patient. Clearly, this creates an unparallel need for novel and more potent therapeutics. In this study, we engineered nanoparticles loaded with Gemcitabine by a solvent evaporation and extrusion method. These ‘GemNano’ formulations achieved high drug loading and were stable over time, as assessed by spectrophotometry and dynamic light scattering (DLS) measurements. In addition, DLS and transmission electron microscopy showed they were smaller than 200 nanometers, a size at which nanoparticles intrinsically home to tumors through the enhanced permeability and retention effect (EPR). GemNanos were taken up by human pancreatic cancer cells and demonstrated sustained release of the active agent, resulting in complete cell death after 6 days, which surpassed the cytotoxic effect of free Gemcitabine, thus demonstrating the validity of nanotherapeutics for pancreatic cancer. However, clinical and experimental data indicates that Gemcitabine administration alone is not efficient to treat pancreatic cancer in the long term, indicating that potentiating Gemcitabine's effect with another drug would be an ideal treatment option. As a second generation therapeutic, we hence used a mini-library of small molecule inhibitors to determine the best agent to couple with Gemcitabine. Our results indicate that AKT/mTOR, DNA intercalating agents and receptor tyrosine kinase (RTK) inhibitors show the most promise. Additionally, we have determined that a spatiotemporal approach, where both drugs are combined within the same nanovector but released at different times, is the most efficient way to target cancer. Strikingly, our results show for the first time that first releasing Gemcitabine for 6 hours predisposes pancreatic cancer cells to the cytotoxic effect of the second drug, whereas this effect is lost when longer time-spans between both drug are used. Our results open the door for novel nanotherapeutics to treat this deadliest of cancer, and further demonstrate the importance of using engineering approaches that focus on deciphering optimal drug permutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3706.