INTRODUCTION. The majority of patients with pancreatic ductal adenocarcinoma (PDAC) succumb to the disease within 12-24 months from their diagnosis mainly due to the intrinsic chemorefractory behavior of this cancer. Chemoresistance is a multifactorial phenomenon, but it is thought that tumor hypovascularity and an excessive desmoplastic stroma reaction are the main contributors in PDAC. To overcome this inherent barrier to therapy, a pancreatobiliary drug-eluting device was built to provide a therapeutic platform for the localized delivery of high doses of anti-tumoral agents for effective cancer cell cytotoxicity.

MATERIALS AND METHODS. With the final goal of developing a pancreatobiliary drug-eluting stent, we designed a drug-delivery platform utilizing a 20% biodegradable polylactic-co-glycolic acid (PLGA) scaffold in which 400 μg of paclitaxel was embedded. This mixture was placed onto a 316 stainless steel disc as a uniform layer as verified by a scanning electron microscope that confirmed a homogeneous deposition (88.1 ± 1.9 μm) with minimal imperfections such as cracks or bubbles. This delivery system allowed us to tune precise dosing and release kinetics of paclitaxel. After an initial latency period of 12 days without significant paclitaxel release the device was able to deliver up to 85% of the encapsulated drug (360 ± 38 μg) in a linear fashion over the course of 40 days. The anti-tumoral effects of this new paclitaxel-eluting device (PED) were compared to systemic intravenous (IV) dosing of paclitaxel measuring the relative growth of two luciferase-transfected PDAC patient-derived cell lines, PDAC-3 and PDAC-6, orthotopically xenografted in NOD/SCID/gamma-c mice. Tumor were monitored by in vivo luciferase imaging and values obtained in relative light units (RLU). A multilevel mixed-effect models (two-way anova) was used to determine statistical significance.

RESULTS. For each cell line, PDAC-3 and PDAC-6, 100,000 cells were othotopically injected in 12 mice and mice were divided into two equal groups based on their preoperative tumor burden. All animals tolerated the insertion of paclitaxel-eluting devices without any evidence of postoperative complications, injuries to any abdominal organs, or postoperative device displacement inside the peritoneal cavity. Mice treated with the paclitaxel-eluting device compared to systemic therapy demonstrated a signiifcant reduction of relative tumor growth (%= day30 RLU/day 0 RLU) in PDAC-3 (12 fold reduction, IV= 343% ± 339%, PED= 29% ± 38%, p=0.02) and PDAC-6 (2 fold reduction, IV=14% ± 6%, PED = 7% ± 4%, p=0.003), respectively.

CONCLUSIONS. These results indicate that the paclitaxel-eluting device is safe and effective in overcoming the drug-delivery impairment observed with systemic chemotherapies and has relevant implications as a novel therapeutic platform to release current and future anti-tumoral agents to combat this deadly disease.

Note: This abstract was not presented at the meeting.

Citation Format: Matteo Ligorio, Laura Indolfi, David T. Ting, Kristina Xega, Nicola Aceto, Francesca Bersani, Cristina R. Ferrone, Daniel A. Haber, Robert Langer, Elazer R. Edelman, Jeffrey W. Clark. A novel drug-eluting platform for localized treatment of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4584. doi:10.1158/1538-7445.AM2014-4584