Pressure-enabled delivery of gemcitabine in an orthotopic pancreatic cancer mouse model.

Abstract

BACKGROUND:

We describe the use of pancreatic retrograde venous infusion in an orthotopic murine model of pancreatic ductal adenocarcinoma and hypothesize that pancreatic retrograde venous infusion delivery of gemcitabine will increase concentrations of gemcitabine in the tumor and the subsequent tumor response to treatment.

METHODS:

Murine pancreatic ductal adenocarcinoma (KPC4580P) was transplanted onto the pancreatic tail of C57BL/6J mice. Groups (n = 15) of mice were assigned to sham laparotomy and 100 mg/kg intraperitoneal infusion of gemcitabine (systemic gemcitabine), pancreatic venous isolation with pancreatic retrograde venous infusion of 100 mg/kg gemcitabine, or pancreatic retrograde venous infusion with saline infusion. Tumor pressures were recorded during pancreatic retrograde venous infusion. Mice were killed at 1 hour or 7 days after infusion.

RESULTS:

Baseline tumor pressures were 45 ± 8 mm Hg, and pancreatic retrograde venous infusion increased tumor pressures by 29 ± 6 mm Hg (P < .01). Pancreatic retrograde venous infusion gemcitabine mice had greater tumor gemcitabine concentrations compared with systemic gemcitabine (127 vs 19 ng/mg; P < .01) and lesser tumor volumes compared with both systemic gem and pancreatic retrograde venous infusion with saline (274 vs 857 vs 629 mm3; P < .01).

CONCLUSION:

Pancreatic retrograde venous infusion increased tumor pressures greater than baseline, improved gemcitabine delivery, and increased the treatment response. These findings suggest that pressurized, regional delivery overcomes the increased pressure barrier in pancreatic ductal adenocarcinoma. Additional preclinical studies with cytotoxic and immunotherapeutic agents and clinical trials using pressure-enabled drug delivery with pancreatic retrograde venous infusion devices are underway.

• Authors: Jayanth S Shankara Narayanan, Diego A Vicente, Partha Ray, Louis F Chai, Suna Erdem, Matthew J Carr, Benedict A Capacio, Bryan F Cox, David B Jaroch, Steven C Katz, Rebekah R White
• Journal: Surgery (Surgery) Vol. 168 Issue 3 Pg. 448-456 (09 2020) ISSN: 1532-7361 [Electronic] United States
• PMID: 32620306 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antimetabolites, Antineoplastic
• Deoxycytidine
• Gemcitabine

Topics

• Animals
• Antimetabolites, Antineoplastic (administration & dosage, pharmacokinetics)
• Carcinoma, Pancreatic Ductal (drug therapy, pathology)
• Cell Line, Tumor (transplantation)
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacokinetics)
• Disease Models, Animal
• Humans
• Infusions, Intralesional (methods)
• Infusions, Intravenous (methods)
• Male
• Mice
• Pancreas (blood supply, pathology)
• Pancreatic Neoplasms (drug therapy, pathology)
• Pressure
• Tissue Distribution
• Gemcitabine