A Study Comparing the Effects of Targeted Intra-Arterial and Systemic Chemotherapy in an Orthotopic Mouse Model of Pancreatic Cancer

Abstract

Systemic chemotherapy is the first line treatment for patients with unresectable pancreatic cancer, however, insufficient drug delivery to the pancreas is a major problem resulting in poor outcomes. We evaluated the therapeutic effects of targeted intra-arterial (IA) delivery of gemcitabine directly into the pancreas in an orthotopic mouse model of pancreatic cancer. Nude mice with orthotopic pancreatic tumors were randomly assigned into 3 groups receiving gemcitabine: systemic intravenous (IV) injection (low: 0.3 mg/kg and high: 100 mg/kg) and direct IA injection (0.3 mg/kg). Treatments were administered weekly for 2 weeks. IA treatment resulted in a significantly greater reduction in tumor growth compared to low IV treatment. To achieve a comparable reduction in tumor growth as seen with IA treatment, gemcitabine had to be given IV at over 300x the dose (high IV treatment) which was associated with some toxicity. After 2 weeks, tumor samples from animals treated with IA gemcitabine had significantly lower residual cancer cells, higher cellular necrosis and evidence of increased apoptosis when compared to animals treated with low IV gemcitabine. Our study shows targeted IA injection of gemcitabine directly into the pancreas, via its arterial blood supply, has a superior therapeutic effect in reducing tumor growth compared to the same concentration administered by conventional systemic injection.

Comparison of regional arterial chemotherapy and systemic intravenous chemotherapy for advanced pancreatic cancer: a systematic review and meta-analysis

“…Tanaka et al [17] demonstrated that pancreatic arterial infusion chemotherapy produces higher regional drug concentrations in the pancreas. Rezaee et al's [14] study compared the effects of RAIC and SIC using an orthotopic mouse model of pancreatic cancer and found that RAIC significantly inhibited tumor growth. If the SIC regimen achieves the same results as RAIC, more than 300 times the dose of the drug must be used.…”

“…[13] In some animal experiments and clinical trials, the therapeutic effect of RAIC has obvious advantages. [14][15][16][17] RAIC may be a new idea to improve the prognosis of pancreatic cancer. This study aims to evaluate the role of RAIC in the treatment of advanced pancreatic cancer by comparing the effectiveness and safety of RAIC and SIC.…”

Management of Pancreatic Cancer and Its Microenvironment: Potential Impact of Nano-Targeting

“…New ideas are circulating in terms of how to target the delivery of chemotherapeutics innovatively and differently than what has been done before. One study suggests studying the combination of nanoparticle drug delivery systems with intra-arterial delivery systems [ 49 ]. Intra-arterial delivery has been studied separately from nano-targeted delivery but bringing the two together could provide an innovative answer for pancreatic cancer.…”

“…In a recent study using an orthotopic mouse model of pancreatic cancer, gemcitabine was delivered intra-arterially, and this suppressed tumor growth compared to dosing intravenously, which could result in poor patient outcomes due to significant toxicity. Intra-arterial delivery, however, can deliver a chemotherapeutic directly to the pancreas [ 49 ].…”

Precision Delivery of Human Bone Marrow-Derived Mesenchymal Stem Cells Into the Pancreas Via Intra-arterial Injection Prevents the Onset of Diabetes

“…Hence, in the present work, we will examine the delivery of BM-MSCs into a mouse model using modification of techniques that we have previously developed to locally deliver therapies into the pancreas. 29 , 30 We will deliver BM-MSCs at the onset of diabetes which we will coordinate at the same time of STZ injection into C57BL/6 mice.…”