Endovascular Ion Exchange Chemofiltration Device Reduces Off-Target Doxorubicin Exposure in a Hepatic Intra-arterial Chemotherapy Model

Abstract

Purpose: To determine if endovascular chemofiltration with an ionic device (ChemoFilter [CF]) can be used to reduce systemic exposure and off-target biodistribution of doxorubicin (DOX) during hepatic intra-arterial chemotherapy (IAC) in a preclinical model.

Materials and methods: Hepatic IAC infusions were performed in six pigs with normal livers. Animals underwent two 10-minute intra-arterial infusions of DOX (200 mg) into the common hepatic artery. Both the treatment group and the control group received initial IAC at 0 minutes and a second dose at 200 minutes. Prior to the second dose, CF devices were deployed in and adjacent to the hepatic venous outflow tract of treatment animals. Systemic exposure to DOX was monitored via blood samples taken during IAC procedures. After euthanasia, organ tissue DOX concentrations were analyzed. Alterations in systemic DOX exposure and biodistribution were compared by using one-tailed t tests.

Results: CF devices were well tolerated, and no hemodynamic, thrombotic, or immunologic complications were observed. Animals treated with a CF device had a significant reduction in systemic exposure when compared with systemic exposure in the control group (P <.009). Treatment with a CF device caused a significant decrease in peak DOX concentration (31%, P <.01) and increased the time to maximum concentration (P <.03). Tissue analysis was used to confirm significant reduction in DOX accumulation in the heart and kidneys (P <.001 and P <.022, respectively). Mean tissue concentrations in the heart, kidneys, and liver of animals treated with CF compared with those in control animals were 14.2 μg/g ± 1.9 (standard deviation) versus 26.0 μg/g ± 1.8, 46.4 μg/g ± 4.6 versus 172.6 μg/g ± 40.2, and 217.0 μg/g ± 5.1 versus 236.8 μg/g ± 9.0, respectively. Fluorescence imaging was used to confirm in vivo DOX binding to CF devices.

Conclusion: Reduced systemic exposure and heart bioaccumulation of DOX during local-regional chemotherapy to the liver can be achieved through in situ adsorption by minimally invasive image-guided CF devices.© RSNA, 2019.

Figure 1a:

In vitro flow model experiments. (a) Graph shows doxorubicin (DOX) filtration over the course of 60 minutes from porcine whole blood (0.05 mg/mL DOX) (n = 6). Data are presented as mean ± standard deviation. (b, c) Photographs of the ChemoFilter device before (b) and after (c) the flow model experiment.

Figure 1b:

In vitro flow model experiments. (a) Graph shows doxorubicin (DOX) filtration over the course of 60 minutes from porcine whole blood (0.05 mg/mL DOX) (n = 6). Data are presented as mean ± standard deviation. (b, c) Photographs of the ChemoFilter device before (b) and after (c) the flow model experiment.

Figure 1c:

In vitro flow model experiments. (a) Graph shows doxorubicin (DOX) filtration over the course of 60 minutes from porcine whole blood (0.05 mg/mL DOX) (n = 6). Data are presented as mean ± standard deviation. (b, c) Photographs of the ChemoFilter device before (b) and after (c) the flow model experiment.

Figure 2:

Experimental protocol for blood and tissue sampling in vivo. The animals in each experimental group underwent a 10-minute intra-arterial infusion of doxorubicin (DOX) (2 mg/mL, 100 mL) at 0 and 120 minutes. Prior to administration of the second dose of DOX in group 2, ChemoFilter (CF) devices were deployed. Blood samples were collected at various timepoints during each treatment for pharmacokinetic analysis. After treatment, the pigs were euthanized and tissue analysis was performed. IAC = intraarterial chemotherapy.

Figure 3a:

ChemoFilter (CF) device deployment in vivo. (a) Schematic drawing of CF devices in place during local-regional treatment of the liver during intra-arterial chemotherapy (IAC). As doxorubicin (DOX) is being infused into the hepatic artery, the CF devices are placed in the venous outflow of the liver. (b) Fluoroscopic image of the in vivo experiments showing deployed CF devices placed in the hepatic vein and inferior vena cava during IAC. Black arrows = distal markerband of CF, white arrow = IAC infusion catheter. Note that gastroduodenal artery has been embolized with coils (yellow arrow) to prevent redirection of DOX away from the liver during IAC.

Figure 3b:

ChemoFilter (CF) device deployment in vivo. (a) Schematic drawing of CF devices in place during local-regional treatment of the liver during intra-arterial chemotherapy (IAC). As doxorubicin (DOX) is being infused into the hepatic artery, the CF devices are placed in the venous outflow of the liver. (b) Fluoroscopic image of the in vivo experiments showing deployed CF devices placed in the hepatic vein and inferior vena cava during IAC. Black arrows = distal markerband of CF, white arrow = IAC infusion catheter. Note that gastroduodenal artery has been embolized with coils (yellow arrow) to prevent redirection of DOX away from the liver during IAC.

Figure 4a:

Blood concentration–time profiles of doxorubicin during in vivo experiments. ChemoFilter (CF) devices decrease peak doxorubicin (DOX) concentration and reduce the area under the curve for drug exposure. The graphs compare profiles of DOX during the first (blue) and second (red) intra-arterial chemotherapy (IAC) infusions for (a) group 1 (IAC vs IAC, n = 3) and (b) group 2 (IAC vs IAC and CF, n = 3). Data are mean ± standard deviation.

Figure 4b:

Blood concentration–time profiles of doxorubicin during in vivo experiments. ChemoFilter (CF) devices decrease peak doxorubicin (DOX) concentration and reduce the area under the curve for drug exposure. The graphs compare profiles of DOX during the first (blue) and second (red) intra-arterial chemotherapy (IAC) infusions for (a) group 1 (IAC vs IAC, n = 3) and (b) group 2 (IAC vs IAC and CF, n = 3). Data are mean ± standard deviation.

Figure 5:

The ChemoFilter (CF) device reduces accumulation of doxorubicin (DOX) in off-target organs. Bar graph shows mean DOX concentrations in organs in groups 1 (IAC + IAC) and 2 (IAC + IAC with CF). Significant decreases in DOX accumulation were observed in all off-target organs (kidneys and heart) in animals treated with CF devices compared with control animals. Data are mean ± standard deviation.

Figure 6a:

In situ doxorubicin (DOX) adsorption by the ChemoFilter (CF) device. (a) Schematic depicting in vivo DOX binding by CF device positioned adjacent to hepatic venous drainage. Prior to euthanasia, CF devices were retrieved through the jugular sheath and were washed with phosphate-buffered saline to remove adsorbed biomolecules. CF devices were viewed with a wide-field fluorescence microscope, and the fluorescence was used to detect DOX (red). Scale bars = 2 mm. (b) Distribution of filtered DOX (red) on CF devices relative to the hepatic venous outflow was observed (left side of image in b is equivalent to the cranial side in a). Enhanced DOX binding onto CF when positioned closer to the hepatic confluence. (c) Fluorescence microscopy was used to confirm DOX binding to strong acid cation ion exchange resin beads within the nylon sac. IVC = interior vena cava.

Figure 6b:

In situ doxorubicin (DOX) adsorption by the ChemoFilter (CF) device. (a) Schematic depicting in vivo DOX binding by CF device positioned adjacent to hepatic venous drainage. Prior to euthanasia, CF devices were retrieved through the jugular sheath and were washed with phosphate-buffered saline to remove adsorbed biomolecules. CF devices were viewed with a wide-field fluorescence microscope, and the fluorescence was used to detect DOX (red). Scale bars = 2 mm. (b) Distribution of filtered DOX (red) on CF devices relative to the hepatic venous outflow was observed (left side of image in b is equivalent to the cranial side in a). Enhanced DOX binding onto CF when positioned closer to the hepatic confluence. (c) Fluorescence microscopy was used to confirm DOX binding to strong acid cation ion exchange resin beads within the nylon sac. IVC = interior vena cava.

Figure 6c:

In situ doxorubicin (DOX) adsorption by the ChemoFilter (CF) device. (a) Schematic depicting in vivo DOX binding by CF device positioned adjacent to hepatic venous drainage. Prior to euthanasia, CF devices were retrieved through the jugular sheath and were washed with phosphate-buffered saline to remove adsorbed biomolecules. CF devices were viewed with a wide-field fluorescence microscope, and the fluorescence was used to detect DOX (red). Scale bars = 2 mm. (b) Distribution of filtered DOX (red) on CF devices relative to the hepatic venous outflow was observed (left side of image in b is equivalent to the cranial side in a). Enhanced DOX binding onto CF when positioned closer to the hepatic confluence. (c) Fluorescence microscopy was used to confirm DOX binding to strong acid cation ion exchange resin beads within the nylon sac. IVC = interior vena cava.