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

Abstract

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 intraarterial 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 mg/g 6 1.9 (standard deviation) versus 26.0 mg/g 6 1.8, 46.4 mg/g 6 4.6 versus 172.6 mg/g 6 40.2, and 217.0 mg/g 6 5.1 versus 236.8 mg/g 6 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.

Progress in Natural Compounds/siRNA Co-delivery Employing Nanovehicles for Cancer Therapy

“…It suppresses malignancy and proliferation of cancer cells via inhibition of DNA topoisomerases, DNA intercalation, and free radical generation . Despite its excellent antitumor activity, DOX adversely affects normal cells because of its off-targeting feature. , This has resulted in using nanoplatforms for the targeted delivery of DOX . In addition, cancer cells are capable of developing resistance against DOX chemotherapy .…”

“…122 Despite its excellent antitumor activity, DOX adversely affects normal cells because of its off-targeting feature. 123,124 This has resulted in using nanoplatforms for the targeted delivery of DOX. 125 In addition, cancer cells are capable of developing resistance against DOX chemotherapy.…”

Multi-Physics Modeling of Doxorubicin Binding to Ion-Exchange Resin in Blood Filtration Devices

“…Dox is positively charged and, therefore, can be filtered from blood by binding to an ionic resin via ionexchange mechanism in order to reduce systemic toxicity caused by the IAC. A catheter-based Chemofilter device was proposed for eliminating Dox from the venous flow after it has had its effect on the malignant cells of the tumor 1,[4][5][6][7][8][9][10] . The Chemofilter deployed during the IAC procedure in veins draining the tumor would adsorb the drug to its surface coated with ionic resin, thus allowing for safer and more efficient treatment.…”

Multi‐physics modeling of doxorubicine binding to ion‐exchange resin in blood filtration devices

“…Dox is positively charged and, therefore, can be filtered from blood by binding to an ionic resin via ion‐exchange mechanism in order to reduce systemic toxicity caused by the IAC. A catheter‐based Chemofilter device was proposed for eliminating Dox from the venous flow after it has had its effect on the malignant cells of the tumor 1,4‐10 . The Chemofilter deployed during the IAC procedure in veins draining the tumor would adsorb the drug to its surface coated with ionic resin, thus allowing for safer and more efficient treatment.…”

“…A catheter-based Chemofilter device was proposed for eliminating Dox from the venous flow after it has had its effect on the malignant cells of the tumor. 1,[4][5][6][7][8][9][10] The Chemofilter deployed during the IAC procedure in veins draining the tumor would adsorb the drug to its surface coated with ionic resin, thus allowing for safer and more efficient treatment.…”