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Research Papers

Development and Validation of Endovascular Chemotherapy Filter Device for Removing High-Dose Doxorubicin: Preclinical Study

[+] Author and Article Information
Anand S. Patel

Department of Radiology and Biomedical Imaging,
University of California San Francisco,
185 Berry Street, Suite 350,
San Francisco, CA 94107-5705
e-mail: anand.patel@ucsf.edu

Maythem Saeed, Erin J. Yee, Jeffrey Yang, Gregory J. Lam, Aaron D. Losey, Prasheel V. Lillaney, Bradford Thorne, Mark W. Wilson, Steven W. Hetts

Department of Radiology and Biomedical Imaging,
University of California San Francisco,
San Francisco, CA 94107

Albert K. Chin, Sheena Malik

ChemoFilter, Inc.,
645 Woodstock Road,
Hillsborough, CA 94010

Xi C. Chen

Materials Sciences Division,
Lawrence Berkeley National Laboratory,
Berkeley, CA 94720

Nitash P. Balsara

Materials Sciences Division,
Lawrence Berkeley National Laboratory,
Berkeley, CA 94720;
Environmental Energy Technologies Division,
Lawrence Berkeley National Laboratory,
Berkeley, CA 94720;
Department of Chemical and
Biomolecular Engineering,
University of California,
Berkeley, CA 94720

1Corresponding author.

Manuscript received November 12, 2013; final manuscript received April 3, 2014; published online xx xx, xxxx. Assoc. Editor: Rupak K. Banerjee.

J. Med. Devices 8(4), 041008 (Aug 19, 2014) (8 pages) Paper No: MED-13-1275; doi: 10.1115/1.4027444 History: Received November 12, 2013; Revised April 03, 2014

To develop a novel endovascular chemotherapy filter (CF) able to remove excess drug from the blood during intra-arterial chemotherapy delivery (IAC), thus preventing systemic toxicities and thereby enabling higher dose IAC. A flow circuit containing 2.5 mL of ion-exchange resin was constructed. Phosphate-buffered saline (PBS) containing 50 mg doxorubicin (Dox) was placed in the flow model with the hypothesis that doxorubicin would bind rapidly to resin. To simulate IAC, 50 mg of doxorubicin was infused over 10 min into the flow model containing resin. Similar testing was repeated with porcine serum. Doxorubicin concentrations were measured over 60 min and compared to controls (without resin). Single-pass experiments were also performed. Based on these experiments, an 18F CF was constructed with resin in its tip. In a pilot porcine study, the device was deployed under fluoroscopy. A control hepatic doxorubicin IAC model (no CF placed) was developed in another animal. A second CF device was created with a resin membrane and tested in the infrarenal inferior vena cava (IVC) of a swine. In the PBS model, resin bound 76% of doxorubicin in 10 min, and 92% in 30 min (P<0.001). During IAC simulation, 64% of doxorubicin bound in 10 min and 96% in 60 min (P<0.001). On average, 51% of doxorubicin concentration was reduced during each pass in single pass studies. In porcine serum, 52% of doxorubicin bound in 10 min, and 80% in 30 min (P<0.05). CF device placement and administration of IAC were successful in three animals. No clot was present on the resin within the CF following the in vivo study. The infrarenal IVC swine study demonstrated promising results with up to 85% reduction in peak concentration by the CF device. An endovascular CF device was developed and shown feasible in vitro. An in vivo model was established with promising results supporting high-capacity rapid doxorubicin filtration from the blood that can be further evaluated in future studies.

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Figures

Grahic Jump Location
Fig. 1

In vitro flow model simulating TACE. 1 L of 0.05 mg/ml Dox solution was mixed and heated to 37 °C. The solution passed via a peristaltic pump through the resin cartridge.

Grahic Jump Location
Fig. 2

The CF catheter (left) and schematic illustrating intra-arterial chemotherapy delivery procedure (right). From a percutaneous femoral approach, a microcatheter is guided through the aorta into the arteries feeding a target in the liver to directly infuse Dox. From a percutaneous jugular approach, the CF device is guided through the SVC and deployed in the veins draining the liver.

Grahic Jump Location
Fig. 3

(a) Fluoroscopic image of the swine demonstrating the CF2 device in place with associated sampling catheters. (b) Photograph of the expanded CF2 device en-face. Notice 22 mm nitinol cage with polymer resin membrane sutured onto the cage. (c) Dox concentration versus time plot with the CF2 device in place during infusion of Dox within the infrarenal IVC. Notice an 85% difference in Dox concentration between prefilter and postfilter samples at 3 min during peak concentration suggesting binding from the CF2 device.

Grahic Jump Location
Fig. 4

Schematic of in vivo swine experiment with the CF2 device. The device was placed in the infrarenal IVC (below the RV and HV) from a jugular vein approach. Via access from the RCFV and LCFV, prefilter and postfilter sampling catheters were placed. A Dox infusion catheter was placed inferior to this. This configuration allows from determination of potential concentration drops due to the CF2 device.

Grahic Jump Location
Fig. 5

Flow experiment. A plot shows Dox (0.05 mg/ml) clearance from PBS over the course of 90 min in the flow model. The maximum clearance was 92% and reached at 30 min, suggesting that resin has been saturated. Data are presented as a mean ± SD, n = 6.

Grahic Jump Location
Fig. 6

IAC experiment. A plot shows Dox clearance over the course of 60 min. A dose of 50 mg Dox (0.05 mg/mL) was infused over the course of 10 min with (diamonds) and without filter (squares). Note the high rate of Dox binding to resin during infusion. Data are presented as a mean ± SD, n = 6.

Grahic Jump Location
Fig. 7

Serum experiment. A plot shows Dox (0.05 mg/mL) clearance from porcine serum over the course of 90 min. The maximum clearance was 84% at 45 min. Data are presented as a mean ± SD, n = 6.

Grahic Jump Location
Fig. 8

Single-pass experiment. The plot demonstrates that Dox concentration was reduced from 0.05 mg/ml to 0.0006 mg/ml (99% of initial drug mass reduced) after 6 single passes through the resin column without recirculation of solution. On average, Dox concentration was lowered by 51% during each pass.

Grahic Jump Location
Fig. 9

X-ray fluoroscopy demonstrates the establishment of the in vivo swine model. Top left image demonstrates introduction of device (18 French) through right jugular vein into the suprahepatic IVC. Top right image demonstrates the device tip in the suprahepatic IVC with guide wire securing access into the right hepatic vein. Bottom left image demonstrates a venogram through the device and the patency of hepatic veins and supra-hepatic IVC. Bottom right, a venogram demonstrates a filling defect in the suprahepatic IVC just inferior to the catheter tip after resin introduction into the catheter tip. Collateral flow to the heart is visualized through the azygos venous system.

Grahic Jump Location
Fig. 10

Blood smears obtained from peripheral blood (left, as a reference) and CF device resin (middle and right) at the conclusion of the in vivo study. Microscopic examination revealed lack of evidence of clot or thrombosis in the CF device resin. Bar = 200 μm.

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