Chemotherapy can be highly effective at treating cancer, but doctors often cannot prescribe the optimal cancer-killing dose due to systemic toxic side effects. When chemotherapy is administered to a cancerous organ via intra-arterial infusion, 50% to 80% of the drug generally does not remain in that organ. The excess passes on to the veins that drain the organ, entering the circulatory system, where it gets distributed to the rest of the body. Researchers from the University of California, Berkeley (UCB), the University of California, San Francisco (UCSF), and the University of North Carolina (UNC) Chapel Hill have now designed a potential solution to this problem: a 3D-printed sponge, or absorber, that prevents excess drug from entering the bloodstream.
The absorber is temporarily placed in the vein draining the target organ. "Surgeons snake a wire into the bloodstream and place the sponge like a stent, and just leave it in for the amount of time you give chemotherapy, perhaps a few hours," explained Nitash Balsara, PhD, Professor of Chemical and Biomolecular Engineering and the Charles W. Tobias Professor in Electrochemistry at UCB.
"An absorber is a standard chemical engineering concept," remarked Dr. Balsara, one of the senior authors of the study, which was published in ACS Central Science. "Absorbers are used in petroleum refining to remove unwanted chemicals such as sulfur. Literally, we've taken the concept out of petroleum refining and applied it to chemotherapy."
The researchers tested their device in three pigs with liver tumors by administering doxorubicin, a common chemotherapeutic agent. In humans, doxorubicin becomes more and more effective at killing cancer at increasingly high doses, but high doses are not often used because they can result in severe side effects such as irreversible cardiac failure.
The pigs received doxorubicin via intra-arterial infusion at a dosage that corresponded to a typical dose used in human patients for the treatment of hepatocellular carcinoma, a cancer of the liver. The investigators monitored doxorubicin concentrations over time using three blood-sampling catheters: a "pre-device" catheter, placed after the doxorubicin injection site but prior to the absorber; a "post-device" catheter, placed just after the absorber; and a third catheter, which was placed far from the doxorubicin injection site in order to measure the systemic concentration of the drug.
The researchers found that with both coated and uncoated absorbers, the doxorubicin capture rate ranged from 57% to 69%, with the coated absorbers exhibiting the higher rate.
The post-device doxorubicin concentrations were considerably lower than the pre-device concentrations, demonstrating that the absorbers effectively trapped the excess drug. In addition, the doxorubicin concentrations at the third catheter, the one located far from the injection site, increased only slightly, indicating that not much of the drug entered the circulatory system.
The researchers hope that the absorbers will be used in human patients soon. "This is a first level in vivo validation that yes, this device will bind up drug in the bloodstream," commented another of the study's senior authors, Stephen Hetts, MD, UCSF professor and Chief of Neurointerventional Radiology at UCSF Mission Bay Hospitals. "But extensive animal testing is not the next path; the next path is getting conditional approval from [the] FDA to do first-in-human studies, because it is much more realistic to test these in people who have cancer as opposed to continuing to test in young pigs who have otherwise healthy livers."
The researchers emphasize that this absorber is not only intended for liver cancer.
"We are developing this around liver cancer because it is a big public health threat—there are tens of thousands of new cases every year—and we already treat liver cancer using intra-arterial chemotherapy," stated Dr. Hetts, who first approached Dr. Balsara, seeking ways to remove drugs from the bloodstream. "But if you think about it, you could use this sort of approach for any tumor or any disease that is confined to an organ and you want to absorb the drug on the venous side before it can distribute and cause side effects elsewhere in the body. Ultimately, we would like to use this technology in other organs to treat kidney tumors and brain tumors."
In addition, the authors note in their study, this method could be modified to capture environmental contaminants, toxins resulting from bacterial infections, or cells themselves. As Dr. Hetts remarked, "We think this is a generally applicable concept."
For More Information
Oh HJ, Aboian MS, Yi MYJ, et al (2019). 3D printed absorber for capturing chemotherapy drugs before they spread through the body. ACS Cent Sci. [Epub ahead of print] DOI:10.1021/acscentsci.8b00700