Novel Delivery Method Repurposes Existing Drug to Treat Liver Cancer
An interdisciplinary collaboration between prominent academic and industry investigators discovered a novel method for repositioning an FDA-approved anticancer compound so it can specifically target liver cancer tumors. The triple-attack technique combines chemotherapy, thermal ablation, and hyperthermia in a highly targeted, yet minimally invasive approach.
"In this study, we repurposed the topical agent bexarotene (Targretin), currently in limited use for cutaneous manifestations of T-cell lymphomas, and re-engineered it for use in solid tumor applications by forming self-assembling nanobubbles," explained Dipanjan Pan, PhD, FRSC, assistant professor of bioengineering at the University of Illinois at Urbana-Champaign, who led the study.
"These tiny bubbles filled with Targretin in prodrug form can be popped to release the drug inside liver cancer cells, activating the prodrug during cellular internalization process. The probability of its undesired systemic release is minimal due to this highly selective activation mechanism, which helps to spare the healthy cells."
The American Cancer Society estimates approximately 1.66 million new cancers will be diagnosed in the United States by the end of 2015, and that number is even higher when global statistics are taken into consideration. Developing new cancer-treatment drugs through a conventional drug discovery pipeline is time-consuming and expensive. One solution is to repurpose drugs already approved for use in human to treat disease.
"Liver cancer is normally difficult to attack and usually requires significant surgical intervention," stated Santosh Misra, PhD, a postdoctoral research associate in Pan's laboratory and first author of the paper (ACS Nano. doi:10.1021/acsnano.5b05974).
"In this study, we successfully repurposed and repackaged bexarotene into a sensitive nanobubble form, inserted it directly into the tumor using a flexible catheter, and used ultrasound ablation therapy to pop the bubbles to release the agent."
The university researchers worked with the biomedical company Acoustic MedSystem to apply a newly designed catheter-based ultrasound therapeutic device with spatially tracked 3D ultrasound imaging.
"Using an in vitro model of hepatocellular carcinoma and an in vivo large animal model of liver ablation, we demonstrated the effectiveness of bexarotene prodrug nanobubbles when used in conjunction with catheter-based ultrasound, thereby highlighting the therapeutic promise of this trimodal approach," Pan added.
"Using a swine cancer model for drug screening is rare, providing us a great opportunity to study this new class of therapeutic nanobubble in a preclinical system closer to human. Furthermore, the study uniquely looks at the system from atomic to molecular to cell, tissue, and then organ level. With this result in hand, the next step could be to test them in humans!"