For cancer patients, the antitumor power of chemotherapeutic drugs is a double-edged sword. Although many cancer drugs kill tumor cells, they can also harm healthy cells when they travel through the bloodstream.
A major limitation of chemotherapy agents is that only a tiny fraction gets to their targeted tumor. As a result, there are side effects that include heart damage.”
Dieter Haemmerich, Ph.D., D.Sc., Professor, Darby Child Research Institute, Department of Pediatrics, Medical University of South Carolina
But what if you could “clean” the blood of chemotherapy drugs to reduce their harmful side effects?
In an article published in March 2022 in the journal Cancer, an MUSC research team led by Haemmerich reported that they had developed a device to remove excess chemotherapeutic drugs from circulation after cancer treatment. Using this device, the team removed 30% of the administered drug one hour after treatment. Seed funding to develop the device was provided by a High Innovation – High Reward grant from the South Carolina Institute for Clinical and Translational Research Pilot Project Program.
Haemmerich and colleagues, including Katherine Twombley, MD, professor in the MUSC Department of Pediatrics, Division of Pediatric Nephrology, focused on doxorubicin (DOX), which is one of the most widely used chemotherapy drugs in adults. and children.
DOX is also known to be toxic to the heart. This toxicity is particularly detrimental in pediatric patients, as any resulting heart failure will have negative health effects for the rest of the child’s life. In a 2006 clinical trial, DOX reduced heart function in children with leukemia and corticosteroid therapy was required to reduce its adverse effects.
Despite its toxicity to the heart, DOX is a popular chemotherapy drug because it is very effective in preventing cancer cells from dividing.
“Doxorubicin works by essentially damaging DNA,” said Yuri Peterson, Ph.D., associate professor in the Department of Drug Discovery and Biomedical Sciences at MUSC College of Pharmacy and author of the paper. “It’s useful for treating cancer, but it can also cause off-target side effects like hair loss and bone marrow loss.”
Recent efforts to more precisely target DOX to the tumor site have included its encapsulation inside temperature-sensitive nanoparticles. These tiny particles are intact at normal body temperature and carry the drug through the blood to the tumor. There they can be heated with a probe to around 105 degrees Fahrenheit to release their DOX cargo.
However, the technique has its own limitations. Only a fraction of the administered nanoparticles release their cargo when heat is applied to the tumor site. Once the nanoparticles break down in the body, which can take as little as an hour, the remaining drug enters the bloodstream and can then cause side effects.
The MUSC research team wanted to improve results with this technique by developing a device that would remove remnants of DOX after treatment.
Using a rodent cancer model, the researchers injected the heat-sensitive DOX nanoparticles and applied heat to the tumor site to release the DOX. After treatment, they cleaned the blood of remnants of DOX by first passing it through a heating element for the nanoparticles to release the drug, then through an activated carbon filter to remove the drug from the blood before it is returned to the rodent circulation.
Marissa Wolfe, DVM, associate professor in the Department of Comparative Medicine at MUSC, was instrumental in developing surgical methods to implant catheters into the small vessels of rodents to allow blood to pass through the filtration device.
Krishna Ramajayam, Ph.D., a postdoctoral fellow in Haemmerich’s lab in MUSC’s Division of Pediatric Cardiology, designed the heating element in the filtration device and supported imaging studies to monitor the release and filtration of medications.
“Since the device is computer-controlled, you can have very precise heating to make sure the drug is released,” Ramajayam said. “The most exciting part for me is both the administration and the withdrawal of the drug, which will significantly improve the quality of life of patients.”
Importantly, the team also developed a method to detect drug levels in the blood in real time to ensure that the drug is effectively eliminated.
“By imaging the blood before and after filtration, we can actually predict the amount of drug removed in real time in the clinic,” said Anjan Motamarry, Ph.D., who completed work on the study as he was a doctoral student in Haemmerich’s laboratory. before moving on to industrial employment. “This would be very useful information for a clinician who had to decide when to stop filtration.”
Reducing patients’ exposure to leftover chemotherapy drugs could allow them to recover faster, with fewer side effects. It could also allow them to receive more cycles of chemotherapy in the future in case additional treatment is needed to kill the cancer cells.
“Each drug has a maximum tolerated dose that you cannot exceed,” Motamarry said. “Since we remove the remaining drug after treatment, you can actually give an extra dose if the first cycle isn’t enough, which wouldn’t be possible if the drug wasn’t removed.”
Filtering blood through the device also led to nearly three times less DOX in the heart, as measured by mass spectrometry at the MUSC Drug Discovery Core. Peterson and Thomas Benton, Ph.D., who was a doctoral student at MUSC at the time of the study, performed the measurements.
These promising results suggest that the new device may reduce cardiac side effects that can be caused by chemotherapy, but more studies will be needed to confirm this promise.
“If you deliver less of the drug to the heart, you’ll likely have fewer side effects,” Haemmerich said. “Our next step is to test heart function directly after using this method in long-term animal tumor studies.”
Further improvements to their device could one day improve the effectiveness and safety of chemotherapy in children and adults.
“It’s really hard for anyone to go through chemotherapy,” Motamarry said. “It’s the least we can do to make it easier for them.”
Medical University of South Carolina
Motamarry, A. et al. (2022) Extracorporeal removal of heat-sensitive liposomal doxorubicin from the systemic circulation after tumor delivery to reduce toxicities. Cancer. doi.org/10.3390/cancers14051322.