oncology

Size Matters for Particles in Bloodstream

UConn Engineering Professor’s Findings Could Mean More Effective Cancer Drugs

UConn researchers used a fluorescence microscope to illuminate a microfluidic device that simulates a blood vessel to observe and measure how particles of different sizes behave in the bloodstream.

UConn researchers used a fluorescence microscope to illuminate a microfluidic device that simulates a blood vessel to observe and measure how particles of different sizes behave in the bloodstream. Their findings could aid the development of more effective cancer drugs. Photo: Anson Ma


A UConn engineering professor has uncovered new information about how particles behave in our bloodstream, an important advancement that could help pharmaceutical scientists develop more effective cancer drugs.

Making sure cancer medications reach the leaky blood vessels surrounding most tumor sites is a critical aspect of treatment and drug delivery. While surface chemistry, molecular interactions, and other factors come into play once drug-carrying particles arrive at a tumor, therapeutic medication doesn’t do much good if it never reaches its intended target.

Anson Ma, assistant professor of chemical and biomolecular engineering, used a microfluidic channel device to observe, track, and measure how individual particles behaved in a simulated blood vessel.

Ma says he wanted to learn more about the physics influencing a particle’s behavior as it travels in human blood, and to determine which particle size might be the most effective for delivering drugs to their targets. His experimental findings mark the first time such quantitative data has been gathered. The study appeared in the Oct. 4, 2016 issue of the Biophysical Journal.

Using a fluorescence microscope, Ma was able to see particles moving in the simulated blood vessel in what could be described as a vascular “Running of the Bulls.” Red blood cells race through the middle of the channel as the particles — highlighted under the fluorescent light — get carried along in the rush, bumping and bouncing off the blood cells until they are pushed to open spaces, called the cell-free layer, along the vessel’s walls.

What Ma found was that larger particles — the optimum size appeared to be about 2 microns — were most likely to get pushed closer to the blood vessel wall, where their chances of carrying medication into a tumor site are greatest. The research team also determined that 2 microns was the largest size that should be used if particles are going to have any chance of going through the leaky blood vessel walls into the tumor site.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, reducing the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

“When it comes to using particles for the delivery of cancer drugs, size matters,” Ma says. “When you have a bigger particle, the chance of it bumping into blood cells is much higher, there are a lot more collisions, and they tend to get pushed to the blood vessel walls.”

The results were somewhat surprising. In preparing their hypothesis, the research team estimated that smaller particles were probably the most effective since they would move the most in collisions with blood cells, much like what happens when a small ball bounces off a larger one. But just the opposite proved true. The smaller particles appeared to skirt through the mass of moving blood cells and were less likely to experience the “trampoline” effect and get bounced to the cell-free layer, says Ma.

Ma proposed the study after talking to a UConn pharmaceutical scientist about drug development at a campus event five years ago.

“We had a great conversation about how drugs are made and then I asked, ‘But how can you be sure where the particles go?’” Ma recalls, laughing. “I’m an engineer. That’s how we think. I was curious. This was an engineering question. So I said, ‘Let’s write a proposal!’”

The proposal was funded by the National Science Foundation’s Early-concept Grants for Exploratory Research, or EAGER, program, which supports exploratory work in its early stages on untested, but potentially transformative, research ideas or approaches.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, Ma says, which in turn will further reduce the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

The findings were particularly meaningful for Ma, who lost two of his grandparents to cancer and who has long wanted to contribute to cancer research in a meaningful way as an engineer.

The results may also be beneficial in bioimaging, where scientists and doctors want to keep particles circulating in the bloodstream long enough for imaging to occur. In that case, smaller particles would be better, says Ma.

Moving forward, Ma would like to explore other aspects of particle flow in the circulatory system, including how particles behave when they pass through a constricted area, such as from a blood vessel to a capillary. Capillaries are only about 7 microns in diameter. The average human hair is 100 microns.

“We have all of this complex geometry in our bodies,” says Ma. “Most people just assume there is no impact when a particle moves from a bigger channel to a smaller channel because they haven’t quantified it. Our plan is to do some experiments to look at this more carefully, building on the work that we just published.”

Melanoma Patients Benefit from New Immunotherapy Drug

Microscopic view of a histology specimen of melanoma on human skin tissue

Microscopic view of a histology specimen of melanoma on human skin tissue.


Patients with advanced melanoma are benefiting from the same drug credited recently with the disappearance of the disease in former President Jimmy Carter.

Physicians with UConn Health’s Carole and Ray Neag Comprehensive Cancer Center are successfully boosting the immune system of some of their advanced melanoma patients with a new, promising immunotherapy tool called Keytruda (pembrolizumab).

The drug was granted accelerated FDA approval in September 2014 for the treatment of melanoma patients who no longer respond to other drug treatments and are not candidates for surgery.

Melanoma is one of the deadliest types of skin cancer. If not detected early and removed from the skin, it can spread deep into the skin and to the body’s other organs, such as the lungs, liver, and brain. It is often fatal.

“Melanoma affects the young and the old, and its incidence is on the rise,” says Dr. Upendra P. Hegde, associate professor in the Department of Medicine, and chief medical oncologist for melanoma and cutaneous oncology and head and neck cancer/oral oncology at UConn Health. More than 75,000 people are diagnosed with melanoma annually, and nearly 10,000 Americans die from it each year.

Hegde says melanoma spreads quickly because tumors evade the immune system’s attack by expressing proteins called PD-L1 and PD-L2 (program death ligand 1 and 2), compromising the ability of a person’s T-cells to fight cancer.

However, Keytruda boosts a patient’s immune system, helping it fight back and preventing the cancer-fighting cells from becoming exhausted.

“Keytruda is the first PD-1 inhibitor drug that is allowing us to shrink the melanoma tumors in up to 35 percent of our UConn Health patients,” says Hegde.

Since not all advanced melanoma patients respond to current available drug therapies including Keytruda, UConn Health researchers are participating in two clinical trials that combine Keytruda with other therapy options. One, called INCYTE and led by principal investigator Dr. Jeffrey Wasser, is testing the efficacy of combining Keytruda with another immunotherapy drug known as an IDO1 inhibitor (INCB024360) to see if together they can enhance the immune system’s response to advanced melanoma and other solid-tumor cancers. A second trial is testing the possible benefits of Keytruda with standard chemotherapy for relapsed head and neck cancer.

UConn Health’s multidisciplinary melanoma team includes Dr. Jane Grant-Kels and Dr. Philip Kerr of dermatology, Hegde of medical oncology, and Dr. Bruce Brenner, a surgeon who specializes in melanoma, among others.

Close at Heart

By Kim Kreiger
Illustration by Yesenia Carrero

Radiation treatment for breast cancer can inadvertently graze the heart, leading to damage and disease years later. UConn doctors are working to change that.

closeatheart


Getting radiation treatment for breast cancer can make you feel vulnerable. Sitting in a machine with radiation pointed directly at your chest, you have to trust that the doctor knows what she’s doing, that the X-rays are aimed right, that the machine is properly calibrated … and then you just sit perfectly still.

But what if you could have some control over the process?

Dr. Robert Dowsett, chief of UConn’s Division of Radiation Oncology, and
colleagues in the Carole and Ray Neag Comprehensive Cancer Center are using a new technique to give breast cancer patients agency in their radiation treatments. And they’re taking better care of the patients’ hearts in the process.

A patient can intentionally increase the heart-chest wall distance by more than a centimeter by controlling her breathing using the Deep Inspiration Breath Hold.

Using the technique, called Deep Inspiration Breath Hold, patients can help control the accuracy and timing of their own radiation dose. The patient takes a breath of specific depth before the radiation machine turns on. Doing this correctly can increase the distance between the heart and the breast by a centimeter or two, lowering the amount of radiation hitting the heart by as much as 50 percent.

Jeryl Dickson, 62, of Manchester, Conn., was one of the first patients at UConn Health to use the technique, from late 2015 through Feb. 2. Her doctors, including Dowsett, prescribed a course of radiation therapy to make sure there were no lingering cancer cells remaining after a lumpectomy removed her breast cancer.

“I practiced deep breathing and breath holds prior to radiation treatment with the radiation oncology staff so I could feel what it would be like,” says Dickson.

Radiation treatment of breast cancer can be very effective, eradicating tumor cells hiding in the chest wall. But breast cancer survivors have a heightened risk of heart disease that shows itself years later. Ironically, the heart disease stems from the radiation that originally saved their lives. Radiation is a type of light, and like visible light, it has a tendency to reflect and scatter. Just as even the sharpest spotlight has blurred edges where it blends into shadow, even the best-aimed medical radiation beam occasionally scatters into tissue outside of the tumor it targets. Sometimes it hits the heart.

Dr. Agnes Kim, director of the Cardio-Oncology Program at UConn Health, analyzes echocardiography images as one way to monitor cancer patients’ risk of heart disease.

Dr. Agnes Kim, director of the Cardio-Oncology Program at UConn Health, analyzes echocardiography images as one way to monitor cancer patients’ risk of heart disease.
Tina Encarnacion/UConn Health Photo

“We worry about heart attacks down the road, 10 to 15 years after radiation treatment of cancer in the chest. We also worry about inflammation on the outside of the heart in the short term. We don’t exactly know how the radiation damages the tissue, but it definitely seems to accelerate damage to blood vessels. It can also cause scarring and fibrosis damage,” says Dowsett.

But the distance between the heart and the chest wall varies from person to person. And a patient can intentionally increase the heart-chest wall distance by controlling her breathing using the Deep Inspiration Breath Hold.

To make the best use of the Deep Inspiration Breath Hold technique, Dowsett and his colleagues at UConn Health combine it with an optical scanning system supplied by C-RAD. The scanning system is essentially a computer with a camera that models the surface of the skin on the patient’s chest. It tracks the patient’s breathing, and coaches her to inhale just the right amount. As the patient, you wear virtual-reality goggles in which you see a bar graph showing your inhalation, with a box at the top. Your goal is to hit the box and then hold your breath for the 20 to 30 seconds it takes to complete the radiation treatment. Some patients can hold their breath that long; others can’t. It doesn’t matter, because if you exhale, or giggle, or cough, the system sees your chest move out of the perfect range and stops the radiation. It won’t restart until you get yourself back in position and inhale to just the right spot again.

“The deep breathing technique was not difficult at all,” says Dickson, “Honestly, I was more focused on my cancer, and heart health never entered my mind. But I am glad I put my trust in my doctors, and I never had any doubts.”

UConn Health is the only hospital using this technology in Central Connecticut. It’s a powerful, precise way to make sure the radiation beam gets the cancer, and to minimize the risk to other organs.

Previously, “the area we treated inevitably ended up being bigger than the target (tumor) itself,” Dowsett says. “Now we’ve expanded this to abdominal targets such as the pancreas and adrenal lesions,” while sparing healthy surrounding organs.