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Laser-Based, Nanoparticle Platform Developed for Improving Identification of Melanoma CTCs


NEW YORK (360Dx) – A group of researchers led by the University of Arkansas has developed a photoacoustic (PA) platform called Cytophone to detect and destroy in vivo circulating tumor cells (CTCs) in patients with melanoma.

Spearheaded by Arkansas Nanomedicine Center lab director Vladimir Zharov, the team aims to commercialize the Cytophone technology through a startup within the next year.  

Clinicians usually identify cases of melanoma by identifying discolored spots on a patient's skin, followed by slicing off tissue that undergoes a pathology exam for additional diagnosis.

"Melanoma is a very aggressive malignancy, which is metastasized at a very early disease stage through release of cancer cells from a small primary tumor in circulation," Zharov explained. Indeed, once melanoma metastasizes to different organs, patients often have a low survival rate over a period of five to 10 years. "On the other hand, melanoma is a good target for non-invasive, label-free photoacoustic detection of melanoma CTCs because natural melanin in melanoma cells has a high contrast photoacoustic agent."

According to Zharov, his team has been developing Cytophone since 2003. The platform is based on a principle called in vivo photoacoustic flow cytometry (PAFC), which uses laser pulses to penetrate through intact skin and into blood vessels to track circulating cells and certain biomarkers.

To detect specific cells like melanoma CTCs, researchers irradiate a person's bloodstream with the nanometer-sized laser that emits targeted pulses. The pulse generates a bright light and transforms it into heat inside the melanin clusters, producing a sound detected by an ultrasound transducer on the patient's skin.

In a study published last week in Science Translational Medicine, Zharov and his team demonstrated Cytophone's ability to identify CTCs in a small group of melanoma patients.

The researchers first used a cohort of 10 healthy controls to define PAFC's parameters and its related measurements. They also used volunteers to test the method's ability to distinguish artifacts — such as hand movements— to determine the tool's false positivity and measure PA signals from vessels of different sizes and depth locations in a patient.

After optimizing the PAFC parameters — including selecting 1.3 to 2.8 mm thick hand veins at a depth of 1 to 2 mm below the skin — on a set of 18 melanoma patients, the researchers tested the tool using a new set of 10 patients with Stage III or IV melanoma. Observing peaks exceeding blood backgrounds on the ultrasound, they saw that the PA signals from CTCs had a specific shape duration and time delay that allowed them to distinguish the signals easily from other artifacts.

Zharov and his team found that the delivery of laser pulses through intact skin to a blood vessel generated acoustic waves from CTCs, which can be amplified by vapor nanobubbles around intrinsic melanin nanoclusters. The group successfully identified CTCs in 17 of 18 patients with melanoma in the training set and all 10 patients in the validation set. In some patients, the researchers observed several CTCs traveling together, which they believe might suggest periodic release of groups of cancer cells from tumors in the bloodstream.

Depending on the concentration of CTCs in the patient's bloodstream, the researchers could detect CTCs between 10 seconds and 60 minutes without producing false positive in the controls. Zharov noted that the team had a limit of detection of 1 CTC per liter.

After collecting PA data on in vivo samples, the group verified the results using six independent ex vivo assays, including two in vitro PACF setups, conventional flow cytometry cell sorting, quantitative RT-PCR, and immunocytochemical staining.  

"In general, conventional assays failed to provide reliable data on the rare CTC presence due to their low sensitivity," the study authors said. "After first testing the Stage III to IV patients with confirmed relatively high CTC concentrations, we stopped using most assays do to their low sensitivity and continued to use only in vitro PAFC."

While the researchers did not mention the exact clinical specificity and sensitivity in the paper, Zharov noted that Cytophone had a clinical specificity of about 95 percent and sensitivity of around 97 percent. However, he emphasized that the data was a preliminary rough estimation and will require more studies and verification in the future.

He said that most of the study's challenges stemmed from financial limitations. Because the study only had a small number of Stage I melanoma patients, Zharov believes that issue limited Cytophone's ability to accurately identify early stage of the disease.  

But, he said, "This tool can be used for personalized medicine through real-time monitoring of individual response to treatment (through CTC counting) and selection of the best treatment and its parameters."

Zharov envisions a version of the platform that could developed into a portable device used in a doctor's office, where a patient would wear a magnetic bracelet for a few hours. Ideally, the magnetic bracelet would cause the CTCs to gather together in a single area within the bloodstream before a doctor performs the test.  

Zharov argued that the platform could also act as a theranostic tool, eradicating CTCs directly in the blood vessels and hopefully limiting the progression of disease. In the study, the researchers successfully killed CTCs through the skin by using the laser to activate nano- and microbubbles around the overheated melanin clusters without damaging healthy cells.

Beyond melanoma, he believes that clinicians could use the assay to detect blood clots for malaria, cardiovascular disorders, and immune dysfunctions.

According to Zharov, his team plans to reach out to academic groups across the US to begin multicenter, large-scale validation studies on thousands of patients that focus on multiple avenues of melanoma-related issues.

Zharov's team will try to diagnose at melanoma at its earliest stages, examine periodical control of melanoma recurrence, monitor conventional therapy efficiency through CTC counting before and after treatment, and explore the potential of photomechanical nanobubble-based CTC destruction as a monotherapy or in combination with immunotherapy.

According to Zharov, his team has received three US  patents related to the Cytophone and PAFC technology and has two patents currently pending with the US Patent and Trademark Office.  

He added that the group plans to launch a startup based on the Cytophone technology by 2020, following fundraising and optimization of the technology in future studies.

Depending on the application (either diagnostic or therapeutic), Zharov estimated that the cost of a potential commercial instrument based on Cytophone would be between $50,000 and $100,000 per device. He explained that the high cost stems from the quality of laser that he believes "is the most integral part of the technology."

After developing a commercial prototype, Zharov said his team will then either pursue 510(k) approval from the US Food and Drug Administration and begin distribution agreements with other firms or potentially license the technology out to a larger company.