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Could Inhalable Sensors Offer a New Path to Early Lung Diagnosis?

Lung cancer diagnosis could soon be as simple as breathing nanoparticle sensors and then undergoing a urine test to determine whether a tumor is present, thanks to new technology developed at MIT.

MIT engineers have designed diagnostic particles that can be aerosolized and inhaled. At bottom is a scanning electron micrograph of the particles, which are coated with nanosensors that interact with cancer-associated proteins in the lungs. Image Credit: Courtesy of the researchers

The novel diagnosis is based on nanosensors that can be administered by nebulizer or inhaler. When the sensors come into contact with cancer-linked proteins in the lungs, they generate a signal that builds up in the urine and can be identified using an easy paper test strip.

Low-dose computed tomography (CT) is now the gold standard for identifying lung cancer; this method could eventually replace or enhance it. The impact might be particularly noteworthy in low- and middle-income nations where CT scanners are not widely available, according to the researchers.

Around the world, cancer is going to become more and more prevalent in low- and middle-income countries. The epidemiology of lung cancer globally is that it’s driven by pollution and smoking, so we know that those are settings where accessibility to this kind of technology could have a big impact.

Sangeeta Bhatia, Study Senior Author and John and Dorothy Wilson Professor, Health Sciences and Technology and of Electrical Engineering and Computer Science, Massachusetts Institute of Technology

The study was published in Science Advances, and Bhatia is the senior author. Lead authors of the study are Edward Tan, a former postdoc at MIT, and research scientist Qian Zhong.

Inhalable Particles

The US Preventive Services Task Force suggests annual CT scans for heavy smokers over 50 to aid in the earliest possible diagnosis of lung cancer. Nevertheless, not all members of this target population undergo these scans, and the scans' high false-positive rate could result in intrusive, needless testing.

Bhatia and her colleagues investigated the potential of employing nanosensors as a more approachable substitute for CT screening for lung cancer in this study. Bhatia has spent the last ten years creating nanosensors for use in diagnosing cancer and other disorders.

Polymer nanoparticles coated with a reporter, such as a DNA barcode, are used in these sensors. The reporter is released from the particle when the sensor comes into contact with proteases, an enzyme frequently hyperactive in tumors. These reporters ultimately build up in the urine and are eliminated by the body.

Previous versions of the sensors were intended to be administered intravenously and targeted other cancer locations, including the liver and ovaries. The goal was to develop an inhalation version for lung cancer diagnostics, which would facilitate deployment in lower-resource environments.

When we developed this technology, our goal was to provide a method that can detect cancer with high specificity and sensitivity, and also lower the threshold for accessibility, so that hopefully we can improve the resource disparity and inequity in early detection of lung cancer.

Qian Zhong, Study Lead Author and Research Scientist, Massachusetts Institute of Technology

The researchers developed two particle formulations: a dry powder that can be inhaled and an aerosolized solution that can be administered using a nebulizer.

When the particles reach the lungs, they are absorbed into the tissue and come into contact with any proteases that are there. Human cells can produce hundreds of distinct proteases, and some of them are hyperactive in tumors, where they aid cancer cells escape by cutting through extracellular matrix proteins.

These malignant proteases break DNA barcodes off sensors, allowing them to circulate in the circulation until eliminated in the urine.

Earlier versions of this technique employed mass spectrometry to examine urine samples and find DNA barcodes. However, mass spectrometry needs equipment that might not be available in low-resource locations, so the researchers developed a lateral flow assay that detects barcodes using a paper test strip for this version.

The up to four distinct DNA barcodes that each signify the presence of a distinct protease are detectable by the researchers’ design of the strip. The urine sample does not require to be pre-treated or processed, and the results are ready to read 20 minutes after the sample is collected.

Bhatia added, “We were really pushing this assay to be point-of-care available in a low-resource setting, so the idea was to not do any sample processing, not do any amplification, just to be able to put the sample right on the paper and read it out in 20 minutes.

Accurate Diagnosis

Using mice that have been genetically modified to grow lung tumors resembling those found in people, the researchers evaluated their diagnostic technique. 7.5 weeks after the tumors first appeared, the sensors were given, a period of time that is probably comparable to stage 1 or stage 2 human cancer.

In their initial series of studies using mice, the scientists assessed the concentrations of 20 distinct sensors made to identify various proteases. After analyzing the data using a machine learning technique, the researchers found that just four sensor combinations were expected to provide reliable diagnostic findings. Upon testing that combination in a mouse model, they discovered that it was capable of correctly identifying lung cancers in their early stages.

More sensors might be required for people to establish an accurate diagnosis, but this can be done by utilizing numerous paper strips, each of which detects four separate DNA barcodes, according to the researchers.

The researchers will now evaluate human biopsy samples to discover if the sensor panels they are employing can detect human tumors as well. They intend to conduct clinical studies on human patients in the future. Sunbird Bio has previously completed phase 1 trials on a similar sensor created by Bhatia’s group for application in identifying liver cancer and nonalcoholic steatohepatitis (NASH).

Given that the findings could be received in a single visit, this method could offer a significant improvement in lung cancer screening in regions of the world where access to CT scanning is restricted.

The idea would be you come in and then you get an answer about whether you need a follow-up test or not, and we could get patients who have early lesions into the system so that they could get curative surgery or lifesaving medicines,” Bhatia concluded.

The National Institute of Environmental Health Sciences, the Howard Hughes Medical Institute, the Johnson & Johnson Lung Cancer Initiative, and the Koch Institute Support (core) Grant from the National Cancer Institute provided funding for the study.

Journal Reference:

Zhong, Q., et. al. (2023) Inhalable point-of-care urinary diagnostic platform. Science Advances. doi:10.1126/sciadv.adj9591.


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