The number of deaths from lung cancer has decreased in developed countries due to early detection, allowing for timely treatment. However, in low- and middle-income countries (LMICs), lung cancer still leads to high mortality rates, where there is a need for new diagnostic tools.
A recent study published in Science Advances describes a non-invasive, cost-effective platform for detecting lung cancer called PATROL and demonstrates its performance and potential impact.
Study: Inhalable Point-of-Care Urinary Diagnostic Platform. Image Source: mi_viri/Shutterstock.com
Low-dose computed tomography (LDCT) is the platform of choice for early-stage lung cancer screening when individuals at high risk for the disease have no symptoms. Its availability and use in clinical studies have led to a reduction in lung cancer deaths by up to a quarter.
However, this is a highly advanced and labor-intensive platform with low penetration in populations with low or middle income.
Liquid biopsies are another promising technology that detects low concentrations of cancer-associated biomarkers in body fluids. These also require extensive resources, limiting their applicability to poorer populations.
Another significant drawback of the widespread use of liquid biopsies is their reliance on blood-circulating biomarkers, although many of them are found in the tumor’s microenvironment.
What Did the Study Find?
The current platform is PATROL, short for Point-of-Care Aerosolizable Nanosensors with tumor-responsive Oligonucleotide Barcodes.
It is based on a set of activity-based nanosensors (ABNs) arranged in an inhalable array of microscale aerosols that can be loaded onto inhalers or nebulizers. Each sensor carries a DNA barcode.
In lung cancer, certain proteases are upregulated. These cleave the ABNs, releasing DNA reporter molecules that eventually exit the body through the urine. Chromatography/spectrometry showed that the urine contained the peptides of interest.
Next, the researchers transitioned to point-of-care detection (POC) to adapt the test to resource-poor environments. They developed a urine analysis tool in the form of a paper-based multiplex lateral flow assay (LFA).
The test is performed by inhaling the ABN biomarker array and conducting LFA of the urine. The ABN signature is available within 20 minutes, and the test is conducted at room temperature.
The ABN particles were redesigned to rapidly transform from nanoscale to aerosolized particles of 1-3 μm in size. Smaller particles are mostly exhaled, while larger particles do not pass through the upper airways.
They then utilized a large ABN library adapted to this platform to form a set of four markers, added DNA barcodes, and multiplexed them with room temperature LFAs.
They determined the protease substrate concentration, air flow pattern, and delivery mode that would provide the best results with minimal background noise.
Using a mouse lung cancer model, the researchers showed that PATROL exhibits high sensitivity and specificity for early-stage lung adenocarcinomas.
However, the overall significance of the area under the curve (AUC) for the predictive power of the probes was an order of magnitude lower than mass spectrometry. Nevertheless, the sensitivity was 75%, similar to micro-CT, with 100% sensitivity.
What are the Implications?
“Overall, PATROL holds significant clinical potential, not only achieving sensitive and specific early-stage lung cancer detection but also enabling easy deployment in resource-constrained environments.”
This highly modular design utilizes a self-administrable format, stabilized oligonucleotide barcodes readily immobilized on paper strips, and multiplex testing to detect the peptide biomarkers indicative of disrupted proteolysis in early-stage lung cancer.
Nebulization and inhalation have been used for decades to treat chronic lung diseases. They are designed to deliver the desired particles to the lungs without being degraded in the body.
This is leveraged here to ensure that the diagnostic particles reach the lungs, especially in peripheral regions, including bronchi, bronchioles, and alveoli, where lung cancer most commonly occurs.
PATROL not only provides amplified signals but also reduces noise, thus increasing the specificity of early-stage lung cancer detection.
By modifying the formulations, the deposition site can be adjusted to target deeper or more superficial regions within the tracheobronchial tree.
Using LFA based on synthetic DNA barcodes detected by direct hybridization on paper strips eliminates the need for amplification such as polymerase chain reaction or CRISP-R methods, enabling rapid and multiplex testing with results within 20 minutes.
Further research could help optimize and adapt the ABN library for other types of lung cancer on this platform. Additionally, extension to chronic lung diseases and infections is possible.
“We envision that by liberating disease screening from its current resource-intensive setting, we could enable viable monitoring tests to identify a disease when it is still easily treatable.”