Deaths from lung cancer have been declining in developed countries due to early detection, enabling timely curative treatments. However, lung cancer still results in high mortality rates in low and middle-income countries (LMICs), where there is a need for new diagnostic tools.
A recent study published in Science Advances details a non-invasive, low-cost lung cancer detection platform called PATROL, demonstrating its performance and potential impact.
Study: Inhalable point-of-care urinary diagnostic platform. Image Credit: mi_viri/Shutterstock.com
Background
Low-dose computed tomography (LDCT) is the platform of choice for early-stage lung cancer screening in the absence of symptoms among people at high risk for the condition. Its availability and use have reduced lung cancer deaths by up to a quarter in clinical trials.
However, this is a sophisticated and personnel-intensive platform, with poor penetrance among low- or middle-income populations.
Liquid biopsies are another promising technology that detects low levels of cancer-associated biomarkers in body fluids. These also require high-level resources, limiting their applicability to poorer populations.
An equally serious flaw in the widespread use of liquid biopsies is that they depend on biomarkers in the bloodstream, though many are found in the tumor microenvironment.
What did the study show?
The current platform is PATROL, which is short for point-of-care aerosolizable nanosensors with tumor-responsive oligonucleotide barcodes.
It is based on a set of activity-based nanosensors (ABNs) arranged into an inhalable array of microscale aerosols that can be loaded on inhalers or nebulizers. Each sensor carries a DNA barcode.
In the presence of lung cancer, specific proteases are upregulated. These split the ABNs, causing the release of DNA reporter molecules that eventually make their way out of the body via urine. The urine was shown by chromatography/spectrometry to contain the peptides of interest.
In the next step, the researchers shifted to point-of-care (POC) detection to adapt the test to low-resource settings. They designed a urine analysis tool in the form of a multiplexed paper-based lateral flow assay (LFA).
The test is carried out by inhaling the ABN biomarker array followed by LFA of urine. The ABN signature is available within 20 minutes, and the test is carried out at room temperature.
The ABN particles were redesigned to rapidly transform from nanoscale to aerosolized particles with 1-3 μm sizes. Smaller particles than this are mostly exhaled, while larger particles do not make it past the upper airways.
They then used a large library of ABNs customized 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, airflow pattern, and delivery mode that would yield the best results with minimum background noise.
Using a mouse lung cancer model, the researchers demonstrated that PATROL possessed 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 one order of magnitude less than with mass spectrometry. Still, the sensitivity was at 75%, similar to that of micro-CT, with 100% sensitivity.
What are the implications?
“Collectively, PATROL holds great clinical potential not only to attain both sensitive and specific lung cancer detection at early stages but also to enable easy deployment in resource-limited settings.”
This highly modular design uses a self-administered format, stabilized oligonucleotide barcodes easily immobilized on paper strips, and multiplexed tests to pick up the peptide biomarkers indicating disordered proteolysis in early-stage lung cancer.
Nebulization and inhalation have been used for decades to treat chronic lung disease. They are well-designed to deliver the particles of interest into the lungs without being broken down in the body.
This is exploited here to ensure the diagnostic particles enter the lungs, especially the peripheral regions, including the bronchi, bronchioles, and alveoli, where lung cancer mostly occurs.
PATROL not only yields amplified signals but reduces noise, thus increasing the specificity of detection of early-stage lung cancer.
By altering the formulations, the deposition site can be tailored to occur deeper or more superficially in the tracheobronchial tree.
The use of LFA based on synthetic DNA barcodes detected by direct hybridization on paper strips does away with amplification as in polymerase chain reaction or CRISP-R methods, and allows rapid and multiplexed testing with results within 20 minutes.
Further research could help customize the library of ABNs to fine-tune and tailor the platform for other lung cancers. In addition, it is potentially extendable to cover chronic lung diseases and infections.
“We envision that by releasing disease screening from its current resource-intensive environment, we may enable feasible surveillance testing that would identify a disease when it is still easy to treat.”
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