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Schematic of a nanopore blockade sensor (PSA: prostate-specific antigen, MNP: magnetic nanoparticle)

UNSW researchers Yanfang Wu and Justin Gooding’s revolutionary nanopore blockage sensor technology lowers the detection limit of PSA screening, allowing earlier detection of prostate cancer.

In Australia, one in six men is likely to be diagnosed with prostate cancer by the age of 85. In its early stages, the growing tumour is confined within the prostate and does not usually cause symptoms, often developing undetected.

By Stage IV, the cancer has metastasised to other parts of the body. Only in this stage do we observe noticeable symptoms like painful urination, fatigue, and bone pain.

Like most cancers, survival is higher if the cancer is detected earlier rather than later. In 2019, the British Medical Journal reported that the 5-year survival rate for prostate cancers detected in Stages I – III is near 100% but declines steeply to 47.7% if detected in Stage IV.

If there are few initial symptoms, how can we detect early-stage prostate cancer? Doctors use the PSA test to measure blood levels of prostate-specific antigen (PSA), a protein made by both normal and cancerous prostate cells but in greater quantities in cancerous cells. Since PSA levels rise throughout tumour progression, regular PSA screening can detect changes in a man’s PSA production, prompting further cancer screening.

However, the PSA test is not always accurate, especially in the earliest stages when very little PSA is being produced and available in circulation. Existing detection technologies seldom reach the low concentrations that are clinically relevant.

An unmet need in the field of biosensors is to develop technologies that selectively detect cancer biomarkers at ultralow concentrations. Recently, University of New South Wales (UNSW) researchers Dr Yanfang Wu and Scientia Prof. Justin Gooding of the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and the Australian Centre for NanoMedicine have developed a new nanopore blockade sensor for biomarker screening.

Typically, a nanopore sensor detects individual molecules moving through a membrane-embedded, nanoscale pore. Molecular passage through the nanopore causes detectable changes in electrical conductance of the nanopore. However, many nanopore sensors are not selective, responding to all molecules small enough to pass through the pore. Non-selectivity is a problem when dealing with complex biological samples like blood.

The Gooding research group has modified nanopore sensor technology to actively and selectively screen a specific biomarker. Their system employs devices containing an array of nanoscale pores and tailored magnetic nanoparticles (MNPs).

Both system components are modified with proteins that bind to PSA. These anti-PSA MNPs will capture the PSA molecules present in a blood sample. The higher the PSA concentration, the more MNPs will be bound to their targets.

The Gooding group’s device can actively shuttle the PSA-bound MNPs to the anti-PSA-modified nanopore array by applying a magnetic field. Once brought to the array, a MNP cannot move through the nanopore, blocking it instead. With both surfaces modified to bind to PSA, a sandwich-complex forms in the nanopore such that a bound MNP cannot be removed when the magnetic field is reversed to pull the unbound nanoparticles out of the array. Blocked nanopores generate large changes in transmembrane current relative to the number of blocked pores.

With PSA-specific binding, other biomolecules will not cause nanopore blockage. As a result, false signals are avoided, and better specificity is achieved. In addition, a MNP nanopore blockade sensor actively brings PSAs to the nanopore by the action of magnetic force rather than relying on passive diffusion, which greatly reduces analysis time. Most importantly for early cancer detection, the nanopore blockade sensor is sensitive to a single molecule and achieves the detection of PSA at sub-femtomolar (fM, 10-15 moles/litre) levels directly from complex biological samples.

ANFF-NSW has provided fabrication and technical support for the development of this nanopore blockage sensor device for the last decade. With ANFF’s assistance, Prof. Gooding and his colleagues have created a revolutionary system that can measure PSA at ultralow concentrations, showing great promise for the earlier detection of prostate cancer. Future work will expand the use of this technique to detect other medically important biomarkers.