On Monday 25th January, we attended the ‘Bioengineering strategies for early disease detection’ webinar by Professor Molly Stevens, hosted as part of the Cancer Research UK Early Detection Programme Annual Symposium. The webinar covered exciting advances and opportunities in the field of cancer diagnostics, in particular focusing on the potential of nanoneedles in biosensing.
Up until recently, finding effective ways of manipulating and visualising the contents of a living cell in vivo has been a challenge. To try and combat this problem, Professor Stevens’ research group at Imperial College London have developed a platform for biodegradable silica-based nanoneedles, which can be applied both in drug delivery and biosensing scenarios. Specific molecules or bio-cargoes can be loaded into nanoneedles and delivered directly to the cell of interest by penetrating the cell membrane efficiently and safely, with the possibility of visualising the cell-nanoneedle interaction using high-detail imaging.
The use of nanoneedle technology has particular applications for early disease detection, including in cancer, by enabling the development of biosensing systems that can monitor pH changes within cells or detect the upregulation of specific enzymes in disease. In the case of cancer cells, certain proteases, such as Cathepsin B, are known to be upregulated intracellularly and enhance the activity of the matrix metalloproteinases (MMPs), which can lead to pro-oncogenic and malignancy phenotypes. Nanoneedle technology can be used to map the location of these cancer cells by delivering nanoparticle-protein complexes into the cell cytosol that react with the upregulated enzyme of interest and thus help to identify areas of high enzymatic activity.
In practical terms, this technology could be used as a cancer diagnostic tool by providing a simple read-out via a urine test, whereby patient urine would be temporarily coloured blue if the presence of tumour-related enzymes is detected. To create this test, Stevens’ team first had to synthesize the necessary nanoparticle-protein complexes by using peptides to link gold nanoclusters to neutravidin, a protein carrier. The complexes were designed in such a way that they would only be cleaved in the presence of MMP enzymes released by cancer cells and thus would only be detectable in the urine of cancer patients.
To test the sensors, the complexes were injected into mice from both healthy and colorectal cancer graft populations. As expected, the absence of cancer-related MMPs in the healthy mice meant that the complexes remained intact in this population and thus were too large to pass through the murine renal system and undergo excretion into the urine. Conversely, the presence of MMP enzymes in mice with colorectal tumour grafts meant that the gold nanoclusters were cleaved from the nanoparticle-protein complexes and could be rapidly excreted into urine within an hour of injection. The urine was tested using the simple addition of hydrogen peroxide and TMB, resulting in the production of a blue compound in the presence of gold-nanoclusters, which act as a catalyst between the two chemicals.
The technology is yet to be tested in humans, however it offers a potentially promising solution in light of the many issues currently faced with other cancer diagnostic tests, including problems with inaccuracy and/or insensitivity, difficulties with implementation, and high associated costs.
1. Nanomaterials as Diagnostic Platforms, http://www.stevensgroup.org/index.php/research/nanomaterials
2. Gold nanoparticle sensor produces simple urine test for cancer, https://cen.acs.org/biological-chemistry/cancer/Gold-nanoparticle-sensor-produces-simple/97/web/2019/09
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