Carbon monoxide (CO) is best known as being an odourless, colourless gas that can kill you. But recent research suggests it could also save your life. That’s because CO has certain anti-inflammatory and immunomodulatory properties that could be used to treat cancer. But to leverage this therapeutic potential, one must first be able to provide a precise, time-controlled dose of CO exclusively to the tumour site – which is what the EU-funded NIRCOThera project intends to do. “The success of advanced cancer diagnosis and treatment relies on the localised enrichment of drugs or imaging agents at the tumour site,” explains He Li, a Marie Sklodowska-Curie fellow who conducted her research at the University of Cambridge.
Improving the effectiveness and safety of tumour imaging
With the support of the Marie Skłodowska-Curie Actions, Li is developing an innovative process for the precise and controlled release of CO to a tumour site. To do this, she initially sought to develop a nanotool that integrates single-walled carbon nanotubes (SWCNTs), PEGylated phospholipids and CO-releasing molecules (CORMs). This tool would then enable the delivery and programmed release of CO at the tumour site(s). “Unfortunately, this combination could not be achieved due to the instability of the organometallic compounds within the given conditions,” adds Li. “Instead, we went back to the drawing board and explored other methodologies for the precise and controlled delivery of such prodrugs as CO to tumour sites.” The winning methodology involves administrating two bioorthogonal reagents via two steps. First, the tetrazine-modified SWCNTs (TZ@SWCNTs) and TCO-carbamate-containing molecules are administered as either a chemotherapeutic prodrug or diagnostic probe. Once enriched in a specific tumour site, the TZ@SWCNTs serve as a bioorthogonal trigger, thus activating the effector molecules in situ while sparing normal tissues. “In the end, we succeeded in developing a prodrug activation strategy for the localised enrichment of an active drug with tumour specificity and spatiotemporal precision,” says Li. “As a result, we have helped improve the effectiveness and safety of tumour imaging and therapy.” The project also demonstrated the first use of a bioorthogonally applicable fluorogenic near-infrared spectroscopy (NIR) probe for the real-time imaging of a xenograft tumour model in living mice, making it a promising candidate for image-guided cancer surgery.
A step change in cancer treatment
According to Li, NIRCOThera’s on-demand prodrug activation platform could significantly improve existing cancer treatment regimes. “By enabling targeted delivery and on-demand activation, this process could represent a step change in cancer treatment,” she notes. Furthermore, the probe developed in the project has the potential to be used for other diagnostic and imaging applications, such as fluorescence-guided tumour surgery, super-resolution bioimaging, and high-throughput screening. Li, who now works as a senior scientist at AstraZeneca, is applying this methodology to organic CO-prodrug delivery and biorthogonal-controlled cancer immunotherapy.
NIRCOThera, cancer, cancer treatment, tumour, tumour imaging, prodrugs