Abstract
The bacterial nitroreductase NfnB has been the focus of a great deal of research for its use in directed enzyme prodrug therapy in combination with the nitroreductase prodrug CB1954 with this combination of enzyme and prodrug even entering clinical trials. Despite some promising results, there are major limitations to this research, such as the fact that the lowest reported Km for this enzyme far exceeds the maximum dosage of CB1954. Due to these limitations, new enzymes are now being investigated for their potential use in directed enzyme prodrug therapy. One such enzyme that has proved promising is the YfkO nitroreductase from Bacillus Licheniformis. Upon investigation, the YfkO nitroreductase was shown to have a much lower Km (below the maximum dosage) than that of NfnB as well as the fact that when reacting with the prodrug it produces a much more favourable ratio of enzymatic products than NfnB, forming more of the desired 4-hydroxylamine derivative of CB1954.
Highlights
Cancer chemotherapy is an area of research that is of the utmost importance with cancer being responsible for over 30% of global deaths each year [1,2]
One chemotherapy strategy that is currently being investigated involving the use of prodrugs is directed enzyme prodrug therapy (DEPT), this strategy involves delivering prodrugactivating enzymes directly to a tumour site before administering a prodrug, thereby activating the prodrug to its more pharmaceutically active products at the cancer site [6]
We have shown in previous work that AuMNPs of this size can be directly uptaken into cancerous cells via endocytosis [33], so this is significant because it means that, if we could form active
Summary
Cancer chemotherapy is an area of research that is of the utmost importance with cancer being responsible for over 30% of global deaths each year [1,2]. To increase the tumour selectivity of cancer chemotherapy treatments and combat the problem of systematic toxicity, alternative treatment methods being explored involve the use of prodrugs [3,4,5,6,7]. One chemotherapy strategy that is currently being investigated involving the use of prodrugs is directed enzyme prodrug therapy (DEPT), this strategy involves delivering prodrugactivating enzymes directly to a tumour site before administering a prodrug, thereby activating the prodrug to its more pharmaceutically active products at the cancer site [6]. We are investigating a novel form of DEPT that utilizes gold coated magnetic nanoparticles (AuMNP). As the delivery vector for genetically modified prodrug activating enzymes called magnetic nanoparticle directed enzyme prodrug therapy (MNDEPT) [15,16].
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