Drug delivery

drug del header

Project introduction

Nitroreductases are enzymes of which the true biological roles are still being elucidated, but have the ability to react with nitro-groups either on explosives or prodrugs and are thus of interest for explosive detection, bioremediation and cancer prodrug therapy.

This project has its interests in cancer prodrug therapy (chemotherapy) specifically, a novel method to deliver nitroreductases to solid tumours. The novel method is based on the use of gold-coated magnetic nanoparticles (Au-MNPs) as a delivery vehicle for bacterial nitroreductases to solid tumours using a focused magnetic beam. This method hopes to overcome the current limitation of poor enzyme expression and inefficient tumour targeting.

Importantly, the Au-MNPs required for this project cannot be obtained commercially, and we have optimised a method to synthesise these in-house. One branch of this research is further optimisation of the current protocol as well as producing particles of various sizes. Also, the identification and expression of known and novel nitroreductases are an ongoing activity in order to select enzymes with greater efficiency than the most studied NfnB from E. coli. This work includes characterising novel enzymes and their enzyme products using HPLC and NMR. We are also investigating the cytotoxicity of enzyme-nanoparticle conjugates on cancer cell lines in order to select the best combinations for testing in mouse trials. Last but not least, we aim to determine the nanotoxicology (biodegradation, elimination, distribution, etc.) of the bare and conjugated nanoparticles. Understanding the impact of nanoparticles is part of the recommendations made by the House of Lords Science and Technology select committee.

References

  • Drug activation carrier, WO2011026898-A2; WO2011026898-A3; EP2473197-A2; US2012232328-A1; EP2473197B
  • V. V. Gwenin, P. Paramasivan, J. Halliwell, P. Ball, G. Robinson, C. D. Gwenin, Identification of novel nitroreductases from Bacillus cereus and their interaction with the CB1954 prodrug, Biochemical Pharmacology, 98 392-402 (2015) DOI: 10.1016/j.bcp.2015.09.01
  • V. V. Gwenin, C. D. Gwenin, M. Kalaji, Colloidal gold modified with a genetically engineered nitroreductase: Towards a novel enzyme delivery system for cancer prodrug therapy. Langmuir, (2011), 27, 14300 DOI: 10.1021/la202951p
  • P. Ball, E. Thompson, S. Anderson, V. Gwenin, C. Gwenin, Time dependant HPLC analysis of the product ratio of enzymatically reduced prodrug CB1954 by a modified and immobilised nitroreductase, European Journal of Pharmaceutical Sciences, 127 (2019) 217-224 DOI.org/10.1016/j.ejps.2018.11.001
  • S. Anderson; V. V Gwenin; C. Gwenin, Magnetic functionalized nanoparticles for biomedical, drug delivery and imaging applications, Nanoscale Research Letters, (2019) 14:188 DOI.org/10.1186/s11671-019-3019-6
  • S. D. Anderson, R. J. Hobbs, V. V. Gwenin, P. Ball, L. A. Bennie, J. A. Coulter, and C. D. Gwenin, Cell-Penetrating Peptides as a Tool for the Cellular Uptake of a Genetically Modified Nitroreductase for use in Directed Enzyme Prodrug Therapy, Journal of Functional Biomaterials, (2019), 10(4), 45 DOI.org/10.3390/jfb10040045
  • P. Ball, J. Halliwell, S. Anderson, V. Gwenin, C. Gwenin, Evaluation of two Xenobiotic Reductases from Pseudomonas putida for their suitability for a novel MNDEPT cancer prodrug therapy approach, MicrobiologyOpen. 00: 1– 10, (2020) DOI.org/10.1002/mbo3.1110
  • C. Thomas and C. D. Gwenin, The role of nitroreductases in resistance to nitroimidazoles, Biology, 10(5), 388 (2021); https://doi.org/10.3390/biology10050388
  • P. Ball, R. Hobbs, S. Anderson, E. Thompson, V. Gwenin. C. Von Ruhland, C. D. Gwenin, The YfkO nitroreductase from Bacillus Licheniformis on gold-coated superparamagnetic nanoparticles: Towards a novel directed enzyme prodrug therapy approach, Pharmaceutics 13, (4), 517 (2021) DOI.org/10.3390/pharmaceutics13040517
  • P. Ball, E. Thompson, S. Anderson, V. Gwenin, A. Ashoorzadeh, J. Smaill and C. Gwenin, The Dinitrobenzamide Mustard Prodrugs, PR-104A and SN27686, for Use in a Novel MNDEPT Cancer Prodrug Therapy Approach, Bioscience reports, 00 1–12. (2023) DOI.org/10.1042/BSR20230627