Team:Hong Kong HKU/Safety
Safety
Safety in lab
Doxorubicin is a widely used chemo-drug for various cancers. Side effects of doxorubicin include nausea, diarrhea, darkening of the skin and dilated cardiomyopathy [1]. The chemical is stored in tightly-closed container in refrigerator. It is avoided from heat, light and other oxidising reagents. Personal protective equipment like gloves and lab coat is always worn when handling.
Safety in Design
The drug carrying-bacteria can be administrated orally. This provides a non-invasive delivery approach for doxorubicin prescription which is usually by injection. The chemical is intercalated within our nanostructure, preventing the diffusion of drug into non-specific target sites. Aptamer sequences on the tetrahedron further reinforce the specificity. They allow the precise targeting of salmonella and cancer stem cells.
With reference to the information sheet suggested by Stanford University, the biosafety level of bacteria Salmonella typhimurium is described as level 2/3, which is an acute gastroenteritis that would cause diarrhea, nausea and vomiting [2]. Yet, the strain SL7207 that our project employs is a genetically attenuated strain derived from strain SL1344 [3]. Despite it has a high therapeutic potency due to its capability of tumor accumulation and gene delivery, the pathogenicity reduction of the strain is confirmed. The virulent aroA gene which is responsible for expressing para-aminobenzoic acid and 2,3-dihydroxybenzoate, is deleted. The parent strain of SL7207, SL3261 was manipulated for vaccination purpose. Thereby, again validated its level of safety in clinical applications [3].
Moreover, in our project, flhDC Expression allows increased specificity to tumour environment of the bacteria. Tumour escaping of bacteria hugely decreases when Salmonella expresses flhDC gene [4]. Spreading of Salmonella, as well as accumulation number also increases within tumour. Therefore, the approach not only increases the efficiency of gene delivery, it also increase the safety of the approach and bacteriotherapy.
Reference
- O’Brien, M. E., Wigler, N., Inbar, M. C. B. C. S. G., Rosso, R., Grischke, E., Santoro, A., ... & Orlandi, F. (2004). Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX™/Doxil®) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Annals of oncology, 15(3), 440-449.
- Biosafety Levels for Biological Agents. (n.d.). Retrieved from https://ehs.stanford.edu/reference/biosafety-levels-biological-agents.
- Johnson, S. A., Ormsby, M. J., & Wall, D. M. (2017). Draft Genome Sequence of the Tumor-Targeting Salmonella enterica Serovar Typhimurium Strain SL7207. Genome Announcements, 5(5). doi: 10.1128/genomea.01591-16
- Raman, V., Dessel, N., O’Connor, O.M. et al. The motility regulator flhDC drives intracellular accumulation and tumor colonization of Salmonella. j. immunotherapy cancer 7, 44 (2019) doi:10.1186/s40425-018-0490-z