Periodic Reporting for period 1 - NIRCOThera (Spatiotemporal, near-infrared light controlled carbon monoxide delivery for cancer immunotherapy)
Berichtszeitraum: 2018-03-01 bis 2020-02-29
The objective of this research is to develop a novel cargo delivery avenue, enabling controlled prodrug release, e.g. the immunomodulatory molecule carbon monoxide (CO) and the chemotherapy drug doxorubicin, exclusively at tumour sites with spatiotemporal precision. The strategy proposed consists of single-walled carbon nanotubes (SWCNTs) and the prodrug cargos. The strategy will enable spatiotemporal control over prodrug activation via integrating the tumour-targeting property of SWCNTs, the stability and non-toxicity of the small molecule prodrugs and the on-demand activation of prodrugs at tumour sites. Besides, the lipid functionalized SWCNTs have shown biocompatibility, ultrahigh tumour uptake and relatively fast clearance and excretion from the health tissues, which impart the platform promising for in vivo application. The biocompatibility of the nanotool, the stability of the prodrug and the active drug release profile would be evaluated, followed by its dose- and time-dependent therapeutic potential on tumour treatment. We expect that this novel on-demand prodrug activation platform would enable significant improvements to the existing cancer treatment regimes in the near future.
With this strategy, we have successfully realized selective doxorubicin prodrug activation and instantaneous fluorescence imaging in living cells with no need of washing. We also demonstrated the bioorthogonal controlled tHCA turn-on NIR fluorescence imaging in the living mice xenograft model with high tumour-to-liver ratio, making it the first bioorthogonal fluorogenic probe actualized for in vivo tumour imaging.
Based on the successful establishment of the two-step pretargeted strategy with SWCNTs and the IEDDA click-to-release reaction, we are applying this methodology for organic CO-prodrug delivery and bioorthogonal-controlled cancer immunotherapy. The bioorthogonal reaction between cyclopentadienone and cyclooctynes (e.g. BCN) are chosen to serve the purpose. This work is in progress and the bioorthogonal controlled CO release is currently being tested.
The outcome of the project has been presented in 3 international academic conferences and introduced to general public during Cambridge Open Day. As to the submission of the report, 3 original articles from the work implemented during the project have been submitted to international journals.
With the support from this project, the researcher received high level of training in the stimulating environment of Cambridge, which enhanced her potential and her career prospects in the field of cancer diagnostics and treatment. To disseminate the research results, the researcher attended conferences and presented her work in the 2019 Cancer Nanotechnology Gordon Research Conference in the United States and the 2020 International Symposium on Chemical Biology in Switzerland, which contributed to the communication among scientists across the globe.
Furthermore, this is an interdisciplinary work of nanomaterials, bioorthogonal chemistry, prodrug design and synthesis, cell biology and cancer diagnosis and treatment. In the course of this project, we built close collaboration with Dr. João Conde in Instituto de Medicina Molecular (iMM), Universidade de Lisboa (recently moved to NOVA Medical School), an expert in cancer nanomedicine, which promoted the transfer of different skills and knowledges and enhanced the collaboration of excellent scientists from different countries within Europe.