Synergy of radiotherapy and chemotherapy delivered via gold nanostructures in glioblastoma multiforme

Glioblastoma multiforme (GBM) is reputable in its aggressiveness because of the inter- and intra- tumor heterogeneity which leads to resistance and recurrence. The aim of our work is to demonstrate the efficacy of a multimodal... [ view full abstract ]

Glioblastoma multiforme (GBM) is reputable in its aggressiveness because of the inter- and intra- tumor heterogeneity which leads to resistance and recurrence. The aim of our work is to demonstrate the efficacy of a multimodal nanotechnology which exploits the chemical and physical properties of a system based on gold nanostructures combined with a tumor targeting element - in this case a tumor homing peptide, in eradicating GBM cell populations in vitro and tumour growth stagnation or reduction in vivo in an orthotopic xenograft model. We have showed previously (1) the synergistic effect of chemotherapy and radiotherapy in a construct based on spherical gold nanoparticles coated with mercaptoundecanoic acid (MUA) to which we attached cis-platinum drug. To further improve this technology we have used a modified construct in which we replace the MUA coating with mixed monolayer made of a small peptide and a polyethylene glycol linker/MUA. The peptide is designed such that it exploits the RGD motif targeting integrins associated with the newly formed blood vessels as well as the CendR rule motif (2) K/RXXK/R which is responsible for targeting of the particle to tumor cells due to binding to receptors such as neuropilin-1(VEGF168R). Furthermore, we are working towards synthesizing a stable porous superstructure built by self-assembly of the peptide and small gold cores, overall smaller than 50 nm which will allow the conjugation of more drug at the surface whilst incorporating the targeting element, therefore improving drug loading and sensitivity of targeting. This would also modify the radiosensitising properties of the system. The end goal of this work is to validate these findings in vivo and to ultimately submit this technology for clinical trials. One other remarkable point, is that even without targeting this technology is potentially deliverable in a stereotactic manner (directly into the brain) which would require a different animal model.
(1) Setua, S., Ouberai, M., Piccirillo, S. G., Watts, C. & Welland, M. Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma. Nanoscale 6, 10865–10873 (2014)
(2) Ruoslahti E., Bhatia S.N., Sailor M.J. Targeting of drugs and nanoparticles to tumors. J Cell Biol. 188(6):759-68 (2010)