• TPP-functionalisation will promote the uptake of nanoparticles by cancer cells.
• Radiosensitisation will be improved by varying the size and ligand density of the TPP-nanoparticles.
• 3D cancer cell cultures, incorporating immune cells, will allow us to more realistically model in vivo tumour responses to nanoparticle uptake and radiosensitisation.
The project will focus on three key cancers:
• Prostate cancer
• Glioblastomer (brain cancer)
• Non-small cell Lung cancer
All three of these cancers are common with increasing prevalence in older patients.
Furthermore, we have established 3D models (alginate) working for prostate (pc3 and LnCap) and also for u87-mg (glioblastoma) and also five established non-small cell lung cancer cell lines including two primary lung cancer lines commercialised by Bio-IVT.
There will be three integrated workstreams:
1. Preparation of nanoparticles (NP). Our research to-date has focussed on TPP-AuNPs with a diameter of 3.5nm. We propose to prepare larger AuNPs that contain fewer TPP groups since evidence suggests that the size of the nanoparticle and density of the TPP critically affects the rate of uptake and their effectiveness as radiosensitisers.
In parallel, we will also investigate a relatively new class of nanoparticles that radiosensitise independent of ligand density. These are formed from scintillators, such as ZnS and CaF2, functionalised with photosensitisers. X-ray irradiation results in the emission of blue/green photons that efficiently transfer energy to the photosensitiser which generates highly toxic singlet oxygen radicals. We would seek to improve the cancer targeting and uptake of this nanoplatform by additionally incorporating TPP. Moreover, because this class of nanoparticle are naturally fluorescent, they would be easy to track in the 3D culture model as a potential theranostic pharmaceutical.
2. Investigate the interaction of the TPP-NPs with the 3D cell model. The pharmacokinetics of nanoparticle uptake and loss from cells will be investigated in order to identify the optimum dose-toxicity parameters and in X-ray experiments to identify the optimum drug-to-irradiation interval. We will use 2 established 3D cell culture models, namely the Alginate spheroid assay, and the OrganDot platform developed with industrial collaborators at Bio-IVT. Both of these models have been successfully adapted for co-culture studies with cancer associated fibroblasts. In this study, we will focus on tumour-associated macrophages (TAMs), which are known to attenuate radiotherapy responses.
3. Radiotherapy Studies. We will compare 2D and 3D cell cultures treated with TPP-NPs and determine dose enhancement factors following X-ray at clinically relevant doses. Radiosensitising nanoparticle treatments will be repeated with TAMs and surviving tumour fraction evaluated Confocal microscopy with function-reporting probes will be used to determine the mode of cell death and the extent of mitochondrial damage.
• Optimised, cancer-selective, chemo-radiotherapeutic TPP-AuNPs
• Mixed TPP-/phthalocyanine NPs
• Use of an immune-competent or tumour micro-environment-relevant 3D cell culture model to assess effectiveness of TPP-NPs
Applicants must apply using the online form on the University Alliance website at https://unialliance.ac.uk/dta/cofund/how-to-apply-2/
. Full details of the programme, eligibility details and a list of available research projects can be seen at https://unialliance.ac.uk/dta/cofund/
The final deadline for application is 12 April 2019.