Abstract
Aim
Auger-electron emitting radionuclides are ideal molecularly targeted radiotherapeutic (mTRT) agents when treating disseminated cancer cells and micro-metastasis. In the present study we evaluate the spatial distribution as well as clonogenic survival (SF) of two mTRT strategies in an in-vitro based 3-D tumour spheroid model; 111In-DTPA-hEGF (a peptide targeting the epidermal growth factor-EGF) and 111In-Trastuzumab (an antibody directed against the human epidermal growth factor receptor-2, HER2/neu). This information is then used to validate Monte Carlo (MC) simulations of a close packed 3-D cellular model in predicting tumour control probability (TCP). Materials and Methods Spheroids were formed from three tumour cell lines, MDA-MB-468 and MDA-MB-231/H2N breast cancer and SQ20B head/neck cancer cells, using a hanging droplet method. Spheroids were treated with 111In-DTPA-hEGF (8 MBq/?g, 40 nM), and 111In-Trastuzumab (6 MBq/?g; 10 nM) and evaluated 1 h and 24 h after treatment. SF was determined using a clonogenic assay and distribution was evaluated by cellular fractionation and micro-autoradiographic (MAR) staining of spheroid sections. The 3-D spheroid models were generated by a closed packed algorithm and MC software, PENELOPE was used to model radiation transport. Results Clonogenic survival correlated with radionuclide penetration, with the smallest SF noted in cell lines expressing the highest number of receptors; for EGFR targeting with 111In-DTPA-EGF, the least survival was noted in MDA-MB-468 spheroids, while the lowest SF was noted in MDA-MB-231/H2N spheroids treated with 111In-Trastuzumab. SQ20B form very tightly packed spheroids and although expressing a high number of EGFR, it showed little radionuclide penetration and corresponding greater survival. MAR staining showed two distinct spatial distribution patterns, i.e. outer rim of activity (1 h post treatment) or uniform distribution (24 h post treatment). TCP depended strongly on spatial distribution of the radionuclides, with uniformly distributed radionuclides achieving TCP1. Conclusion Tumour spheroids offer a viable model for investigating the penetration and spatial distribution of radiolabelled probes in tumour cells. Data was employed to inform mathematical modelling, in order to be able to use in silico methods to simulate drug distribution in tumour cells.
Auger-electron emitting radionuclides are ideal molecularly targeted radiotherapeutic (mTRT) agents when treating disseminated cancer cells and micro-metastasis. In the present study we evaluate the spatial distribution as well as clonogenic survival (SF) of two mTRT strategies in an in-vitro based 3-D tumour spheroid model; 111In-DTPA-hEGF (a peptide targeting the epidermal growth factor-EGF) and 111In-Trastuzumab (an antibody directed against the human epidermal growth factor receptor-2, HER2/neu). This information is then used to validate Monte Carlo (MC) simulations of a close packed 3-D cellular model in predicting tumour control probability (TCP). Materials and Methods Spheroids were formed from three tumour cell lines, MDA-MB-468 and MDA-MB-231/H2N breast cancer and SQ20B head/neck cancer cells, using a hanging droplet method. Spheroids were treated with 111In-DTPA-hEGF (8 MBq/?g, 40 nM), and 111In-Trastuzumab (6 MBq/?g; 10 nM) and evaluated 1 h and 24 h after treatment. SF was determined using a clonogenic assay and distribution was evaluated by cellular fractionation and micro-autoradiographic (MAR) staining of spheroid sections. The 3-D spheroid models were generated by a closed packed algorithm and MC software, PENELOPE was used to model radiation transport. Results Clonogenic survival correlated with radionuclide penetration, with the smallest SF noted in cell lines expressing the highest number of receptors; for EGFR targeting with 111In-DTPA-EGF, the least survival was noted in MDA-MB-468 spheroids, while the lowest SF was noted in MDA-MB-231/H2N spheroids treated with 111In-Trastuzumab. SQ20B form very tightly packed spheroids and although expressing a high number of EGFR, it showed little radionuclide penetration and corresponding greater survival. MAR staining showed two distinct spatial distribution patterns, i.e. outer rim of activity (1 h post treatment) or uniform distribution (24 h post treatment). TCP depended strongly on spatial distribution of the radionuclides, with uniformly distributed radionuclides achieving TCP1. Conclusion Tumour spheroids offer a viable model for investigating the penetration and spatial distribution of radiolabelled probes in tumour cells. Data was employed to inform mathematical modelling, in order to be able to use in silico methods to simulate drug distribution in tumour cells.
| Original language | English |
|---|---|
| Title of host publication | 28th Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) |
| Pages | S116-S116 |
| Number of pages | 1 |
| Volume | 42 |
| Publication status | Published - Oct 2015 |
| Event | 28th Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) - Hamburg, Germany Duration: 10 Oct 2015 → 14 Oct 2015 |
Conference
| Conference | 28th Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) |
|---|---|
| Country/Territory | Germany |
| Period | 10/10/2015 → 14/10/2015 |