1. 1 NANO AMPLIFIED THERAPY INFN-Milano, INFN-Torino, INFN-Pisa, INFN- Roma3, CNR-Pisa, University of Torino - Biotechnology Department

2. Rational: 2 Hadrontherapy and Radiotherapy are well known and widely used methods to treat cancer when surgery is not suitable or as a complement to a surgical treatment. The investigation of the use of nanoparticles to increase the average Z and therefore the interaction cross sections has already started. Use of nanoparticles bound to FDG: no literature is available on a combined use of this approach: nanoparticles bound to FDG (glucose), when injected, should accumulate in the tumour volume at a rate higher than in other cells. The purpose of the present proposal is to investigate the feasibility and the in-vitro net effect of the proposed approach, called nano-amplified therapy. 2 years project

3. 1° year Nano-particles production Gold nanoparticles are emerging as promising agents for cancer therapy and are being investigated as drug carriers, photothermal agents, contrast agents and radiosensitisers. For this project 18FDG-AuNPs and Glucose-AuNP (Glu-AuNPs) will be synthetized by University of Torino – Biotechnology Department 3

4. 1° year Nano-particles distribution and uptake The first milestone is the evaluation of the differences in the distribution of FDG with respect to Au-FDG. It is a critical measurement, as it will allow to measure to what extent binding Au nanoparticles to FDG changes the radiotracer distribution and the uptake time. In order to quantify the comparison, measurements with PET/CT on small animals will be carried out in collaboration between Torino and Pisa 4

5. 5 1° year PET/CT-based assesment on Small Animals The uptale of FDG inside different tissues should be modeled with a compartment model estimating the influx and retention costant of FDG and FDG/Au separately. Alternatively a simple Standardized Uptake Value calculation could be carried out to estimate the metabolic rate. Co-registered micro-CT and micro-PET images will allow the accurate localizzation of the nano-FDG distribution and will permit to study the differences, if any, respect to FDG case and the averaged tumor/normal tissues ratios. The micro-PET/CT scan will be analyzed and the search for high uptake regions will be performed by means of Support Vector Machine and Virtual Ant colonies

6. 6 IF THESE 1° YEAR MEASUREMENTS WILL BE SUCCESSFULL WE WILL PROCEED WITH THE NEXT YEAR

7. 2° year In-vitro beam test Cultured human tumor cells will be used. The glioblastoma U373 and LN229 cell lines and the Non Small Cell Lung Cancer A549 line are already available at INFN-Milano (Radiobiology Laboratory. All these cell lines are derived from tumors that, due to their resistance to conventional therapies, are eligible for multimodal therapies and hadrontherapy. Dose- survival curves will be measured for cells irradiated with protons, C-ions and, for comparison, with 6 MeV photons. Irradiations with protons (therapeutic beam) and C-ions (50 keV/um) will be performed at INFN-LNS. The 6 MeV photon beam will be made available by Istituto Tumori, Milano. 7

8. 8 In-vitro beam test The results will be analyzed following the linear quadratic model of cell survival, in order to determine the alpha and beta parameters. RBE values for the different conditions will be determined and compared. 2° year