Targeted Polymeric Nanoparticles: Radiolabelling with GA-67 and in vivo evaluation in a mouse model of pancreatic adenocarcinoma using single photon emission computerized tomography

Abstract

Nanoparticle (NP) based theranostics may play a pivotal role in oncology in the near future. However, determination of the pharmacokinetic (PK) properties of novel nanomedicines, which is essential for the determination of the effective dose and potential translation into the clinical setting, is extremely challenging. Radiolabelling of the NPs with positron or gamma emitters and subsequent imaging studies using nuclear imaging techniques can provide relevant information on the PK properties of novel nanomedicines, aiding in the selection of the most promising candidates while enabling the discontinuation of non-appropriate drugs at early stages in the process of drug development. Within the frame of the EU-funded project SaveMe , NP-based theranostic agents for the early detection and treatment of Pancreatic Cancer (PaCa, the fourth deadliest cancer type), have been developed. Different polymeric and protein-based NPs were synthesised by different partners and decorated with targeting moieties with high affinity for somatostatin (SST) or galectin (Gal) receptors, both over-expressed in PaCa cells. In this PhD thesis, the different particles have been radiolabelled with Ga-67 via formation of chelator-radiometal complexes or by taking advantage of unspecific interactions between the radionuclide and the NP core. After assessing radiochemical integrity of the labelled NPs, Single Photon Emission Computerised Tomography (SPECT) studies were carried out in a subcutaneous mouse model of PaCa, which was implemented by subcutaneous injection of Panc-1 (human pancreatic adenocarcinoma) cells. The biodistribution of the labelled NPs and the accumulation of NPs in the tumour could be determined from SPECT images, which were combined with Computerised Tomography (CT) images for proper localisation of the radioactive signal. Complementary studies were performed with Magnetic Resonance Imaging, which provided relevant information regarding tumour heterogeneity. Imaging studies enabled the selection of the most appropriate NP core and the investigation of the effect of the targeting moieties and other surface decorations on the accumulation of the NPs in the tumour. Results obtained with a SST-derived targeting moiety anchored to polymeric NPs prepared by partner CID suggested that these NPs might find application as therapeutic or diagnostic tools in the context of pancreatic cancer.