Preclinical evaluation of theranostic strategy using nanoplatform and transferrin to target hyperactivity of cMYC in the context of non-small cell lung cancer

Non-small cell lung cancer affects 1.3 million people annually worldwide. The cMYC pathway regulates a large number of physiological processes and is hyperactivated in many cancers, including lung cancers. Due to the high avidity of cancer cells for iron, transferrin receptor complex (TFRC) has been demonstrated to be overexpressed when the cMYC pathway is hyperactivated. On this basis, there has been extensive interest in targeting TFRC therapeutically and in imaging TFRC expression. Our objective here is to develop a theranostic method targeting the transferrin receptor. We propose to target TFRC through a ligand scaffold based on a peptide able to be radiolabelled with either 18-Fluor (18F) for imaging or with 177-Lutetium (177Lu) for internal radiotherapy. To fully exploit the internal radiotherapy potential, nano-radioenhencer agent (platinum agent) will be used to exalt the irradiation impact. We radiolabelled the anti-TFRC peptide thanks to direct 18F labeling or via the conjugation of a chelate for 177Lu. We carried out in vitro tests to select a cell line overexpressing TFRC (human and murine). We evaluated the ability of the modified peptide to bind to TFRC thanks to binding assays. C57BL/6J mice were implanted with NSCLC (CMT167) or melanoma (B16F10) xenografts to establish the biodistribution of the new theranostic platform and the nanoparticles distribution. The distribution of the nanoparticles was also assessed by PET imaging. We radiolabelled and validated in vitro the functionality of the peptide with specific radiolabelling through a pyridine modified prosthetic group. The affinity of the modified peptide to TFRC remains sufficient to accumulate specifically within the tumor (Kd∼500 nM). We were able to assess the ability of the peptide to bind to TFRC by preclinical PET imaging through pharmacokinetic and biodistribution data. Nanoparticle presents a high tumor uptake (4.5%ID/cc, at 24 h). High liver TFRC expression can limit the performance of such cMYC theranostic platform. The peptide distribution may present some advantages to decreasing liver accumulation. The biodistribution and pharmacokinetics of either the nanoparticles or the peptides offer a promising therapeutic perspective. This novel therapeutic approach will have the potential to redirect the community's effort to ablative reagents that target downstream pathobiology regulated by cMYC.