(676h) Chemically Tuned NIR Light-Activated Bionanoconjugates for the Selective Destruction of Tumor Cells in Heterocellular 3D Models and for Quantitative In Vivo tumor Imaging

The synthetic complexity involved in the nanofabrication of tumor specific bionanoconjugates and the lack of clinically relevant screening platforms to rapidly establish their selectivity are both major hurdles in their development. Using a fine-tuned synthetic chemical approach, we engineer NIR light-activated bionanoconjugates (NABs) directed towards the tumor-associated biomarker, epidermal growth factor receptor (EGFR), using the approved antibody cetuximab. In order to rapidly asses their efficacy, we developed a high-throughput 3D heterocelluar model of pancreatic ductal adenocarcinoma including patient-derived cancer-associated fibroblasts as a robust screening platform to evaluate the developed NABs. Using this 3D platform, we demonstrate that the NABs efficiently permeate the 3D tumor tissue within 1 hour and provide up to 8-fold binding specificity towards 3D tumor tissue. This resulted in a striking 16-fold improvement in targeted phototoxicity of the heterocellular 3D nodules following irradiation with non-toxic NIR light. To validate the tumor specificity of the NABs in vivo, we leveraged a powerful paired-nanotracer molecular imaging approach to validate their successful engagement with EGFR-positive tumors in vivo and are equally as available for binding as the natural ligand, EGF. The stepwise approach described here provides a rational workflow whereby the fine chemical tuning of NABs, combined with rapid testing in complex 3D tumor models and quantitative in vivo molecular imaging, promises to accelerate the translation of such therapeutic approaches with higher specificities and lower patient toxicities.