Feasibility of a Protease Activity-Based Nanosensor for Breast Cancer Screening

Early detection of any form of cancer increases the number of successful treatments, but a lack of predictive biomarkers is limiting progress as low tumor-to-background ratios cause current tumor biomarkers to miss early signs of disease. Activity-based nanosensors, sensing nanoparticles administered in a prodiagnostic form, tackle this limitation by generating synthetic biomarkers at disease sites and leveraging enzymatic turnover and urinary enrichment to amplify tumor signals that would otherwise remain hidden. We inform that successful activity-based nanosensor tumor accumulation requires more than engineered nanoparticles with size, surface charge, and shape to ease the entry into tumors and the use of tumor models known to have vasculature permeable to nanoparticles. We found that a protease activity-based nanosensor with a half-life amenable to distribution in organs did not accumulate in an invasive mammary tumor model characterized by diffusive and active transport entry of nanoparticles with sizes within our nanosensor size distribution. Moreover, nonspecific and off-target activations decreased the nanosensor half-life in blood, which further aided in lowering the entry into tumors, yielding no distinct increases in the tumor activity signal in urine. These findings prompted refinements of the current design criteria of activity-based nanosensors, pushing for the development of nanosensors that rely on more specific properties of tumor proteolytic activity.