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

## TL;DR

This paper explores the challenges of using protease activity-based nanosensors for early breast cancer detection and highlights the need for design improvements.

## Contribution

The study identifies design limitations of protease activity-based nanosensors and proposes the need for more tumor-specific properties.

## Key findings

- A protease activity-based nanosensor with suitable half-life failed to accumulate in an invasive mammary tumor model.
- Nonspecific activations reduced the nanosensor's blood half-life and hindered tumor signal amplification in urine.
- The findings suggest the need for nanosensors that better target tumor-specific proteolytic activity.

## Abstract

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.