Protease Profiling and Triggered Drug Delivery for Personalized Cancer Therapy

Introduction

Proteases are involved in all hallmarks of cancer and are key regulators of tumor progression. The difficulties to monitor protease activity in vivo with sufficient sensitivity and selectivity make the development of protease-targeting cancer drugs and the implementation of protease activity as a diagnostic and prognostic biomarker very challenging.

Project Aim

The aim of PROTECT is to develop a novel comprehensive protease activity profiling platform for cancer-associated extracellular proteases that can address the main limitations of current strategies for in vivo protease activity monitoring. The ambition is to enable a dramatic increase in sensitivity and multiplexing capabilities.

Methodology

1. Liposomal Activity-Based Sensors (LABS):

   • We will design LABS that can amplify proteolytic cleavage by triggering the release of liposome-encapsulated synthetic biomarkers.

2. Personalized Drug Delivery:

   • We will further leverage the possibilities to extract tumor-specific protease profiles for the development of personalized protease-triggered liposomal drug delivery vehicles (PROVES) for precision medicine.

3. Development of proMAPs:

   • Sophisticated protease-responsive membrane active peptides (proMAPs) will be developed to couple protease activity to biomarker and drug release.

4. Correlation Methods:

   • Methods to correlate biomarker release patterns to protease activity profiles in 3D breast cancer models will be explored.

Platform Repurposing

The PROTECT platform can then rapidly be repurposed for precision drug delivery. The PROVES concept will combine the excellent properties of liposomes for drug delivery and the optimal combination of proMAPs, based on the protease activity profile retrieved from the LABS, for optimized protease-triggered liposomal drug release.

Conclusion

Combined, the LABS and PROVES concepts represent a unique and comprehensive platform for diagnostics and personalized cancer therapy. The proposed work goes far beyond state-of-the-art and will address a significant and real bottleneck that hampers drug development and the exploitation of proteases as diagnostics and prognostic cancer biomarkers.