Urokinase-controlled tumor penetrating peptide

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Tumor penetrating peptides require C-terminal exposure of a CendR element for neuropilin-1 (NRP-1) binding and tissue penetration.
• The proteases responsible for activating these peptides are largely unknown.
• Designing peptides activated by specific tumor proteases is a key challenge in cancer therapy.

Purpose of the Study:

• To design and validate a novel tumor-penetrating peptide activated by a specific tumor protease.
• To investigate the mechanism of activation and tumor targeting of the designed peptide.
• To explore the potential of this strategy for targeted drug delivery in cancer.

Main Methods:

• De novo design of a peptide (uCendR) based on urokinase-type plasminogen activator (uPA) cleavage motif.
• Expression of uCendR on phage and conjugation to silver nanoparticles.
• In vitro cleavage assays with uPA and binding studies with NRP-1.
• In vivo studies in mice with uPA-overexpressing breast tumors.
• Evaluation of cellular internalization and tumor penetration in explants.

Main Results:

• The designed uCendR peptide was specifically cleaved by uPA.
• Cleavage triggered binding to NRP-1 and NRP-1-expressing cells.
• uCendR peptide and nanoparticles showed preferential accumulation in tumors after systemic administration.
• Combination with a tumor-homing module (CRGDC) enhanced internalization and penetration.

Conclusions:

• The study demonstrates the successful design of a tumor-penetrating peptide activated by a specific tumor protease (uPA).
• This protease-activated strategy holds promise as a generic approach for targeted delivery of payloads in cancer therapy.
• The findings support the development of novel therapeutic strategies leveraging tumor-specific protease activity.