Peptide-dendrimer conjugates target and destruct neutrophil extracellular traps to block tumor metastasis

Area of Science:

• Biomaterials Science
• Cancer Research
• Immunology

Background:

• Neutrophil extracellular traps (NETs) promote tumor metastasis by interacting with CCDC25 on cell membranes.
• Existing cationic materials for NET disruption lack targeting specificity.
• Developing targeted therapies is crucial for inhibiting NET-facilitated metastasis.

Purpose of the Study:

• To design and synthesize a peptide-dendrimer conjugate (AAPVRnS(5-n)-G2.5) for targeted NET disruption.
• To investigate the NET-targeting and neutrophil elastase (NE)-responsive properties of the conjugate.
• To evaluate the efficacy of the conjugate in inhibiting tumor metastasis in vivo.

Main Methods:

• Synthesis and characterization of AAPVRnS(5-n)-G2.5 peptide-dendrimer conjugates.
• Assessment of NET targeting and NE responsiveness in vitro.
• Evaluation of DNA binding ability and zeta potential changes post-NE treatment.
• In vivo studies using a 4T1 orthotopic breast cancer mouse model to assess metastasis inhibition and toxicity.

Main Results:

• The synthesized AAPVRnS(5-n)-G2.5 conjugates demonstrated NET targeting and NE responsiveness.
• NE-treated conjugates (RnS(5-n)-G2.5) exhibited enhanced cationic properties and DNA binding.
• The conjugates effectively destroyed NETs, blocked NET-DNA/CCDC25 interaction, and inhibited NET-induced cytoskeleton remodeling.
• In vivo, AAPVR4S1-G2.5 significantly reduced lung and liver metastasis in breast cancer models with prolonged circulation and no obvious toxicity.

Conclusions:

• Peptide-dendrimer conjugates offer a targeted and responsive strategy for NET disruption.
• The developed materials effectively inhibit tumor metastasis by interfering with NETs.
• This approach presents a promising alternative for precise anti-metastasis therapy with reduced side effects.