Click Reaction-Assisted Peptide Immune Checkpoint Blockade for Solid Tumor Treatment

Area of Science:

• Biomedical Engineering
• Immunotherapy
• Materials Science

Background:

• Immune checkpoint blockade (ICB) is challenged by poor antibody penetration in solid tumors.
• Developing strategies for enhanced drug delivery and efficacy in solid tumors is crucial.

Purpose of the Study:

• To develop a novel click reaction-assisted peptide immune checkpoint blockade (CRICB) strategy.
• To improve the penetration and accumulation of immune checkpoint inhibitors in solid tumors.
• To achieve enhanced tumor inhibition and prolonged PD-L1 occupancy.

Main Methods:

• Utilized DBCO-modified targeting peptides (TP) for PD-L1 binding.
• Employed azide-tethered assembled peptides (AP) for in situ self-aggregation via click reaction.
• Assessed peptide penetration in solid tumor tissues.
• Evaluated therapeutic efficacy and side effects in mouse tumor models (4T1 and CT26).

Main Results:

• TP-AP demonstrated significantly enhanced penetration (121.2 ± 15.5 μm) compared to antibodies (19.9 ± 5.6 μm).
• The CRICB strategy led to enhanced accumulation and prolonged PD-L1 occupancy.
• Significant tumor inhibition and negligible side effects were observed in vivo.

Conclusions:

• The CRICB strategy effectively overcomes the challenge of poor penetration in solid tumors.
• Assembling peptides via click chemistry offer a promising approach for enhanced ICB therapy.
• This strategy holds potential for broader biomedical applications in cancer immunotherapy.