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Dual Enzyme-Responsive Zwitterionic Peptide for High Cancer Selectivity via Intralysosomal Self-Assembly.

Dohyun Kim1, Jiwon Jang1, Seongeon Jin1

  • 1Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.

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This study introduces a novel peptide amphiphile that selectively targets cancer cells. The assembly self-assembles inside cancer cells, leading to cell death with minimal toxicity to healthy tissues.

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Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Cancer Research

Background:

  • Chemotherapy faces challenges due to severe side effects from off-target toxicity.
  • Peptide amphiphiles offer biocompatible alternatives but struggle with cancer selectivity.
  • Enzyme-instructed self-assembly is a promising strategy for targeted drug delivery.

Purpose of the Study:

  • To develop a dual enzyme-responsive peptide amphiphile for enhanced cancer cell targeting.
  • To investigate the sequential enzymatic process for selective cancer cell death.
  • To evaluate the anti-cancer efficacy and in vivo toxicity of the designed peptide amphiphile.

Main Methods:

  • Designed a zwitterionic peptide amphiphile with dual enzyme responsiveness (MMP and Cathepsin B).
  • Investigated matrix metalloproteinase (MMP)-induced disassembly and cathepsin B-instructed assembly within lysosomes.
  • Assessed lysosomal membrane permeabilization and cancer cell death induction.
  • Evaluated in vivo anti-tumor activity and toxicity in a human colorectal adenocarcinoma xenograft model.

Main Results:

  • The peptide amphiphile demonstrated sequential enzymatic assembly within cancerous lysosomes.
  • This process led to lysosomal membrane permeabilization and cancer cell death at low micromolar concentrations.
  • Achieved a high cancer selectivity index of 64.1.
  • Showed significant tumor regression in vivo with no observed toxicity.

Conclusions:

  • The dual enzyme-responsive peptide amphiphile exhibits high cancer selectivity.
  • This approach offers a promising strategy for developing safer and more effective cancer therapeutics.
  • The designed system effectively induces cancer cell death and tumor regression with minimal toxicity.