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Published on: September 6, 2024
Glucuronidase-Instructed Glycopeptide Self-Assembly for Selective Killing of Cancer Cells through Lysosomal Membrane
Zhongxin Xu1, Changdong He1, Xinyu Li1
1State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, and School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Abstract:
Current cancer treatments face significant challenges, including limited tumor specificity and drug resistance. Enzyme-instructed supramolecular peptide assembly targeting lysosomes offers a promising strategy to address these issues; however, self-assembling units that withstand lysosomal conditions are still scarce. Herein, we present a versatile glycopeptide incorporating glucuronic acid and glucose that undergoes glucuronidase-triggered self-assembly to form nanofibers, leading to lysosomal membrane permeabilization (LMP) in cancer cells. Mechanistic studies revealed that in glucuronidase-overexpressing HepG2 cells, glycopeptide assembly induces cytoskeletal disruption and apoptosis. The involvement of carbohydrate-binding receptor in enhancing the cellular entry of glycopeptides and improving proteolytic stability highlights the importance of glycan modification. Notably, combining this glycopeptide with cisplatin or Adriamycin results in synergistic cytotoxicity, including in drug-resistant cancer cell lines. These findings establish a novel, LMP-inducing glycopeptide scaffold for developing targeted approaches for cancer treatment.
Insights
A novel glycopeptide triggers self-assembly in cancer cells, causing lysosomal membrane permeabilization and apoptosis. This approach enhances chemotherapy efficacy, even in drug-resistant cancers.
Area of Science:
- Biochemistry
- Materials Science
- Oncology
Background:
- Current cancer therapies suffer from poor tumor specificity and acquired drug resistance.
- Enzyme-instructed supramolecular peptide assembly targeting lysosomes is a promising strategy, but suitable self-assembling units are limited.
- Lysosomal membrane permeabilization (LMP) is a key mechanism for inducing cancer cell death.
Purpose of the Study:
- To develop a novel glycopeptide that self-assembles upon enzyme-triggering within cancer cells.
- To investigate the glycopeptide's ability to induce lysosomal membrane permeabilization (LMP) and subsequent cancer cell death.
- To evaluate the synergistic effects of the glycopeptide with existing chemotherapeutic agents.
Main Methods:
- Synthesis of a versatile glycopeptide incorporating glucuronic acid and glucose.
- Glucuronidase-triggered self-assembly into nanofibers within cancer cells.
- Assessment of lysosomal membrane permeabilization (LMP), cytoskeletal disruption, and apoptosis induction.
- Evaluation of cellular uptake, proteolytic stability, and synergistic cytotoxicity with cisplatin and Adriamycin.
Main Results:
- The glycopeptide self-assembled into nanofibers, inducing LMP in glucuronidase-overexpressing cancer cells (HepG2).
- Glycopeptide assembly led to cytoskeletal disruption and apoptosis.
- Carbohydrate-binding receptor involvement enhanced cellular entry and proteolytic stability.
- Combination therapy demonstrated synergistic cytotoxicity, overcoming drug resistance.
Conclusions:
- A novel glycopeptide scaffold capable of enzyme-triggered self-assembly and LMP induction was developed.
- Glycan modification is crucial for enhancing cellular uptake and stability.
- This approach offers a promising strategy for targeted cancer therapy, potentially overcoming drug resistance.
