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Published on: May 3, 2024
Spatiotemporal Self-Assembly of Peptides Dictates Cancer-Selective Toxicity
Seongeon Jin1, M T Jeena1, Batakrishna Jana1
1Department of Chemistry, School of Natural Science, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
Abstract:
The intracellular or pericellular self-assembly of amphiphilic peptides is emerging as a potent cancer therapeutic strategy. Achieving the self-assembly of amphiphilic peptides inside a cell or cellular organelle is challenging due to the complex cellular environment, which consists of many amphiphilic biomolecules that may alter the self-assembling propensity of the synthetic peptides. Herein, we show that the hydrophobic-hydrophilic balance of the amphiphilic peptides determines the self-assembling propensity, thereby controlling the fate of the cell. A series of peptides were designed to target and self-assemble inside the mitochondria of cancer cells. The hydrophobicity of the peptides was tuned by varying their N-terminus capping. The analysis showed that the largest hydrophobic peptide was self-assembled before reaching the mitochondria and showed no selectivity toward cancer cells, whereas hydrophilic peptides could not self-assemble inside the mitochondria. Optimum balance between hydrophobicity and hydrophilicity is a critical factor for achieving self-assembly inside the mitochondria, thereby providing greater selectivity against cancer cells.
Insights
Optimizing peptide hydrophobicity is key for cancer therapy. Fine-tuning this balance enables self-assembly within mitochondria, enhancing cancer cell selectivity.
Area of Science:
- Biochemistry
- Nanotechnology
- Cancer Therapeutics
Background:
- Intracellular self-assembly of amphiphilic peptides shows promise for cancer treatment.
- The cellular environment complicates peptide self-assembly due to competing biomolecules.
Purpose of the Study:
- To investigate how the hydrophobic-hydrophilic balance of amphiphilic peptides influences their self-assembly within cancer cells.
- To design peptides that selectively self-assemble inside cancer cell mitochondria for therapeutic purposes.
Main Methods:
- Systematic design of amphiphilic peptides with varied N-terminus capping to tune hydrophobicity.
- Evaluation of peptide self-assembly propensity and cellular targeting, specifically to mitochondria.
- Assessment of cellular fate and selectivity based on peptide characteristics.
Main Results:
- Peptides with excessive hydrophobicity self-assembled prematurely, losing cancer cell selectivity.
- Highly hydrophilic peptides failed to self-assemble within the mitochondria.
- An optimal hydrophobic-hydrophilic balance was identified as crucial for mitochondrial self-assembly.
Conclusions:
- The hydrophobic-hydrophilic balance critically dictates peptide self-assembly and cellular fate.
- Achieving targeted intracellular self-assembly requires precise control over peptide amphiphilicity.
- Optimized peptides demonstrate enhanced selectivity against cancer cells through mitochondrial self-assembly.
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