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Updated: Feb 6, 2026
Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
Novel cell-penetrating-amyloid peptide conjugates preferentially kill cancer cells
John R Veloria1, Luxi Chen2, Lin Li1
1Department of Biological Sciences , The University of Texas at Dallas , 800 W. Campbell Rd , Richardson , TX 75080 , USA.
Abstract:
The goal of this study was to develop a peptide which could use the toxic effects of amyloid, a substance which is the hallmark of over 25 known human diseases, to selectively kill cancer cells. Here we demonstrate that two separate amyloid-forming hexapeptides, one from the microtubule associated protein Tau involved in formation of paired helical filaments of Alzheimer's disease, and the other an amyloid forming sequence from apolipoprotein A1, when conjugated to a cell penetrating peptide (CPP) sequence, form toxic oligomers which are stable for up to 14 h and able to enter cells by a combination of endocytosis and transduction. The amyloid peptide conjugates showed selective cytotoxicity to breast cancer, neuroblastoma and cervical cancer cells in culture compared to normal cells. Fluorescence imaging experiments showed the CPP-amyloid peptide oligomers formed intracellular fibrous amyloid, visible in the endosomes/lysosomes, cytosol and nucleus with thioflavin S (ThS) staining. Further experiments with rhodamine-conjugated Dextran, propidium iodide (PI), and acridine orange (AO) suggested the mechanism of cell death was the permeability of the lysosomal membrane brought about by the formation of amyloid pores. Cytotoxicity could be abrogated by inhibitors of lysosomal hydrolases, consistent with a model where lysosomal hydrolases leak into the cytosol and induce cytotoxicity in subsequent downstream steps. Taken together, our data suggest that CPP-amyloid peptide conjugates show potential as a new class of anti-cancer peptides (ACPs).
Insights
Researchers developed amyloid peptides linked to cell-penetrating peptides (CPPs) that selectively kill cancer cells. These CPP-amyloid conjugates form toxic amyloid structures, offering a novel approach for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Amyloidogenic peptides are implicated in over 25 human diseases.
- Targeting cancer cells selectively remains a significant challenge in oncology.
Purpose of the Study:
- To develop a novel peptide capable of selectively killing cancer cells by leveraging the inherent toxicity of amyloid.
- To investigate the potential of amyloid-peptide conjugates as anti-cancer agents.
Main Methods:
- Conjugation of amyloid-forming hexapeptides (from Tau and apolipoprotein A1) to a cell-penetrating peptide (CPP) sequence.
- Assessment of oligomer stability, cellular uptake mechanisms (endocytosis and transduction), and cytotoxicity against various cancer cell lines.
- Intracellular localization studies using fluorescence imaging and thioflavin S staining.
- Mechanistic studies involving lysosomal membrane permeability and the role of lysosomal hydrolases.
Main Results:
- CPP-amyloid peptide conjugates formed stable, toxic oligomers capable of cellular entry.
- Selective cytotoxicity was observed against breast cancer, neuroblastoma, and cervical cancer cells, with minimal impact on normal cells.
- Intracellular amyloid formation was confirmed within endosomes/lysosomes, cytosol, and nucleus.
- Cell death was attributed to lysosomal membrane permeabilization, potentially mediated by amyloid pores and subsequent hydrolase leakage.
Conclusions:
- CPP-amyloid peptide conjugates represent a promising new class of anti-cancer peptides (ACPs).
- The study elucidates a mechanism of cancer cell death involving amyloid-induced lysosomal damage.
- This approach offers a potential strategy for targeted cancer therapy by exploiting amyloid's cytotoxic properties.
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