Novel Matrixyl-Derived Lipopeptide C16KTTβAH Selectively Kills Breast Cancer Cells and Forms High-Modulus Hydrogels

Peptide-based biomaterials are a major area of research due to their biocompatibility and potential for therapeutic applications. Specifically, self-assembling peptides that can form hydrogels are sought after for drug delivery, tissue engineering, and direct therapeutic action. Lipopeptides, which combine a peptide sequence with a lipid chain, often exhibit enhanced self-assembly properties. This study focuses on designing a novel lipopeptide by combining a sequence from the well-known "Matrixyl" family of cosmetic peptides (KTT) with the bioactive carnosine dipeptide (βAH). The goal is to create a multi-functional material that not only possesses unique physical properties like hydrogel formation but also exhibits targeted biological activity, such as selective anti-cancer effects, a significant challenge in oncology.

Researchers designed and synthesized a novel lipopeptide, C16KTTβAH, by attaching a hexadecyl (C16) lipid chain to a peptide sequence containing the KTT tripeptide from Matrixyl and the βAH dipeptide from carnosine. They investigated its self-assembly properties in water, phosphate-buffered saline (PBS), and cell culture media, measuring the critical aggregation concentration. They used imaging techniques to visualize the resulting nanostructures. The anti-cancer activity of C16KTTβAH was assessed in vitro using two model breast cancer cell lines (MCF-7) and two fibroblast cell line controls to determine selective cytotoxicity. Finally, the hydrogels formed by the lipopeptide were tested for their ability to absorb and release the model diagnostic compound Congo red.

The lipopeptide C16KTTβAH self-assembles into β-sheet nanotape structures above a critical aggregation concentration. In PBS, these nanotapes form bundles, leading to hydrogelation. These hydrogels demonstrated tunable stiffness based on concentration and aqueous conditions, with direct dissolution in PBS creating stiff gels. Furthermore, injecting dilute aqueous solutions into PBS produced hydrogels with exceptionally high modulus compared to previously reported β-sheet peptide materials. The peptide also showed selective, concentration-dependent cytotoxicity against MCF-7 breast cancer cells in the mM concentration range.

Importantly, this cytotoxic effect occurred below the critical aggregation concentration, indicating that the anti-cancer activity is an intrinsic property of the individual lipopeptide molecules, not a result of their self-assembled structures. The resulting hydrogels also demonstrated the ability to slowly uptake and release the model dye, Congo red.