Quadruply Stranded Metallo-Supramolecular Helicate [Pd₂(hextrz)₄]⁴⁺ Acts as a Molecular Mimic of Cytolytic Peptides

[Pd₂(hextrz)₄]⁴⁺ is a quadruply stranded helicate, a novel bioinorganic complex designed to mimic the structure and function of proteins due to its high stability and supramolecular size. We have previously reported that [Pd₂(hextrz)₄]⁴⁺ exhibited cytotoxicity toward a range of cell lines, with IC₅₀ values ranging from 3 to 10 μM. Here we demonstrate that [Pd₂(hextrz)₄]⁴⁺ kills cells by forming pores within the cell membrane, a mechanism of cell death analogous to the naturally occurring cytolytic peptides. [Pd₂(hextrz)₄]⁴⁺ induced cell death is characterized by an initial influx of Ca²⁺, followed by nuclear condensation and mitochondrial swelling. This is accompanied by progressive cell membrane damage that results in the formation of large blebs at the cell surface. This allows the efflux of molecules from the cell leading to loss of cell viability. These data suggest that it may be possible to design metallo-supramolecular complexes to mimic the cytotoxic action of pore forming proteins and peptides and so provide a new class of drug to treat cancer, autoimmune disorders, and microbial infection.