Enzyme-mimetic, cascade catalysis based on self-assembly of triblock polypeptides for tumor therapy

Abstract

Peptide self-assembly can reproduce the structures and functionalities of the active sites of natural enzymes since they share essential similarities i.e., they are both composed of encoded amino acids and assembled through non-specific and weak supramolecular interactions. Copper metalloenzymes contain a specific ‘His-brace’ structural unit which can perform a peroxygenase catalytic pathway with the generation of hydroxyl radicals based on Fenton-type reactions. In mimicry of the functionality of ‘His-brace’, a triblock polypeptide, HxK10L10, was designed and synthesized with oligohistidines terminated block which can chelate copper ions. The self-assembly pathways of its diblock precursor (KnLm) and itself were systematically investigated i.e., the responsiveness to pH and Cu2+ ions. The assembled (Cu2+)H6K10L10 shows spherical micelles at mild acidic environments and becomes fibrils at neutral pH. Furthermore, (Cu2+)H6K10L10 can perform Fenton-type chemistry that converting hydrogen peroxide into hydroxyl radicals. Such capability can combat tumors through disrupting intracellular redox homeostasis. The treatment efficacy can be promoted by utilizing a customized nanomedicine system, (Cu2+)H6K10L10-GOx, where the administered glucose oxidase induces starvation and supplies hydrogen peroxide thereby further increasing the production of hydroxyl radicals. The synthetic triblock polypeptide as coordinated ligands can function with other metal ions or components. The metal-mediated structures and functionalities through the self-assembly can facilitate on-demand manipulation and functionalization of metallo-nanodrugs with diverse therapeutic functions.