Encapsulation of Gold-Based Anticancer Agents in Protease-Degradable Peptide Nanofilaments Enhances Their Potency

Abstract

We investigated the use of amphiphilic, protease-cleavable peptides as encapsulation moieties for hydrophobic metallodrugs, in order to enhance their bioavailability and consequent activity. Two hydrophobic, gold-containing anticancer agents varying in aromatic ligand distribution (Au(I)-N-heterocyclic carbene compounds 1 and 2) were investigated. These were encapsulated into amphiphilic decapeptides that form soluble filamentous structures with hydrophobic cores, varying supramolecular packing arrangements and surface charge. Peptide sequence strongly dictates the supramolecular packing within the aromatic core, which in turn dictates drug loading. Anionic peptide filaments can effectively load 1, and to a lesser extent 2, while their cationic counterparts could not, collectively demonstrating that loading efficiency is dictated by both aromatic and electrostatic (mis)matching between drug and peptide. Peptide nanofilaments were nontoxic to cancerous and noncancerous cells. By contrast, those loaded with 1 and 2 displayed enhanced cytotoxicity in comparison to 1 and 2 alone, when exposed to Caki-1 and MDA-MB-231 cancerous cell lines, while no cytotoxicity was observed in noncancerous lung fibroblasts, IMR-90. We propose that the enhanced in vitro activity results from the enhanced proteolytic activity in the vicinity of the cancer cells, thereby breaking the filaments into drug-bound peptide fragments that are taken up by these cells, resulting in enhanced cytotoxicity toward cancer cells.

Gold Complexes in Anticancer Therapy: From New Design Principles to Particle‐Based Delivery Systems

“…Finally, the use of amphiphilic, protease‐cleavable peptides to encapsulate hydrophobic metallodrugs was recently reported by Contel, Ulijn and co‐workers [290] . Thus, two lipophilic [Au I (NHC)Cl] complexes were encapsulated into amphiphilic decapeptides forming filamentous nano‐structures with hydrophobic cores ( P19 ), varying supramolecular packing arrangements and surface charge.…”

Next Generation Gold Drugs and Probes: Chemistry and Biomedical Applications

“…It is assumed that the proteolytic degradation of peptide filament encapsulating the drug facilitate the drug uptake by the cancer cells. 458 Hence, this highlights an interesting approach to improve drug selectivity for cancer cells and consequently its cytotoxic effect.…”

“…The gold-loaded nanostructures displayed significant cytotoxicity in MDA-MB-231 and Caki-1 (renal carcinoma) cells with selectivity compared to noncancerous cells, IMR-90 (lung fibroblast). It is assumed that the proteolytic degradation of peptide filament encapsulating the drug facilitate the drug uptake by the cancer cells . Hence, this highlights an interesting approach to improve drug selectivity for cancer cells and consequently its cytotoxic effect.…”

“…Illustration of drug-loaded peptides and structures of drugs and peptides used in this study. Reproduced from ref . Copyright 2022 American Chemical Society.…”

Modulating the Chemical Reactivity of Gold Complexes in Living Systems: From Concept to Biomedical Applications

“…Among them, N-heterocyclic carbene (NHC) has been demonstrated to be particularly useful since this ligand can be easily modified to tune lipophilicity, steric hindrance, and hence reactivities with thiols. , Berners-Price and co-workers have carefully examined the ligand exchanges between [Au­(NHC) 2 ] + and Cys or Sec, and a stepwise release of NHC ligand was observed together with a 20- to 80-fold higher reaction rate for Sec than Cys . This study has laid the foundation to develop a surge of NHC-gold­(I) complexes with different functionalities that can inhibit both thiol-enzymes and nonthiol targets. ,− Another useful type of carbon donor ligand is alkynyl. For example, Ott and co-workers prepared alkynyl gold­(I) complexes which showed increased stability, selective inhibition toward TrxR, and antiangiogenisis activity in zebrafish models .…”