Encapsulation of the Dinuclear Trithiolato‐Bridged Arene Ruthenium Complex Diruthenium‐1 in an Apoferritin Nanocage: Structure and Cytotoxicity

Abstract

The effects of encapsulating the cytotoxic dinuclear trithiolato‐bridged arene ruthenium complex [(η6‐p‐MeC6H4iPr)2Ru2(μ2‐S‐p‐C6H4tBu)3]Cl (DiRu‐1) within the apoferritin (AFt) nanocage were investigated. The DiRu‐1‐AFt nanocarrier was characterized by UV/Vis spectroscopy, ICP‐MS, CD and X‐ray crystallography. In contrast to previously reported Au‐ and Pt‐based drug‐loaded AFt carriers, we found no evidence of direct interactions between DiRu‐1 and AFt. DiRu‐1‐AFt is cytotoxic toward immortalized murine BALB/c‐3T3 fibroblasts transformed with SV40 virus (SVT2) and human epidermoid carcinoma A431 malignant cells, and exhibits moderate selectivity for these cancer cells over normal BALB/c‐3T3 cells. DiRu‐1‐AFt triggers the production of reactive oxygen species, depolarization of mitochondrial membrane potential, and induces cell death via p53‐mediated apoptosis. Comparison between our data and previous results suggests that the presence of specific interactions between a metal‐based drug and AFt within the protein cage is not essential for drug encapsulation.

Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity

“…Since more than one molecule of AP-1 per AFt chain is present, analysis of the protein structure points out that there are a lot of free AP-1 molecules trapped within the bulk. Similar results were found for other metallodrug-encapsulated Ft systems [40][41][42]. These molecules are responsible for the biological activity of the nanocomposite.…”

Ferritin Nanocage: A Versatile Nanocarrier Utilized in the Field of Food, Nutrition, and Medicine

“…The cell experiments showed that ferritin-cisplatin NPs could inhibit the growth of tumor cells slowly and continuously, and enhance the cell absorption of cisplatin [55,123]. Similar to cisplatin, alternative metal compounds based on Ru and Au have been prepared and evaluated for their cytotoxic activity in recent years, mostly by Merlino and co-workers [89,[92][93][94][95]. The adducts of these compounds with ferritin are less toxic than free drugs and are moderately selective towards cancer cells compared with non-malignant cells [80].…”

“…However, passive diffusion of some metallic compounds into apoferritin turned out to be unfavorable, attributed to the limited pore size of the cage shell. Therefore, many metallodrugs including cisplatin [ 55 ], Auoxo3 [ 92 ], Auoxo4, Au2phen [ 93 ], 4-PF6 [ 94 ], Di-Ruthenium-1 [ 95 ], [Ru(bpy) 2 dppz] 2+ , [Ru(phen) 2 dppz] 2+ , and [Ru(bpy) 3 ] 2+ [ 96 ] have been encapsulated into ferritin cage through biomineralization coupled with pH-induced disassembly and reassembly. The binding efficiency depends on the metal ion, ferritin species, and preparation conditions.…”

“…Until now, several metallodrugs including cisplatin, carboplatin, oxaliplatin [ 55 , 122 , 123 ], Auoxo3 [ 92 ], Auoxo4, Au2phen [ 93 ], 4-PF6 [ 94 ], NAMI A [ 89 ], Ru(II)(η 6 -p-cymene) [ 90 ], Di-Ruthenium-1[ 95 ], [Ru(bpy) 2 dppz] 2+ , [Ru(phen) 2 dppz] 2+ , and [Ru(bpy) 3 ] 2+ [ 96 ], as well as non-metallic drugs including DOX [ 21 ], curcumin [ 124 ], and cytochrome C [ 62 ], have been encapsulated in ferritin cavity to improve their bioavailability, tumor-selectivity, and cellular permeability and reduce the toxicity to normal cells. Guo and co-workers first proposed the cisplatin encapsulation and explored the cell absorption of ferritin-cisplatin nanoparticles (NPs) and their applications in tumor therapy.…”

Ferritin nanocomposites for the selective delivery of photosensitizing ruthenium-polypyridyl compounds to cancer cells

“…In this regard, only a few examples concerning the encapsulation of Ru( ii ) compounds into ferritin nanocages, accomplished by the pH assisted method, have been reported so far. Merlino and coworkers 37 encapsulated up to 36 molecules of [(h 6 - p -MeC 6 H 4 iPr) 2 Ru 2 (m 2 -S- p -C 6 H 4 t Bu) 3 ]Cl per ferritin cage whereas the hydrophobic [Ru(bpy) 3 ] 2+ , [Ru(bpy) 2 dppz] 2+ and [Ru(phen) 2 dppz] 2+ compounds reported by Feng et al 30 were loaded in a ratio between 7–40 molecules per ferritin cage. However, all these studies referred to horse-spleen ferritin.…”