Controversial Role of Transferrin in the Transport of Ruthenium Anticancer Drugs.

Abstract

Ruthenium complexes are at the forefront of developments in metal-based anticancer drugs, but many questions remain open regarding their reactivity in biological media, including the role of transferrin (Tf) in their transport and cellular uptake. A well-known anticancer drug, KP1019 ((IndH)[RuIIICl4(Ind)2], where Ind = indazole) and a reference complex, [RuIII(nta)2]3- (nta = nitrilotriacetato(3-)) interacted differently with human apoTf, monoFeTf, or Fe2Tf. These reactions were studied by biolayer interferometry (BLI) measurements of Ru-Fe-Tf binding to recombinant human transferrin receptor 1 (TfR1) in conjunction with UV-vis spectroscopy and particle size analysis. Cellular Ru uptake in human hepatoma (HepG2) cells was measured under the conditions of the BLI assays. The mode of Tf binding and cellular Ru uptake were critically dependent on the nature of Ru complex, availability of Fe(III) binding sites of Tf, and the presence of proteins that competed for metal binding, particularly serum albumin. Cellular uptake of KP1019 was not Tf-mediated and occurred mostly by passive diffusion, which may also be suitable for treatments of inoperable cancers by intratumoral injections. High cellular Ru uptake from a combination of [RuIII(nta)2]3- and Fe2Tf in the absence of significant Ru-Tf binding was likely to be due to trapping of Ru(III) species into the endosome during TfR1-mediated endocytosis of Fe2Tf.

• Authors: Aviva Levina, Anthony R M Chetcuti, Peter A Lay
• Journal: Biomolecules (Biomolecules) Vol. 12 Issue 9 (09 18 2022) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 36139158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Ferric Compounds
• Indazoles
• Organometallic Compounds
• Receptors, Transferrin
• Ruthenium Compounds
• Serum Albumin
• Transferrin
• indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III))
• Ruthenium

Topics

• Antineoplastic Agents (chemistry)
• Ferric Compounds (metabolism)
• Humans
• Indazoles (chemistry)
• Organometallic Compounds (chemistry)
• Receptors, Transferrin (metabolism)
• Ruthenium (chemistry, pharmacology)
• Ruthenium Compounds
• Serum Albumin
• Transferrin (metabolism)