Human transferrins (hTf) are a family of single-chain glycoproteins, working as the iron transporter in blood. Cancer cells often require a high level of iron(III) in order to facilitate rapid cell growth and thereby express a high level of the hTf receptors (hTfR). The heterometal-transferrin complexes, such as ruthenium(III), gallium(III), indium(III), and titanium(IV) complexes, are still recognized by TfR, and can be thus transported to cells via TfR-mediated endocytosis. Accordingly, there is a potential use of hTf as a carrier for metal-based chemotherapeutic agents, allowing the targeted delivery of the metallodrugs to cancer cells.
The Wang’s group in the CAS Key Laboratory of Analytical Chemistry for Living Biosystems in ICCAS focus on developing novel analytical methods based on mass spectrometry to study the interaction between antitumor drugs and proteins, and the influences in the transportation, metabolism and activity of drugs. Taking advantage of molecular modelling and LC-MS analysis, they previously demonstrated the arene ligands of organometallic ruthenium anticancer complexes can control the binding of Ru centre to the only free thiol of albumin, inducing the oxidation of the thiol (Chem. Eur. J. 2009, 15, 6586-6594). They also indicated by LC-MS/MS analysis that the antitumor drug cisplatin can occupy the interdomain zinc site on human albumin via cross-linking, leading to hyperzincuria which is known to develop in patients treated with cisplatin (Chem. Commun. 2011, 47, 6006-6008). By comparing the interactions of cisplatin and Ru-based anticancer complexes with metallothionein, they found that under physiological conditions, the ability of replacing Zn2+ in metallothionein of cisplatin is much higher than that of Ru-based antitumor drugs. This may be related to the lower toxic side-effects of Ru-based antitumor drugs compared to cisplatin (Int. J. Mass Spectrom. 2011, 307, 79-84).
As a continuous effort in this attractive area, the researchers in Wang’s group have recently developed a MS-based approach in combination with molecular modelling and confocal laser scanning microscope imaging to study the interactions between Ru/Pt-based anticancer complexes and hTf. They found that organometallic ruthenium anticancer complexes tend to bind to the histidines on the surface of proteins, while cisplatin can coordinate to not only histidines, but also the methionines exposed on the surface. Moreover, the coordination of Ru or Pt to the protein does not affect the binding of Fe ions to hTf, and the ruthenated/platinated Fe-hTf complexes could still be recognized by hTfR and internalized via hTfR-mediated endocytosis. The Ru anticancer complexes bound to hTf can be released inside cells, so as to bind to DNA in the nucleus, thus the bioavailability of the Ru complexes can be well preserved. By contrast, the conjugation with hTf significantly reduced the cellular uptake of cisplatin and the ability of binding to DNA, leading to dramatic reduction of its cytotoxicity. These findings suggest that hTf can serve as a mediator for the targeting delivery of organometallic Ru anticancer complexes whereas the irreversible binding of cisplatin to hTf leads to deactivation or side-effect of cispaltin. This work has been published in Inorganic Chemistry (2013, 52, 5328-5338).
Figure 1 The schematic representation of the binding of Ru/Pt based antitumor drugs to hTf and the intracellular transportation of the protein-drug complexes.
