Biodistribution of anti‐diabetic Zn(II) complexes in human serum and in vitro protein‐binding studies by means of CZE–ICP‐MS

Abstract

Application of modern analytical technology for studying the fate of metallodrugs after administration to the blood is of utmost importance for drug development. Zn(II) compounds are under development as insulin-enhancing drugs with potential use in the treatment of diabetes. In comparison to the well-established vanadium compounds, especially the lower risk of adverse effects due to the essentiality of the element in biological processes is advantageous. Herein, CZE-ICP-MS studies on the interaction of Zn(II)-maltolato, -2-picolinato and -2,6-dipicolinato complexes with human serum proteins are discussed and modeling calculations were confirmed by experimental results. Studies with human serum reveal preference for HSA over other less abundant proteins and serum components.

Development of the application of speciation in chemistry

“…However, protein-metal equilibria cannot be excluded, especially in faster complexation processes with the proteins. Indeed, protein interactions were included in computer simulations of the distributions of Al(III) [32], V(IV)O [33], Zn(II) [34], Ga(III) [35], and Gd(III) [36] complexes in serum. In the case of speciation in natural/industrial waters, the redox processes, solubility properties, and adsorption interactions must also be considered (see Section 4.2).…”

“…Detailed speciation and spectroscopic methods have shown that under biological conditions, in the case of the V(IV)O containing antidiabetic compounds human serum transferrin (Tf) is the main V(IV)O transporter in the serum [33,68,69], whereas human serum albumin (HSA) is the main transporters in the case of the Zn(II) complexes [34]. Modeling calculations can determine the detailed distributions of metal ions among the LMM and HMM components of serum.…”

“…Modeling calculations can determine the detailed distributions of metal ions among the LMM and HMM components of serum. Various separation techniques such as ultrafiltration [70] and capillary zone electrophoresis inductively coupled plasma MS (CZE-ICP-MS) [34] have been employed in the fractionation of different LMM and HMM fractions to confirm the basic findings of the modeling calculations, e.g., the distribution of Zn(II)-dipic complexes in serum systems (0.1 mM, serum diluted with buffer: 1:4, 24 h incubation at 25C), where most of the Zn(II) was bound to HSA, although a minor amount of Zn(II) was bound to dipic, whereas no Zn(II) was bound to Tf (Fig. 3).…”

“…100 M level [159]. The potential interactions of drug candidate complexes in the serum with LMM components have been studied in detail by pH-potentiometry [34,70] based on modeling calculations of these binders (without the HMM components) with His and Cys, and their ternary complexes as primary Zn(II) binders.…”

“…2M also has considerable Zn(II) binding properties, but it is present at a much lower concentration in the blood serum than albumin (2-6 M), with conditional formation constants of log K 1 = 7.49 and log K 2 = 5.12 [168][169][170][171]. The third possible Zn(II) binder is Tf, where the Zn(II) binding constants are log K 1 = 7.8 and log K 2 = 6.4 (15 mM NaHCO 3 ) [172,173] If both the HMM and the LMM serum binders are considered together, then modeling calculations indicate that most of the total serum Zn(II) is bound to the serum proteins (~98%), where HSA is the primary binder (80-90%) [29,34,169,173] followed by 2M (5-15%) [169][170][171]. However, the role of apoTf is still under discussion [170,173] and it has been reported that a minority of Zn(II) circulates unbound or attached to LMM components in blood serum.…”