X-ray Absorption Spectroscopy of an Investigational Anticancer Gallium(III) Drug: Interaction with Serum Proteins, Elemental Distribution Pattern, and Coordination of the Compound in Tissue

Abstract

Tris(8-quinolinolato)gallium(III) (1, KP46) is a very promising investigational anticancer drug. Its interaction with serum proteins, elemental distribution, and coordination in tissue were investigated with X-ray absorption (XAS) methods. Model compounds with mixed O, N, and/or S donor atoms are reported. The coordination and structure of 1 in cell culture medium (minimum essential medium, MEM) and fetal calf serum (FCS) were probed by XANES and EXAFS. The interaction of 1 with the serum proteins apotransferrin (apoTf) and human serum albumin (HSA) was addressed as well. By application of micro-XAS to tissue samples from mice treated with 1, the gallium distribution pattern was analyzed and compared to those of physiological trace elements. The complex 1 turned out to be very stable under physiological conditions, in cell culture media and in tissue samples. The coordination environment of the metal center remains intact in the presence of apoTf and HSA. The gallium distribution pattern in tumor and liver tissue revealed high similarities to the distribution patterns of Zn and Fe, minor similarities to Cu and Ni, and no similarity to Ca.

Interaction of the anticancer gallium(III) complexes of 8-hydroxyquinoline and maltol with human serum proteins

“…The similar character of the 1 H and STD NMR spectra suggests that the complex does not decompose in the presence of HSA, the original ligand HQ is not replaced, and thus the coordination mode around Ga(III) is retained. The unchanged metal center of KP46 in the presence of HSA was also found by X-ray absorption spectroscopy measurements [16].…”

“…In addition, KP46 has a relatively high lipophilic character, which is an important issue when transport protein binding is considered. Only a few data can be found in the recent literature on the interaction of KP46 with serum proteins [10,[15][16][17], since such investigations are very often hampered by the low aqueous solubility of KP46 (36 μM [15]), and this can be a reason why the data are not congruent. A capillary electrophoresis-mass spectrometry method was used to study the interaction between KP46 and Tf or human serum albumin (HSA), and the metal ion was found to bind to Tf exclusively and only a low affinity toward HSA was observed [10].…”

“…A capillary electrophoresis-mass spectrometry method was used to study the interaction between KP46 and Tf or human serum albumin (HSA), and the metal ion was found to bind to Tf exclusively and only a low affinity toward HSA was observed [10]. On the other hand, X-ray absorption spectroscopy studies showed that the coordination environment of the metal center remains intact in the presence of human serum apotransferrin (apoTf) or HSA, and Hummer et al [16] suggested that the interaction mechanism is based on a noncovalent, more hydrophobic binding. HSA is the most abundant blood plasma protein (630 μM) and has nonspecific binding pockets where chemically diverse endogenous and exogenous compounds can bind [18].…”

Coordination compounds in cancer: Past, present and perspectives

“…20b). Interestingly, this complex is not destroyed in the blood (Enyedy et al, 2012(Enyedy et al, , 2015Hummer et al, 2012). It shows in vitro a cytotoxic activity higher than that of gallium nitrate (Lessa et al, 2012).…”

Rákellenes gallium- és platinafém komplexek oldatkémiája, kölcsönhatásuk vérszérum-fehérjékkel és DNS-sel

“…CE-MS vizsgálatok szerint a fémion szinte kizárólag Tf-hez kötődött, míg a HSA szerepe igen mérsékelt volt [72]. Másrészről röntgenabszorpciós spektroszkópiás mérések szerint a fémion körüli koordinációs szféra nem változott sem Tf, sem HSA jelenlétében, ami a nem koordinatív, másodlagos kötésmódok lehetőségét veti fel [73]. A GaM oldhatósága sokkal jobb (~24 mM), kevésbé lipofil komplex (lgP = 0,41) [65], szérumfehérjékhez való kötődéséről azonban nem sokat tudunk.…”