Influence of the binding of reduced NAMI-A to human serum albumin on the pharmacokinetics and biological activity

Abstract

NAMI-A is a ruthenium-based drug endowed with the unique property of selectively targeting solid tumour metastases. Although two clinical studies had already been completed, limited information exists on the behavior of NAMI-A after injection into the bloodstream. PK data in humans informs us of a rather low free drug concentration, of a relatively high half-life time of elimination and of a linear relationship between the administered dose and the corresponding AUC for up to toxic doses. In the present study, we examined the chemical kinetics of albumin binding with or without the presence of reducing agents, and we evaluated how these chemical aspects might influence the in vivo PK and the in vitro ability of NAMI-A to inhibit cell migration, which is a bona fide, rapid and easy way to suggest anti-metastatic properties. The experimental data support the binding of NAMI-A to serum albumin. The reaction is facilitated when the drug is in its reduced form and, in agreement with already reported data, the adduct formed with albumin maintains the biological activity of the ruthenium drug. The formation of the adduct is favored by low ratios of NAMI-A : HSA and by the reduction of the drug with ascorbic acid. The difference in in vivo PK and the faster binding to albumin of the reduced NAMI-A seem to suggest that the drug is not rapidly reduced immediately upon injection, even at low doses. Most probably, cell and protein binding prevail over the reduction of the drug. This observation supports the thesis that the reduction of the drug before injection must be considered relevant for the pharmacological activity of NAMI-A against tumour metastases.

Bis‐picolinamide Ruthenium(III) Dihalide Complexes: Dichloride‐to‐Diiodide Exchange Generates Single trans Isomers with High Potency and Cancer Cell Selectivity

“…The reduction of NAMI‐A strongly depends on pH and is accelerated on increasing the pH, resulting in the generation of active Ru II product(s) . Amongst potential intracellular targets, reduced NAMI‐A binds human serum albumin . Unlike cisplatin, DNA is not the main pharmacological target for NAMI‐A, although it has been reported that this complex can bind to DNA and inhibit DNA replication in vitro .…”

“…[27] Amongst potential intracellular targets,r educed NAMI-Ab inds human serum albumin. [28] Unlike cisplatin, DNA is not the main pharmacological target for NAMI-A, although it has been reportedt hat this complex can bind to DNA and inhibit DNA replication in vitro. [29,30] KP1019 is thought to be reduced in vivo to an active Ru II species and also offers ad ifferent mode of action to cisplatin, with increased selectivity.…”

Spectroscopic studies on interactions of the tetrakis(acetato)chloridodiruthenium(II,III) complex and the Ru2(II,III)-NSAID-derived metallodrugs of ibuprofen and ketoprofen with human serum albumin

“…NAMI-A binding to HSA has been suggested to involve covalent interactions. However, it has also been found that the Ru(II)-reduced form of the complex favors protein binding, although the reduction is disfavored for the covalently bonded in relation to the non-covalently bonded species (which are readily reduced by ascorbic acid) [68][69][70][71]. Conversely, the binding of KP1019 to HSA occurs mostly in a noncovalent manner, probably due to favorable interactions of the indazole ligands with the hydrophobic domains of the protein [72].…”

Influence of redox activation of NAMI-A on affinity to serum proteins: transferrin and albumin

“…It was proposed that reduction of NAMI-A prior to injection improves pharmacological activity against tumor metastases [18]. The binding of NAMI-A to serum albumin was facilitated when the drug was in its reduced form [18]. Due to relatively high reduction potential (+ 235 mV) [19] NAMI-A can be reduced by biological reductants in vivo.…”

“…It was proposed that reduction of NAMI-A prior to injection improves pharmacological activity against tumor metastases [18]. The binding of NAMI-A to serum albumin was facilitated when the drug was in its reduced form [18].…”