Protein Binding of a Novel Platinum-Based Anticancer Agent BP-C1 Containing a Lignin-Derived Polymeric Ligand

Elena Fedoros,Megan Westbury,Sergey Pigarev,Nikolay Solovyev,Natalya Ivanenko

doi:10.3390/app112211008

Abstract

Platinum (Pt) antineoplastic agents remain indispensable for the treatment of oncological disease. Pt-based drugs are mainly used in the therapy of ovarian cancer and non-small-cell lung carcinoma. A novel platinum-containing antineoplastic agent BP-C1 is a complex of diamminoplatinum with an oxygen-donor polymeric ligand of benzene-polycarboxylic acids, isolated from natural lignin. The aim of the study was to investigate ex vivo protein binding of BP-C1. Protein binding of BP-C1 was tested using equilibrium dialysis. Pooled blood plasma was used in the study. Control solutions contained the same dosages of BP-C1 in PBS (pH 7.2). Plasma and control solutions were submitted to equilibrium dialysis across a vertical 8 kDa cut-off membrane for 4 h at 37 °C under gentle shaking. Platinum was quantified in dialysis and retained fractions using inductively coupled plasma mass spectrometry after microwave digestion. The dialysis system was tested and validated; this showed no protein saturation with platinum. A medium degree of binding of platinum to macromolecular species of ca. 60% was observed. The study showed the maintenance of a high fraction of free BP-C1 in the bloodstream, facilitating its pharmacological activity.

Highlights

Platinum-based drugs have been actively exploited for the treatment of oncological diseases since the middle of the twentieth century [1,2]
The dialysis duration was tested in a preliminary experiment with dialysis tubes in a Float-A-Lyzer G2 Dialysis Device (Repligen, Rancho Dominguez, CA, USA) with 8–10 kDa cut-off, indicating that 2 h is sufficient for stable dialysis; cisplatin was used as a control compound—see Tables S1 and S2 (Supplementary Information)
Equilibrium dialysis is a gold-standard technique used when determining the concentration of free, non-protein-bound drugs [28]

Summary

Introduction

Platinum-based drugs have been actively exploited for the treatment of oncological diseases since the middle of the twentieth century [1,2]. Platinum (Pt) antineoplastic agents remain indispensable for the treatment of ovarian cancer and non-small-cell lung carcinoma [3,4]. The mechanism of action for these drugs is not fully understood; the most well-accepted pathway is the binding of active platinum moieties to DNA, forming non-reparable adducts and driving cancer cell apoptosis [5]. A novel platinum-containing antineoplastic agent BP-C1 was tested. BP-C1 contains two O-donor ligands in the coordination sphere of platinum similar to carboplatin (Figure 1b). The ligand in BP-C1 has a wide spectrum of biological activity [8]; the molecular mechanism is the interaction of the lignin-derived polymer with glucocorticoid and serotonin/5-HT1 receptors, regulating inflammatory responses [9]. Clinical trials of BP-C1 were undertaken in female patients with metastatic breast carcinoma

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