Please cite this article in press as: N.D. Solovyev, et al., Anticancer activity and tissue distribution of platinum (II) complex with lignin- derived polymer of benzene-poly-carboxylic acids, J Trace Elem Med Biol (2016), http://dx.doi.org/10.1016/j.jtemb.2016.11.009 ARTICLE IN PRESS G Model JTEMB-25855; No. of Pages 8 Journal of Trace Elements in Medicine and Biology xxx (2016) xxx–xxx Contents lists available at ScienceDirect Journal of Trace Elements in Medicine and Biology journal homepage: www.elsevier.com/locate/jtemb Analytical methodology Anticancer activity and tissue distribution of platinum (II) complex with lignin-derived polymer of benzene-poly-carboxylic acids Nikolay D. Solovyev a,∗ , Elena I. Fedoros b,c , Evgenii J. Drobyshev c,d , Natalya B. Ivanenko a,d , Sergey E. Pigarev b,c , Margarita L. Tyndyk c , Vladimir N. Anisimov c , Yury A. Vilpan e , Andrey V. Panchenko b,c a Institute of Chemistry, St. Petersburg State University, St. Petersburg, Russian Federation b RD Pharm LTD, St. Petersburg, Russian Federation c N.N. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation d Institute of Toxicology of Federal Medico-Biological Agency, St. Petersburg, Russian Federation e Russian Scientific Centre ‘Applied Chemistry’, St. Petersburg, Russian Federation a r t i c l e i n f o Article history: Received 25 July 2016 Received in revised form 30 October 2016 Accepted 16 November 2016 Keywords: Benzene-poly-carboxylic acids Platinum Antineoplastic Breast cancer Tissue distribution Non-clinical studies tumour suppression a b s t r a c t Platinum-containing antineoplastic agents with physiologically active ligands seem to be a promising direction in anticancer drug design. PDBA is a novel promising antineoplastic agent, containing poly- mer ligand of natural origin (international patent WO2013/143549 A1). Polymer ligand of PDBA has a highly functionalised polyphenolic backbone, which exerts its own pharmacological effect via immune modulation and regulation of gene expression. PDBA is a cis-diammineplatinum(II) complex, containing mono-deprotonated benzene-poly-carboxylic acids, derived from lignin, and hydroxyl group as O-donor ligands (approximate bulk formula C 83 H 70 N 2 O 27 Pt). The agent is being evaluated in Phase II controlled clinical trials in metastatic breast cancer patients. In the present study, tissue distribution and tumour growth inhibition effects of PDBA, cisplatin and carboplatin were compared in SHR female mice, bearing inoculated solid Ehrlich carcinoma. The agents were administered subcutaneously every second day for the period of 10 days (5 injections) at 62.5 mg/kg, 3.0 mg/kg and 18.5 mg/kg for PDBA, cisplatin and carbo- platin, respectively. Experimental animals were sacrificed on the Days 11, 16 and 23 after the inoculation of the tumour. The doses of all studied drugs were selected to obtain similar antitumour efficacy with ca. 50% growth inhibition of the Ehrlich tumour at the end of the study. The efficacy of a single platinum reactive moiety [cis-diammineplatinum(II)] was shown to be the highest for cisplatin, followed by PDBA and finally carboplatin. However, the toxicity of PDBA was considerably lower than that of carboplatin and especially cisplatin. The drugs were mainly distributed in lungs, kidneys, liver, spleen and tumour tissue. PDBA showed quite high accumulation in the tumour tissue, possibly, owing to the effect of the lignin-derived ligand. © 2016 Elsevier GmbH. All rights reserved. 1. Introduction Since the discovery of the cytostatic properties of platinum (Pt) complexes in the late 1960s [1], a great number of complexes of platinum and other d-elements were synthesized and studied as perspective anticancer drugs. However, only few of these have received marketing authorisation [2]. Only 3 platinum compounds, of which cisplatin, cis-diamminedichloroplatinum(II), is a parent ∗ Corresponding author at: 199034 Universitetskaya nab 7/9, St. Petersburg, Rus- sian Federation. E-mail address: n.solovyev@spbu.ru (N.D. Solovyev). compound in the group of ‘platins’ have been approved by the United States Food and Drug Administration (FDA) [3]. The other two are carboplatin and oxaliplatin, which are known to have less pronounced side effects, such as nephrotoxicity, ototoxicity and peripheral nervous system disorders, compared to cisplatin [4–6]. Finally, in 1995 nedaplatin was approved for clinical use in Japan [5]. Platinum agents exert their biological effects through DNA- binding by platinum atom and the arrest of DNA replication [7]. Although numerous studies, describing synthesis and evaluation of efficacy of Pt compounds [8], have been undertaken, insufficient selectivity for malignant cells, severe side effects and drug resis- tance for some tumours, are still amongst the shortcomings of these drugs [9,10]. http://dx.doi.org/10.1016/j.jtemb.2016.11.009 0946-672X/© 2016 Elsevier GmbH. All rights reserved.