Polymer complex of WR 2721. Synthesis and radioprotective efficiency Neli Koseva a , Ivelina Tsacheva a , Violeta Mitova a , Elitsa Vodenicharova a , Jessica Molkentine b , Kathy Mason b,1,⇑ , Kolio Troev a,1,⇑ a Institute of Polymers, Bulgarian Academy of Sciences, Acad. Georgi Bonchev Str., Bl. 103A, Sofia 1113, Bulgaria b M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 066, Houston, TX 77030-4009, USA article info Article history: Received 17 April 2014 Received in revised form 7 August 2014 Accepted 15 August 2014 Available online 23 August 2014 Keywords: Poly(hydroxyoxyethylene phosphate) WR 2721 Polymer complex Radioprotector Protection factor abstract Polymer complex constructed from WR 2721 and poly(hydroxyoxyethylene phosphate) was synthesized. The structure of complex formed was elucidated by 1 H-, 13 C, 31 P NMR and FT-IR spectroscopy. The radio- protector was immobilized via ionic bonds. Radioprotective efficacy was evaluated by clonal survival of stem cells in crypts of mouse small intestine, and incidence and latency of the acute radiation induced bone marrow syndrome. Protection factors were assessed for WR 2721 and for the polymer complex. Pro- tection factors for the polymer complex ranged from 2.6 for intestinal stem cell survival to 1.35 for 30 day survival (LD50) following whole body radiation exposure. In all cases, the polymer complex was a signif- icantly better radiation protector than the parent compound. Ó 2014 Elsevier B.V. All rights reserved. 1. Introduction The research interest in amifostine (WR 2721) continues long after its discovery due to its potential role in reducing the biolog- ical effects of ionizing radiation, including lethality, mutagenicity, and carcinogenicity. WR 2721 demonstrated some potential for use as an emergency whole-body radioprotector as well as for use with radiotherapy (Brown et al., 1988). Several studies have demonstrated that amifostine protects normal tissue from both acute and late radiation damage without protecting the tumor, i.e. amifostine is a selective cytoprotector of normal tissues (Burkon et al., 2003; Koukourakis, 2003; Wasserman, 1999; Wasserman and Brizel, 2001). Maximum radioprotection by ami- fostine is observed when the drug is administered intravenously by a 15 min infusion starting 30–60 min before irradiation (Bukowski, 1996). It is shown that its side-effects, such as hypoten- sion, nausea, and vomiting are significantly augmented upon intra- venous administration (Bonner and Shaw, 2002; Cassatt et al., 2002; Schuchter et al., 2002). A promising approach to improve some characteristics of low molecular weight drugs, already approved and used in practice, as well as to impart new valuable properties is the macromolecular approach, i.e. application of appropriate polymers for drug immo- bilization, chemically conjugated or physically bound to a polymer chain. Polymer chemistry has contributed in various ways to the present progress in biology, biochemistry, medicine and pharmacy, providing new highly specific materials. Synthetic polymer formu- lations are becoming more and more attractive as delivery vehicles because of the great flexibility regarding: (i) the type and size of the bioactive molecules/agents delivered, (ii) the degree of carrier loading and (iii) the immobilization techniques applied (Duncan, 1992; Hoste et al., 2004; Ottenbrite et al., 1978; Rihova et al., 2001; Ringsdorf, 1975; Uhrich, 1997; Uhrich et al., 1999). The bio- degradable, biocompatible and low toxic polyphosphoesters – a family of polymers including poly(alkylene H-phosphonate)s and derived from them polyphosphates and polyphosphoamidates – are very promising polymers for drug and gene delivery (Tsevi et al., 1993; Georgieva et al., 2002; Huang et al., 2004; Jiang et al., 2007; Troev et al., 2010, 2007; Pencheva et al., 2008; Zhao et al., 2003). Polyphosphoesters have the following advantages (Troev, 2012): (i) relative ease of preparation from commercially available reagents; (ii) the possibility to be constructed from non- toxic and water soluble blocks; (iii) possibility to control the hydrophilic/hydrophobic balance; (iv) relatively narrow molecular weight distributions; (v) the drug-loading capacity is not limited to the end groups; (vi) the reactive PAH group in repeating units allows chemical modification, as well as drug conjugation under http://dx.doi.org/10.1016/j.ejps.2014.08.006 0928-0987/Ó 2014 Elsevier B.V. All rights reserved. ⇑ Corresponding authors. Address: Dept. Experimental Radiation Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 066, Houston, TX 77030-4009, USA. Tel.: +1 713 792 4860 (K. Mason). Institute of Polymers, Bulgarian Academy of Sciences, Acad. Georgi Bonchev Str., Bl. 103A, Sofia 1113, Bulgaria. Tel.: +359 2 9792203 (K. Troev). E-mail addresses: kmason@mdanderson.org (K. Mason), ktroev@polymer.bas.bg (K. Troev). 1 These authors contributed equally. European Journal of Pharmaceutical Sciences 65 (2014) 9–14 Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps