Delivery of cisplatin from thermosensitive co-cross-linked chitosan hydrogels M.J. Moura a,b,⇑ , M.H. Gil b , M.M. Figueiredo b a Department of Chemical and Biological Engineering, Polytechnic Institute of Coimbra, Av. Marnoco de Sousa, 30, 3000-271 Coimbra, Portugal b Research Centre for Chemical Processes Engineering and Forest Products, Department of Chemical Engineering, University of Coimbra, R. Sílvio Lima, 3030-790 Coimbra, Portugal article info Article history: Received 23 July 2012 Received in revised form 27 February 2013 Accepted 28 February 2013 Available online 14 March 2013 Keywords: Thermosensitive hydrogel Chitosan Genipin Cisplatin Drug release abstract The aim of the present study was to investigate the in vitro cisplatin release from thermo- sensitive chitosan hydrogels, produced by ionic cross-linking and by ionic/covalent co- cross-linking. For that, two types of cisplatin-loaded hydrogels were prepared: chitosan hydrogels cross-linked with glycerol-phosphate disodium salt (as an ionic cross-linker) and chitosan hydrogels ionic/covalent co-cross-linked (using different amounts of genipin as covalent cross-linker). Both hydrogels were able to be produced in situ at physiologic conditions. Regarding cisplatin release, all hydrogels exhibited a first initial rapid release reaching a maximum at about 3 h. However, the total amount of drug released was only 20% for the ionic hydrogel (without genipin) and about 60–70% for the ionic/covalent co-cross-linked hydrogels. This disparity was explained in terms of the type of cross-linking and hydrogels network structure. Changes in the initial drug loadings (0.6 and 1 mg/mL) as well as in the covalent cross-linker concentrations (0.10% and 0.20%, w/w) did not significantly affect the cisplatin release profiles. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Cisplatin, a platinum-chelated complex with four li- gands (two ammonias and two chlorides), in short CDDP [cis-diamminedichloroplatinum (II)], is one of the most effective cytotoxic agents used for the treatment of various malignancies, ranging from solid tumors to melanomas [1– 3]. The CDDP, as well as all platinum compounds available for clinical use, is usually administered intravenously. The main problems related with this type of administration are the serious systemic side-effects and the low drug concen- trations at cancerous site [3]. Alternative approaches that have been used involve the incorporation of the platinum agent in liposomes [4–6], microspheres/nanoparticles [2,7,8], and polymeric micelles [1]. However, most of these particulate systems have been typically designed for intra- venous administration. To minimize the adverse effects caused by CDDP, it is necessary to deliver the drug directly to the tumor site and to retain it for convenient duration and concentration levels to elicit pharmacological actions as well as to control the release profile. Recent strategies to deliver the drug to the local envi- ronment of a solid tumor involve the use of polymeric hydrogels [9]. Although hydrogels have been extensively explored as drug delivery vehicles [10], much interest has been focused on injectable in situ forming hydrogels, since these are capable of forming stable gels at body tem- perature within a short period after injection [11,12]. Such behavior endows the hydrogel with injectability, most sui- ted for localized and minimally invasive drug delivery, pro- viding, simultaneously, a reservoir for the sustained release of the drug. Chitosan-based systems have been 0014-3057/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.eurpolymj.2013.02.032 ⇑ Corresponding author at: Department of Chemical and Biological Engineering, Polytechnic Institute of Coimbra, Av. Marnoco de Sousa, 30, 3000-271 Coimbra, Portugal. Tel.: +351 239791250. E-mail address: mjmoura@isec.pt (M.J. Moura). European Polymer Journal 49 (2013) 2504–2510 Contents lists available at SciVerse ScienceDirect European Polymer Journal journal homepage: www.elsevier.com/locate/europolj