Co-delivery of cisplatin and doxorubicin from calcium phosphate beads/ matrix scaffolds for osteosarcoma therapy Ulrike Hess a , Shakiba Shahabi a , Laura Treccani a, ⁎ ,1 , Philipp Streckbein b,d , Christian Heiss c,d , Kurosch Rezwan a,e a Advanced Ceramics, University of Bremen, Am Biologischen Garten 2, 28359 Bremen, Germany b Department for Cranio-Maxillofacial and Plastic Surgery, University Hospital of Giessen-Marburg GmbH, Campus Giessen, Klinikstrasse 33, 35392 Giessen, Germany c Department of Trauma, Hand and Reconstructive Surgery, University Hospital of Giessen-Marburg GmbH, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35392 Giessen, Germany d Laboratory of Experimental Surgery, Justus-Liebig-University of Giessen, Kerkrader Strasse 9, 35394 Giessen, Germany e MAPEX Center for Materials and Processes, University of Bremen, Am Fallturm 1, 28359 Bremen, Germany abstract article info Article history: Received 28 November 2016 Received in revised form 15 March 2017 Accepted 17 March 2017 Available online 21 March 2017 Bone substitute materials with a controlled drug release ability can fill cavities caused by the resection of bone tumours and thereby combat any leftover bone cancer cells. The combined release of different cytostatics seems to enhance their toxicity. In this study, calcium phosphate beads and matrix scaffolds are combined for a long-term co-delivery of cis-diamminedichloroplatinum (cisplatin, CDDP) and doxorubicin hydrochloride (DOX) as clinical relevant model drugs. Tricalcium phosphate/alginate beads as additional drug carrier are pro- duced by droplet extrusion with ionotropic gelation and incorporated in scaffold matrix by freeze gelation with- out sintering. CDDP shows a short burst release while DOX has a continuous release measurable over the entire study period of 40 days. Drug release from matrix is decreased by ~30% compared to release from beads. Never- theless, all formulations follow the Korsmeyer-Peppas release kinetic model and show Fickian diffusion. Cytotox- ic activity was conducted on MG-63 osteosarcoma cells after 1, 4, and 7 days with WST-1 cell viability assay. Co- loaded composites enhance activity towards MG-63 cells up to ~75% toxicity while reducing the released drug quantity. The results suggest that co-loaded beads/matrix scaffolds are highly promising for osteosarcoma ther- apy due to synergistic effects over a long period of more than a month. © 2017 Elsevier B.V. All rights reserved. Keywords: Co-delivery Scaffold Drug carrier Doxorubicin Cisplatin 1. Introduction Despite improved surgical, radio, and chemotherapeutic techniques, bone cancer still is one of the major causes of severe functional and structural skeletal defects or even death. A major risk for pathologic fractures, severe pain, life-threatening hypercalcaemia, and an overall increased mortality is the local recurrence by residual neoplastic cells remaining due to incomplete marginal resection [1–3]. To control or prevent the risk of local recurrence of bone cancer, local administration by drug carriers can deliver cytostatics in high concen- trations with enhanced efficacy to the tumour while minimizing the drug concentrations in the bloodstream or other organs and improving the patient comfort. These carriers include hydrogels [4,5], micro- and nano-particles [5–7], liposomes [8], biodegradable polymers [9,10], or calcium phosphates [6,11]. However, degrading fragments or acidic byproducts, from biodegradable polymer-based drug delivery systems or harsh solvents required for their degradation may adversely affect the drugs to be delivered or the surrounding tissues [12]. For polymer- based systems, often an undesired massive and uncontrolled late stage drug release was observed [13]. In contrast, drug release from calcium phosphates (CaP), usually driven by desorption, is more evenly and can be better controlled [12]. CaP has excellent biocompatibility, bioactivity, and osteoconductivity due to its chemical and physical resemblance to bone mineral [14,15]. Especially apatites has high surface interaction properties and can bind neutral, positively, and negatively charged molecules enabling a delivery of a wide range of pharmaceuticals such as anticancer drugs [12,16]. The localized drug release from CaP-based drug delivery systems can result in tumour inhibition and can minimize high systemic drug concentration to much lower, less-toxic systemic values and can thereby reduce the need for repeated dosing making it more Materials Science and Engineering C 77 (2017) 427–435 ⁎ Corresponding author at: Petroceramics SpA c/o Kilometro Rosso Science & Technology Park, Viale Europa 2, 24040 Stezzano, BG, Italy. E-mail addresses: uhess@uni-bremen.de (U. Hess), shahabi@uni-bremen.de (S. Shahabi), treccanilaura@gmail.com, treccani@petroceramics.com (L. Treccani), philipp.streckbein@uniklinikum-giessen.de (P. Streckbein), christian.heiss@chiru.med.uni-giessen.de (C. Heiss), krezwan@uni-bremen.de (K. Rezwan). 1 Present address: Petroceramics SpA c/o Kilometro Rosso Science & Technology Park, Viale Europa 2, 24040 Stezzano, BG, Italy. http://dx.doi.org/10.1016/j.msec.2017.03.164 0928-4931/© 2017 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec