A chitosan–dipotassium orthophosphate hydrogel for the delivery of Doxorubicin in the treatment of osteosarcoma Hang T. Ta a , Crispin R. Dass b, * , Ian Larson c , Peter F.M. Choong b, d , Dave E. Dunstan a a Department of Chemical and Biomolecular Engineering, University of Melbourne, VIC 3010, Australia b Departments of Orthopaedics and Surgery, St Vincent’s Hospital Melbourne, Melbourne, VIC 3065, Australia c Monash Institute of Pharmaceutical Sciences, Monash University, VIC 3052, Australia d Sarcoma Service, Peter MacCallum Cancer Centre, VIC 3002, Australia article info Article history: Received 30 January 2009 Accepted 13 March 2009 Available online 5 April 2009 Keywords: Chitosan Orthophosphate Drug delivery Hydrogel Osteosarcoma Cancer abstract The current management of primary osteosarcoma (OS) and its secondary metastasis is limited by the lack of an efficient drug delivery system. Here we report an in situ gelling chitosan/dipotassium orthophosphate hydrogel system designed to directly deliver the frontline chemotherapeutic agent (Doxorubicin) in a sustained time period to tumor sites. A significant reduction of both primary and secondary OS in a clinically relevant orthotopic model was measured when doxorubicin was administered with the hydrogel. This hydrogel delivery system also reduced cardiac and dermal toxicity of Doxorubicin in mice. The results obtained from this study demonstrate the potential application of a biodegradable hydrogel technology as an anti-cancer drug delivery system for successful chemotherapy. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Osteosarcoma (OS) is the most common type of malignant bone cancer, and the sixth most common type of cancer in children and young adults [1,2]. It also represents the second highest cause of cancer-related death in this age group [3]. OS begins in bones, frequently localizes in the distal femur and proximal tibia region, and usually metastasizes to the lungs or other bones. The overall survival rate of patients was 10% before the 1970s when treatment was mainly limb amputation [1]. The rate dramatically increased to approximately 60–70% once multi-agent chemotherapy followed by surgery has been introduced [4]. Currently, chemotherapy drugs are administered both before and after surgery. Despite significant effort in the field, no major changes in treatment and outcome have been achieved. Contemporary chemotherapy for OS is normally the combination of different chemotherapeutic agents administered intravenously or orally [5,6]. However, most chemotherapeutics also carry the risk of both short-term and long-term toxic effects. Doxorubicin (Dox) for example, can cause nausea, vomiting, heart and skin complications. When the cumulative dose of Dox reaches 700 mg/m 2 , the risks of developing cardiac side-effects dramatically increase [7]. Due to its high toxicity and hence narrow therapeutic index, increasing systemic dose to achieve desirable high concentration of drug at the tumor site is difficult. In addition, the concentration of system- ically-administered drug at the bony cancerous site is likely to be very low because the bone is only a moderately-perfused organ [8]. It has been reported that only 0.52 mg of Dox accumulated in 1 g marrow after an intravenous administration of 30 mg/m 2 of Dox [9]. Therefore, a localized and targeted drug delivery system (DDS) is essential to overcome these problems in the treatment of OS. Most of the studied Dox DDSs such as liposomes [10,11], microspheres [12], polymeric micelles [13,14] and conjugates [15] are usually administered intravenously, limiting the dosage for treatment of OS. Magnetic liposomes [16] and hydroxyapatite implants [17] have been developed and tested successfully in in vivo models of OS. However, these DDSs require the surgical insertion of magnets and implants at treatment sites, which reduces the comfort and convenience to patients. In this study, we developed a biodegradable and non-cytotoxic in situ gelling chitosan/dipo- tassium orthophosphate (Chi/DPO) hydrogel DDS for delivery of Dox in OS treatment. Different Chi/DPO formulations were char- acterized and the optimal formulation was selected. A clinically relevant orthotopic mice model of OS [3] was employed for the in vivo study. * Corresponding author. E-mail address: crispin.dass@svhm.org.au (C.R. Dass). Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2009.03.022 Biomaterials 30 (2009) 3605–3613