Biodegradable Thermosensitive Hydrogel for SAHA and DDP Delivery: Therapeutic Effects on Oral Squamous Cell Carcinoma Xenografts Jing Li1., Changyang Gong2., Xiaodong Feng 1 , Xikun Zhou 2 , Xiaoping Xu1, Liang Xie1, Ruinan Wang 1 , Dunfang Zhang 1 , Hui Wang1, Peng Deng 1 , Min Zhou 1 , Ning Ji1, Yu Zhou 1 , Yun Wang 1 , Zhiyong Wang 1 , Ga Liao1, Ning Geng1, Liangyin Ch u1 , Zhiyong Q2i*a,nZhi Wang1*, Qianming Chen1* 1 State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, China, 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China Abstract Background: OSCC is one of the most common malignancies and numerous clinical agents currently applied in combinative chemotherapy. Here we reported a novel therapeutic strategy, SAHA and DDP-loaded PECE (SAHA-DDP/PECE), can improve the therapeutic effects of intratumorally chemotherapy on OSCC cell xenografts. Objective/Purpose: The objective of this study was to evaluate the therapeutic efficacy of the SAHA-DDP/PECE in situ controlled drug delivery system on OSCC cell xenografts. Methods: A biodegradable and thermosensitive hydrogel was successfully developed to load SAHA and DDP. Tumor- beared mice were intratumorally administered with SAHA-DDP/PECE at 50 mg/kg (SAHA) +2 mg/kg (DDP) in 100 ul PECE hydrogel every two weeks, SAHA-DDP at 50 mg/kg(SAHA) +2 mg/kg(DDP) in NS, 2 mg/kg DDP solution, 50 mg/kg SAHA solution, equal volume of PECE hydrogel, or equal volume of NS on the same schedule, respectively. The antineoplastic actions of SAHA and DDP alone and in combination were evaluated using the determination of tumor volume, immunohistochemistry, western blot, and TUNEL analysis. Results: The hydrogel system was a free-flowing sol at 10uC, become gel at body temperature, and could sustain more than 14 days in situ. SAHA-DDP/PECE was subsequently injected into tumor OSCC tumor-beared mice. The results demonstrated that such a strategy as this allows the carrier system to show a sustained release of SAHA and DDP in vivo, and could improved therapeutic effects compared with a simple additive therapeutic effect of SAHA and DDP on mouse model. Conclusions: Our research indicated that the novel SAHA-DDP/PECE system based on biodegradable PECE copolymer enhanced the therapeutic effects and could diminished the side effects of SAHA/DDP. The present work might be of great importance to the further exploration of the potential application of SAHA/DDP-hydrogel controlled drug release system in the treatment of OSCC. Citation: Li J, Gong C, Feng X, Zhou X, Xu X, et al. (2012) Biodegradable Thermosensitive Hydrogel for SAHA and DDP Delivery: Therapeutic Effects on Oral Squamous Cell Carcinoma Xenografts. PLoS ONE 7(4): e33860. doi:10.1371/journal.pone.0033860 Editor: Jingwu Xie, Indiana University School of Medicine, United States of America Received August 17, 2011; Accepted February 22, 2012; Published April 18, 2012 Copyright: 2012 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the National Science Foundation for Distinguished Young Scholars of China (No. 30725041), State Key Program of National Natural Science of China (No. 30930100), the National Natural Science Foundation of China (No. 30901676, 81072218, 30801294), the Science Funds for Talented Professionals of Sichuan Province in China (No. 09ZQ026-037), the Fok Ying-Tong Education Foundation, China (No. 122030). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: wangzhi0506@vip.163.com (ZW); anderson-qian@163.com (QZ); qmchen@scu.edu.cn (QC) . These authors contributed equally to this work. Introduction Oral squamous cell carcinoma (OSCC) is one of the most common malignancies leading to death that accounts for more than 90% of all oral cancers [1]. Although the aetiological risk factors are well documented and advances in diagnosis and therapy have been made in the different treatment modalities, the morbidity of OSCC have not improved significantly over the last decades [2,3]. Histone deacetylase (HDAC) inhibitors have been shown to acetylate the nucleosomal histones of condensed chromatin, and cause the reactivation of genes silenced by hyperacetylated histones [4]. HDAC inhibitors, including suberoylanilide hydro- xamic acid (SAHA), have demonstrated therapeutic benefit as monotherapy on a variety of hematological and solid tumor cancer such as glioma, head and neck cancer, hematologic malignancies and nonsmall-cell lung cancer (NSCLC) [5,6,7,8]. Cisplatin (DDP) is another strong and widely used chemotherapy PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e33860