chemical drugs to the tumor. And the administration of SAHA- DDP/PECE complexes led to the significant inhibition tumor grows of OSCC with no conspicuous systemic toxicity. So the treating oral squamous cell carcinoma by the PECE hydrogel delivered DDP and SAHA may be a new and interesting cancer chemotherapy protocol. SAHA-DDP/PECE hydrogel system with direct intratumoral injections may be a useful method in treatment for oral cancer and other solid tumors. References 1. Bagan J, Sarrion G, Jimenez Y (2010) Oral cancer: Clinical features. Oral Oncology 46: 414–417. 2. Brandwein-Gensler A, Teixeira MS, Lewis CM, Lee B, Rolnitzky L, et al. (2005) Oral squamous cell carcinoma - Histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. American Journal of Surgical Pathology 29: 167–178. 3. McCaul JA, Gordon KE, Minty F, Fleming J, Parkinson EK (2008) Telomere dysfunction is related to the intrinsic radio-resistance of human oral cancer cells. Oral Oncology 44: 261–269. 4. De Ruijter AJM, Van Gennip AH, Caron HN, Kemp S, Van Kuilenburg ABP (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochemical Journal 370: 737–749. 5. Yin D, Ong JM, Hu JW, Desmond JC, Kawamata N, et al. (2007) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor: Effects on gene expression and growth of glioma cells in vitro and in vivo. Clinical Cancer Research 13: 1045–1052. 6. Marks PA (2007) Discovery and development of SAHA as an anticancer agent. Oncogene 26: 1351–1356. 7. Blumenschein GR, Kies MS, Papadimitrakopoulou VA, Lu C, Kumar AJ, et al. (2008) Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza (TM), suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/ or metastatic head and neck cancer. Investigational New Drugs 26: 81–87. 8. Crump M, Coiffier B, Jacobsen ED, Sun L, Ricker JL, et al. (2007) Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in relapsed diffuse large B-cell lymphoma (DLBCL). Ejc Supplements 5: 346–346. 9. Debaere D, Poorten VV, Nuyts S, Hauben E, Schoenaers J, et al. (2011) Cyclophosphamide, doxorubicin, and cisplatin in advanced salivary gland cancer. B-Ent 7: 1-+. 10. Gregorc V, De Braud FG, De Pas TM, Scalamogna R, Citterio G, et al. (2011) Phase I Study of NGR-hTNF, a Selective Vascular Targeting Agent, in Combination with Cisplatin in Refractory Solid Tumors. Clinical Cancer Research 17: 1964–1972. 11. Maisch B, Pankuweit S, Rupp H (2010) Intrapericardial cisplatin treatment in neoplastic and triamcinolone in radiation induced pericardial effusion prevent recurrence effectively. European Heart Journal 31: 337–338. 12. Plummer R, Wilson RH, Calvert H, Boddy AV, Griffin M, et al. (2011) A Phase I clinical study of cisplatin-incorporated polymeric micelles (NC-6004) in patients with solid tumours. British Journal of Cancer 104: 593–598. 13. Prestwich RJ, Oeksuez DC, Dyker K, Coyle C, Sen M (2011) Induction TPF Combined with Concurrent Cisplatin Chemoradiotherapy for Stage IV Head and Neck Squamous Cell Cancer. Clinical Oncology 23: S23–S23. 14. Xu LP, Yin SP, Banerjee S, Sarkar F, Reddy KB (2011) Enhanced Anticancer Effect of the Combination of Cisplatin and TRAIL in Triple-Negative Breast Tumor Cells. Molecular Cancer Therapeutics 10: 550–557. 15. Kelly WK, Richon VM, O’Connor O, Curley T, MacGregor-Curtelli B, et al. (2003) Phase I clinical trial of histone deacetylase inhibitor: Suberoylanilide hydroxamic acid administered intravenously. Clinical Cancer Research 9: 3578–3588. 16. Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, et al. (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. Journal of Clinical Oncology 23: 3923–3931. 17. Koberle B, Tomicic MT, Usanova S, Kaina B (2010) Cisplatin resistance: Preclinical findings and clinical implications. Biochimica Et Biophysica Acta- Reviews on Cancer 1806: 172–182. pp 172–182. 18. El-Awady EE, Moustafa YM, Abo-Elmatty DM, Radwan A (2011) Cisplatin- induced cardiotoxicity Mechanisms and cardioprotective strategies. European Journal of Pharmacology 650: 335–341. 19. Gong CY, Shi SA, Dong PW, Kan B, Gou ML, et al. (2009) Synthesis and characterization of PEG-PCL-PEG thermosensitive hydrogel. International Journal of Pharmaceutics 365: 89–99. 20. Gong C, Qian Z, Liu C, Huang M, Gu Y, et al. (2007) A thermosensitive hydrogel based on biodegradable amphiphilic poly(ethylene glycol)–polycapro- lactone–poly(ethylene glycol) block copolymers. Smart Materials and Structures 16: 927. 21. Gong CY, Dong PW, Shi S, Fu SZ, Yang JL, et al. (2009) Thermosensitive PEG-PCL-PEG hydrogel controlled drug delivery system: sol-gel-sol transition and in vitro drug release study. J Pharm Sci 98: 3707–3717. 22. Wang YS, Gong CY, Yang L, Wu QJ, Shi SA, et al. (2010) 5-FU-hydrogel inhibits colorectal peritoneal carcinomatosis and tumor growth in mice. Bmc Cancer 10: -. Anti-Tumor Effect of Controlled Drug Delivery Author Contributions Conceived and designed the experiments: QC ZW ZQ. Performed the experiments: JL CG XF XZ LX RW XX DZ. Analyzed the data: JL XZ HW PD. Contributed reagents/materials/analysis tools: NJ MZ YZ YW ZW GL NG LC. 23. Gong CY, Shi SA, Peng XY, Kan B, Yang L, et al. (2009) Biodegradable thermosensitive injectable PEG-PCL-PEG hydrogel for bFGF antigen delivery to improve humoral immunity. Growth Factors 27: 377–383. 24. Fang F, Gong CY, Qian ZY, Zhang XN, Gou ML, et al. (2009) Honokiol Nanoparticles in Thermosensitive Hydrogel: Therapeutic Effects on Malignant Pleural Effusion. Acs Nano 3: 4080–4088. 25. Gong CY, Wang YJ, Wang XH, Wei XW, Wu QJ, et al. (2011) Biodegradable self-assembled PEG-PCL-PEG micelles for hydrophobic drug delivery, part 2: in vitro and in vivo toxicity evaluation. Journal of Nanoparticle Research 13: 721–731. 26. Gong CY, Wei XW, Wang XH, Wang YJ, Guo G, et al. (2010) Biodegradable self-assembled PEG-PCL-PEG micelles for hydrophobic honokiol delivery: I. Preparation and characterization. Nanotechnology 21: -. 27. Gong CY, Shi SA, Dong PW, Zheng XL, Fu SZ, et al. (2009) In vitro drug release behavior from a novel thermosensitive composite hydrogel based on Pluronic f127 and poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) copolymer. Bmc Biotechnology 9: -. 28. Shen J, Huang C, Jiang L, Gao F, Wang Z, et al. (2007) Enhancement of cisplatin induced apoptosis by suberoylanilide hydroxamic acid in human oral squamous cell carcinoma cell lines. Biochemical Pharmacology 73: 1901–1909. 29. Iamaroon A, Pongsiriwet S, Jittidecharaks S, Pattanaporn K, Prapayasatok S, et al (2003) Increase of mast cells and tumor angiogenesis in oral squamous cell carcinoma. J Oral Pathol Med 32: 195–199. 30. Shieh YS, Lee HS, Shiah SG, Chu YW, Wu CW, et al. (2004) Role of angiogenic and non-angiogenic mechanisms in oral squamous cell carcinoma: correlation with histologic differentiation and tumor progression. J Oral Pathol Med 33: 601–606. 31. Shivamallappa SM, Venkatraman NT, Shreedhar B, Mohanty L, Shenoy S (2011) Role of angiogenesis in oral squamous cell carcinoma development and metastasis: an immunohistochemical study. Int J Oral Sci 3: 216–224. 32. Shen J, Huang CH, Jiang L, Gao F, Wang Z, et al. (2007) Enhancement of cisplatin induced apoptosis by suberoylanilide hydroxamic acid in human oral squamous cell carcinoma cell lines. Biochemical Pharmacology 73: 1901–1909. 33. Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000) Histone deacetylase inhibitor selectively induces p21(WAF1) expression and gene-associated histone acetylation. Proceedings of the National Academy of Sciences of the United States of America 97: 10014–10019. 34. Rikiishi H, Shinohara F, Sato T, Sato Y, Suzuki M, et al. (2007) Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid. International Journal of Oncology 30: 1181–1188. 35. Jin KL, Park JY, Noh EJ, Hoe KL, Lee JH, et al. (2010) The effect of combined treatment with cisplatin and histone deacetylase inhibitors on HeLa cells. Journal of Gynecologic Oncology 21: 262–268. 36. Suzuki M, Endo M, Shinohara F, Echigo S, Rikiishi H (2009) Enhancement of cisplatin cytotoxicity by SAHA involves endoplasmic reticulum stress-mediated apoptosis in oral squamous cell carcinoma cells. Cancer Chemotherapy and Pharmacology 64: 1115–1122. 37. Dong GE, Luo J, Kumar V, Dong Z (2010) Inhibitors of histone deacetylases suppress cisplatin-induced p53 activation and apoptosis in renal tubular cells. American Journal of Physiology-Renal Physiology 298: F293–F300. 38. Sato T, Suzuki M, Sato Y, Echigo S, Rikiishi H (2006) Sequence-dependent interaction between cisplatin and histone deacetylase inhibitors in human oral squamous cell carcinoma cells. International Journal of Oncology 28: 1233–1241. 39. Gong CY, Wu QJ, Dong PW, Shi S, Fu SZ, et al. (2009) Acute toxicity evaluation of biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PEG-PCL-PEG hydrogel. J Biomed Mater Res B Appl Biomater 91: 26–36. 40. Gou M, Gong C, Zhang J, Wang X, Gu Y, et al. (2010) Polymeric matrix for drug delivery: honokiol-loaded PCL-PEG-PCL nanoparticles in PEG-PCL-PEG thermosensitive hydrogel. J Biomed Mater Res A 93: 219–226. 41. Gong C, Shi S, Wang X, Wang Y, Fu S, et al. (2009) Novel composite drug delivery system for honokiol delivery: self-assembled poly(ethylene glycol)- poly(epsilon-caprolactone)-poly(ethylene glycol) micelles in thermosensitive poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) hydrogel. J Phys Chem B 113: 10183–10188. 42. Gong C, Shi S, Dong P, Kan B, Gou M, et al. (2009) Synthesis and characterization of PEG-PCL-PEG thermosensitive hydrogel. Int J Pharm 365: 89–99. PLoS ONE | www.plosone.org 8 April 2012 | Volume 7 | Issue 4 | e33860