International Journal of Pharmaceutics 365 (2009) 89–99 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Synthesis and characterization of PEG-PCL-PEG thermosensitive hydrogel ChangYang Gong a , Shuai Shi a,1 , PengWei Dong a , Bing Kan a , MaLing Gou a , XianHuo Wang a , XingYi Li a , Feng Luo a , Xia Zhao b , YuQuan Wei a , ZhiYong Qian a,∗ a State Key Laboratory of Biotherapy, West China Hospital, and School of Life Sciences, Sichuan University, Chengdu 610041, China b Department of Gynecology and Obstetrics, Second West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China article info Article history: Received 11 June 2008 Received in revised form 15 August 2008 Accepted 20 August 2008 Available online 28 August 2008 Keywords: Biodegradable Thermosensitive hydrogel Sol–gel–sol transition Degradation In vitro drug release abstract In this work, a series of biodegradable triblock poly(ethylene glycol)-poly(-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) copolymers were successfully synthesized by ring-opening copolymeriza- tion, and were characterized by 1 H NMR, FT-IR, GPC, and DSC. Aqueous solutions of PECE copolymers underwent thermosensitive sol–gel–sol transition as temperature increases when the concentration was above corresponding critical gel concentration (CGC). Sol–gel–sol phase transition diagrams were recorded using test tube inverting method, which depended on hydrophilic/hydrophobic balance in macromolecular structure, as well as some other factors, including topology of triblock copolymers and solution composition of the hydrogel. As a result, the sol–gel–sol transition temperature range could be varied, which might be very useful for its application as injectable drug delivery systems. The in vivo gel formation and degradation behavior was conducted by injecting aqueous PECE solution into KunMing mice subcutaneously. In vitro degradation behavior, in vitro drug release behavior, and cytotoxicity were also investigated in this paper. Therefore, owing to great thermosensitivity and biodegradability of these copolymers, PECE hydrogel is believed to be promising for in situ gel-forming controlled drug delivery system. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Hydrogels are a special class of materials that could absorb considerable amount of water while maintaining their integrity in water. In past decades, stimuli-sensitive copolymer hydrogels have gained increasing attention owing to their smart respon- sibility to the environmental stimuli and good biocompatibility. Especially, thermosensitive physically crosslinked hydrogels con- sisted of hydrophobic and hydrophilic blocks have been extensively studied because of their potential biomedical applications in in situ gel-forming controlled drug delivery, etc. (Kissel et al., 2002; Gong et al., 2007; Gariépy and Leroux, 2004; Choi et al., 1999; Jeong et al., 1999a,b, 2000, 1997; Lee et al., 2001a; Song et al., 2004; Kim et al., 2003; Li et al., 2003a, 2005; Liu et al., 2008; Malsmsten and Lindman, 1992; Nicolas et al., 1993; Zentner et al., 2001). Poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene gly- col) triblock copolymer (PEG-PPG-PEG), known as Pluronic or Poloxamer, has been extensively studied as a potential drug delivery vehicle due to their excellent biodegradability and thermosensitiv- ∗ Corresponding author. Tel.: +86 28 85164063; fax: +86 28 85164060. E-mail address: anderson-qian@163.com (Z. Qian). 1 This author contributed equally with Gong CY, and is the co-first author for this paper. ity (Xiong et al., 2003). These copolymers have been widely used as emulsifiers, wetting agents, and solubilizers (Rangelov et al., 2005). However, the critical micelle concentration (CMC) of Pluronic is high due to the weak hydrophobicity of PPG block. Pluronic copoly- mer forms a fast-eroding gel but cannot persist longer than a few hours. Furthermore, Pluronic was found to induce the toxic enhancement of plasma cholesterol and triglycerol because it is non-biodegradable and can be accumulated in the body (Choi et al., 1999; Lee et al., 2001b). Thus, the application of Pluronic in biomedical fields has been greatly restricted. To solve the problems mentioned above, substituting PPG with poly(-caprolactone) (PCL) in the Pluronic copolymer back- bone was attempted. Incorporation of biodegradable and more hydrophobic blocks into Pluronic copolymer backbone will result in a distinct decrease in macromolecular weight after degradation, faster elimination from the body, and an evident decrease in CMC (Kissel et al., 2002; Hwang et al., 2005). PCL and PEG are both well- known FDA-approved biodegradable and biocompatible materials, which have been widely used in the biomedical field (Chung et al., 2002; Chen et al., 2008; Bea et al., 2005; Jeong et al., 2002; Li et al., 2006, 2003b,c; Liu et al., 2007; Jeong et al., 1999c; Hatefi and Amsden, 2002; Iza et al., 1998). And PCL is non-toxic and has great permeability (Zhou et al., 2003). Due to the integration of respective advantages of PEG and PCL, PEG-PCL-PEG copolymer might have even wider applications in the biomedical field. 0378-5173/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2008.08.027