International Journal of Pharmaceutics 331 (2007) 11–18 pH- and temperature-sensitive, injectable, biodegradable block copolymer hydrogels as carriers for paclitaxel Woo Sun Shim a,1 , Jong-Ho Kim b,1 , Kwangmeyung Kim b , Yoo-Shin Kim c , Rang-Woon Park c , In-San Kim c , Ick Chan Kwon b , Doo Sung Lee a,∗ a Department of Polymer Science & Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea b Biomedical Research Center, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea c Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu 700-412, Republic of Korea Received 27 April 2006; received in revised form 24 August 2006; accepted 10 September 2006 Available online 23 September 2006 Abstract Paclitaxel (PTX) was loaded into synthetic pH/T-sensitive block copolymer (OSM–PCLA–PEG–PCLA–OSM) solution with various concentra- tions. The phase diagram of PTX-loaded block copolymer solution shifted to lower temperature region compared to net block copolymer because of the salting-out effect of PTX. Release profiles of PTX showed sustained manner regardless of loading amount of PTX. To evaluate anti-tumor effect of PTX-loaded block copolymer, solutions were injected subcutaneously to tumor-bearing mice and TUNEL assay examined. PTX-loaded block copolymer hydrogel for in vivo use showed good anti-tumor effect for 2 weeks and induced strong apoptosis in tumor tissue. Therefore, we conclude OSM–PCLA–PEG–PCLA–OSM block copolymer as an effective injectable carrier of PTX. © 2006 Elsevier B.V. All rights reserved. Keywords: pH/T-sensitive block copolymer hydrogel; Injectable hydrogel; Paclitaxel; In vivo anti-tumor effect; TUNEL assay 1. Introduction Paclitaxel (PTX) is one of the best anti-neoplastic drugs found in nature known for decades. It interacts with tubulin dimers in the G2 mitotic phase of cell division that promote microtubule polymerization to make highly stable microtubules, therefore, to prevent cell division (Horwitz, 1992). In addition to its anti-proliferative effects, PTX is a potent inhibitor of angio- genesis, cell migration, and collagenase production (Burt et al., 1995; Stearns and Wang, 1992). For another aspect, PTX is a hydrophobic molecule and therefore, a non-ionic polyethoxy- lated castor oil solubilizer, Cremophor ® EL is used to enable its clinical administration. However, the large quantity administra- tion of Cremophor ® EL to deliver the required doses of PTX causes serious side effects, particularly hypersensitivity reac- tions, some of which are life-threatening (Onetto et al., 1993; Rowinsky et al., 1993; Dorr, 1994). In order to eliminate the ∗ Corresponding author. Tel.: +82 31 290 7282; fax: +82 31 292 8790. E-mail address: dslee@skku.edu (D.S. Lee). 1 These authors contributed equally to this paper. toxicity of Cremophor ® EL, to improve the drug’s efficacy and to eliminate chances of premedication, recent research has been focused on developing new drug delivery systems. A variety of approaches have been investigated including emulsification (Kan et al., 1999; Constantinides et al., 2000; He et al., 2003), introducing microspheres (Harper et al., 1999; Mu and Feng, 2001), liposomes (Ceruti et al., 2000; Crosasso et al., 2000; Koshina et al., 2001), nanoparticles (Kim and Lee, 2001; Mu and Feng, 2003) and polymeric micelles (Miwa et al., 1998; Kim et al., 2001a). One of the novel alternate is the development of injectable formula that forms a semisolid implant. There are countless reports on hydrogel-based injectable polymer delivery systems that have been developed for a variety of drugs, based on the polymeric materials possessing thermo- sensitivity and biodegradability (Jeong et al., 1997; Ha et al., 2006). The polymers exhibiting properties of reversible ther- mal gelation are triblock copolymers consisting of A-blocks and B-blocks, arranged as BAB or ABA, where A is poly(d,l-lactic- co-glycolic acid) (PLGA) and B is PEG. Aqueous solutions of these polymers undergo a reversible sol–gel transition and form free-flowing sol at room temperature, and become gel at body temperature (Jeong et al., 1997, 2000a; Kim et al., 2001b; 0378-5173/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2006.09.027