Available online at www.sciencedirect.com International Journal of Pharmaceutics 357 (2008) 318–322 Note Block copolymer design for stable encapsulation of N-(4-hydroxyphenyl)retinamide into polymeric micelles in mice Tomoyuki Okuda a , Shigeru Kawakami a , Masayuki Yokoyama b , Tatsuhiro Yamamoto b , Fumiyoshi Yamashita a , Mitsuru Hashida a,∗ a Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan b Kanagawa Academy of Science and Technology, KSP East 404, Sakado 3-2-1, Takatsu-ku, Kawasaki-shi, Kanagawa 213-0012, Japan Received 5 October 2007; received in revised form 22 January 2008; accepted 24 January 2008 Available online 3 February 2008 Abstract For stable encapsulation of N-(4-hydroxyphenyl)retinamide (4-HPR) into polymeric micelles, four types of block copolymers were synthesized with different esterified functional groups: heptyl (C7), nonyl (C9), benzyl (Bz), and phenylpropyl (C3Ph). The stability of 4-HPR encapsulated polymeric micelles was evaluated by measuring the blood concentration of 4-HPR in mice. After intravenous administration of 4-HPR and 4-HPR encapsulated PEG liposomes, the blood concentration of 4-HPR was about 2.8% and 2.2% of the dose/mL, suggesting the rapid release of 4-HPR from PEG liposomes. In contrast, the blood concentration of 4-HPR after intravenous administration of all 4-HPR encapsulated polymeric micelles studied was much higher (about 22–34% of the dose/mL). Among them, the polymeric micelles prepared by block copolymers (Bz) showed the highest blood concentration of 4-HPR. As far as the effects of the level of Bz groups in the block copolymers are concerned, the blood concentration of 4-HPR was enhanced by Bz groups at a level of 72% and 77%, but not by Bz groups at a level of 43% and 51%. These results suggest that 4-HPR is stably encapsulated in polymeric micelles prepared by block copolymers (Bz) but a level of over 72% of Bz groups is needed. These findings will be of value in the future use, design, and development of polymeric micelles for in vivo application of 4-HPR. © 2008 Elsevier B.V. All rights reserved. Keywords: 4-HPR; Fenretinide; Polymeric micelle; Controlled release; Drug delivery systems N-(4-Hydroxyphenyl)retinamide (4-HPR, fenretinide) is a synthetic retinoid which shows high anti-tumor activity against a variety of malignant cells (Formelli et al., 1996). Although oral administration of 4-HPR has been used in clinical trials so far, its bioavailability is very limited because of its low membrane per- meability (Kokate et al., 2006). In addition, intravenous 4-HPR is rapidly eliminated from body (Swanson et al., 1980; Hultin et al., 1986). Therefore, 4-HPR cannot exert a high enough anti- tumor activity because its low blood concentration (Formelli et al., 1993). Raffaghello et al. and Takahashi et al. have reported that 4-HPR encapsulated liposomes containing monoclonal anti- body or sterylglucoside mixture exert anti-tumor activities when given intravenously. Therefore, the development of a targeting carrier for 4-HPR is needed in order to obtain potent in vivo ∗ Corresponding author. Tel.: +81 75 753 4545; fax: +81 75 753 4575. E-mail address: hashidam@pharm.kyoto-u.ac.jp (M. Hashida). anti-tumor activity (Raffaghello et al., 2003; Takahashi et al., 2003). Polymeric micelles prepared by block copolymers, which are composed of both hydrophilic and hydrophobic segments, have been reported to be suitable drug carriers for lipophilic drugs (Kataoka et al., 2001; Gaucher et al., 2005). Recently, we have reported the efficient encapsulation of hydrophobic drugs in polymeric micelles by optimizing the hydrophobic segments with esterified functional groups of poly(ethylene glycol)–poly(aspartate ester) block copolymers (Yokoyama et al., 2004; Kawakami et al., 2005; Watanabe et al., 2006; Chansri et al., 2008). These observations prompted us to investigate the potential use of polymeric micelle formulations by opti- mizing the hydrophobic segments with esterified functional groups to enhance the blood retention of 4-HPR following intravenous administration. Here, four types of poly(ethylene glycol)–poly(aspartate ester) block copolymers with different esterified functional groups were synthesized to optimize the 0378-5173/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2008.01.044