Encapsulation of an Antioxidant in Redox-Sensitive Self-Assembled Albumin Nanoparticles for the Treatment of Hepatitis
- Kengo YasudaKengo YasudaGraduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JapanMore by Kengo Yasuda
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- Hitoshi MaedaHitoshi MaedaGraduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JapanMore by Hitoshi Maeda
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- Ryo KinoshitaRyo KinoshitaGraduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JapanMore by Ryo Kinoshita
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- Yuki MinayoshiYuki MinayoshiGraduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JapanMore by Yuki Minayoshi
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- Yuki MizutaYuki MizutaGraduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JapanMore by Yuki Mizuta
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- Yuka NakamuraYuka NakamuraGraduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JapanMore by Yuka Nakamura
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- Shuhei ImotoShuhei ImotoFaculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, JapanDDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, JapanMore by Shuhei Imoto
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- Koji NishiKoji NishiFaculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, JapanMore by Koji Nishi
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- Keishi YamasakiKeishi YamasakiFaculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, JapanMore by Keishi Yamasaki
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- Mina SakuragiMina SakuragiFaculty of Engineering, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, JapanMore by Mina Sakuragi
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- Teruya NakamuraTeruya NakamuraGraduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JapanMore by Teruya Nakamura
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- Mayumi Ikeda-ImafukuMayumi Ikeda-ImafukuSchool of Pharmaceutical Sciences, Wakayama Medical University, 25-1 Shichiban-Cho, Wakayama 640-8156, JapanMore by Mayumi Ikeda-Imafuku
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- Yasunori IwaoYasunori IwaoSchool of Pharmaceutical Sciences, Wakayama Medical University, 25-1 Shichiban-Cho, Wakayama 640-8156, JapanMore by Yasunori Iwao
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- Yu IshimaYu IshimaInstitute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JapanMore by Yu Ishima
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- Tatsuhiro IshidaTatsuhiro IshidaInstitute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JapanMore by Tatsuhiro Ishida
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- Yasuko IwakiriYasuko IwakiriSection of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut 06510, United StatesMore by Yasuko Iwakiri
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- Masaki OtagiriMasaki OtagiriFaculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, JapanMore by Masaki Otagiri
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- Hiroshi Watanabe*Hiroshi Watanabe*Email: [email protected]Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JapanMore by Hiroshi Watanabe
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- Toru Maruyama*Toru Maruyama*Email: [email protected]Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JapanMore by Toru Maruyama
Abstract
Hepatitis is an inflammation of the liver caused by the inadequate elimination of reactive oxygen species (ROS) derived from Kupffer cells. Edaravone is clinically used as an antioxidant but shows poor liver distribution. Herein, we report on the design of a Kupffer cell-oriented nanoantioxidant based on a disulfide cross-linked albumin nanoparticle containing encapsulated edaravone (EeNA) as a therapeutic for the treatment of hepatitis. Since the edaravone is bound to albumin, this results in a soluble and stable form of edaravone in water. Exchanging the intramolecular disulfide bonds to intermolecular disulfide bridges of albumin molecules allowed the preparation of a redox responsive albumin nanoparticle that is stable in the blood circulation but can release drugs into cells. Consequently, EeNA was fabricated by the nanoscale self-assembly of edaravone and albumin nanoparticles without the additives that are contained in commercially available edaravone preparations. EeNA retained its nanostructure under serum conditions, but the encapsulated edaravone was released efficiently under intracellular reducing conditions in macrophages. The EeNA was largely distributed in the liver and subsequently internalized into Kupffer cells within 60 min after injection in a concanavalin-A-induced hepatitis mouse. The survival rate of the hepatitis mice was significantly improved by EeNA due to the suppression of liver necrosis and oxidative stress by scavenging excessive ROS. Moreover, even through the postadministration, EeNA showed an excellent hepatoprotective action as well. In conclusion, EeNA has the potential for use as a nanotherapeutic against various types of hepatitis because of its Kupffer cell targeting ability and redox characteristics.
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