Novel pH-sensitive multifunctional envelope-type nanodevice for siRNA-based treatments for chronic HBV infection

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• 作者：Naoki Yamamoto¹ ; ^&dagger ; ; Yusuke Sato² ; ^&dagger ; ; Tsubasa Munakata¹ ; Masakazu Kakuni³ ; Chise Tateno³ ; Takahiro Sanada¹ ; Yuichi Hirata¹ ; Shuko Murakami⁴ ; Yasuhito Tanaka⁴ ; Kazuaki Chayama⁵ ; Hiroto Hatakeyama² ; Mamoru Hyodo² ; Hideyoshi Harashima² ; Michinori Kohara¹ ; ^{kohara-mc@igakuken.or.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HBV ; hepatitis B virus ; ETV ; entecavir ; MEND ; pH-sensitive multifunctional envelope-type nanodevice ; cccDNA ; covalently closed circular DNA ; HBsAg ; hepatitis B virus surface antigen ; HBeAg ; hepatitis B virus e antigen ; HBcAg ; hepatitis B virus core antigen ; IFN ; interferon ; RT ; reverse transcriptase ; PHH ; primary human hepatocytes ; PTH ; primary tupaia hepatocytes ; NTCP ; sodium taurocholate cotransporting polypeptide ; siRNA ; short-interfering RNA ; Geq ; genome equivalents ; pDNA ; plasmid DNA ; CTLs
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：64
• 期：3
• 页码：547-555
• 全文大小：1350 K

文摘

Antiviral agents including entecavir (ETV) suppress the replication of the hepatitis B virus (HBV) genome in human hepatocytes, but they do not reduce the abundance of viral proteins. The present study focused on effectively reducing viral protein levels.

Methods

We designed siRNAs (HBV-siRNA) that target consensus sequences in HBV genomes. To prevent the emergence of escaped mutant virus, we mixed three HBV-siRNAs (HBV-siRNAmix); the mixture was encapsulated in a novel pH-sensitive multifunctional envelope-type nanodevice (MEND), a hepatocyte-specific drug delivery system. Coagulation factor 7 siRNA was used to assess delivery and knockdown efficiencies of MEND/siRNA treatments in mice. The potency of MEND/HBV-siRNAmix was evaluated in primary human hepatocytes and in chimeric mice with humanized liver persistently infected with HBV.

Results

Effective knockdown of targets, efficient delivery of siRNA, and liver-specific delivery were each observed with MEND. MEND/HBV-siRNA caused efficient reduction of HBsAg and HBeAg in vitro and in vivo. However, ETV treatment did not efficiently reduce HBsAg or HBeAg when compared with a single MEND/HBV-siRNAmix treatment. Furthermore, the suppressive effects of a single dose of MEND/HBV-siRNAmix persisted for 14 days in vitro and in vivo.

Conclusion

We demonstrated that MEND/HBV-siRNA controlled HBV more efficiently than did ETV. Furthermore, the effect of a single dose of MEND/HBV-siRNA persisted for a long time. These results indicated that MEND/HBV-siRNA may be a promising novel HBV treatment that is more effective than reverse transcriptase inhibitors.