Systemic delivery of siRNA by actively targeted polyion complex micelles for silencing the E6 and E7 human papillomavirus oncogenes

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• 作者：Haruka Nishida^a ; Yoko Matsumoto^a ; Kei Kawana^a ; ^{kkawana-tky@umin.org" class="auth_mail" title="E-mail the corresponding author} ; R. James Christie^b ; Mitsuru Naito^b ; Beob Soo Kim^c ; Kazuko Toh^b ; Hyun Su Min^c ; Yu Yi^c ; Yu Matsumoto^b ; Hyun Jin Kim^b ; Kanjiro Miyata^b ; ^c ; ^{miyata@bmw.t.u-tokyo.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Ayumi Taguchi^a ; Kensuke Tomio^a ; Aki Yamashita^a ; Tomoko Inoue^a ; Hiroe Nakamura^a ; Asaha Fujimoto^a ; Masakazu Sato^a ; Mitsuyo Yoshida^a ; Katsuyuki Adachi^a ; Takahide Arimoto^a ; Osamu Wada-Hiraike^a ; Katsutoshi Oda^a ; Takeshi Nagamatsu^a ; Nobuhiro Nishiyama^d ; ^e ; Kazunori Kataoka^b ; ^c ; ^e ; ^{kataoka@bmw.t.u-tokyo.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Yutaka Osuga^a ; Tomoyuki Fujii^a
• 关键词：Human papillomavirus (HPV) E6/E7 ; Small interfering RNA (siRNA) ; Polyion complex (PIC) micelle ; Cervical cancer ; Drug delivery system
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：10 June 2016
• 年：2016
• 卷：231
• 期：Complete
• 页码：29-37
• 全文大小：1149 K

文摘

Human papillomavirus (HPV) E6 and E7 oncogenes are essential for the immortalization and maintenance of HPV-associated cancer and are ubiquitously expressed in cervical cancer lesions. Small interfering RNA (siRNA) coding for E6 and E7 oncogenes is a promising approach for precise treatment of cervical cancer, yet a delivery system is required for systemic delivery to solid tumors. Here, an actively targeted polyion complex (PIC) micelle was applied to deliver siRNAs coding for HPV E6/E7 to HPV cervical cancer cell tumors in immune-incompetent tumor-bearing mice. A cell viability assay revealed that both HPV type 16 and 18 E6/E7 siRNAs (si16E6/E7 and si18E6/E7, respectively) interfered with proliferation of cervical cancer cell lines in an HPV type-specific manner. A fluorescence imaging biodistribution analysis further revealed that fluorescence dye-labeled siRNA-loaded PIC micelles efficiently accumulated within the tumor mass after systemic administration. Ultimately, intravenous injection of si16E6/E7 and si18E6/E7-loaded PIC micelles was found to significantly suppress the growth of subcutaneous SiHa and HeLa tumors, respectively. The specific activity of siRNA treatment was confirmed by the observation that p53 protein expression was restored in the tumors excised from the mice treated with si16E6/E7- and si18E6/E7-loaded PIC micelles for SiHa and HeLa tumors, respectively. Therefore, the actively targeted PIC micelle incorporating HPV E6/E7-coding siRNAs demonstrated its therapeutic potential against HPV-associated cancer.