TY - JOUR
T1 - Enhancing chemotherapy response with sustained EphA2 silencing using multistage vector delivery
AU - Shen, Haifa
AU - Rodriguez-Aguayo, Cristian
AU - Xu, Rong
AU - Gonzalez-Villasana, Vianey
AU - Mai, Junhua
AU - Huang, Yi
AU - Zhang, Guodong
AU - Guo, Xiaojing
AU - Bai, Litao
AU - Qin, Guoting
AU - Deng, Xiaoyong
AU - Li, Qingpo
AU - Erm, Donald R.
AU - Aslan, Burcu
AU - Liu, Xuewu
AU - Sakamoto, Jason
AU - Chavez-Reyes, Arturo
AU - Han, Hee Dong
AU - Sood, Anil K.
AU - Ferrari, Mauro
AU - Lopez-Berestein, Gabriel
PY - 2013/4/1
Y1 - 2013/4/1
N2 - Purpose: RNA interference has the potential to specifically knockdown the expression of target genes and thereby transform cancer therapy. However, lack of effective delivery of siRNA has dramatically limited its in vivo applications. We have developed a multistage vector (MSV) system, composed of discoidal porous silicon particles loaded with nanotherapeutics, that directs effective delivery and sustained release of siRNA in tumor tissues. In this study, we evaluated therapeutic efficacy of MSV-loaded EphA2 siRNA (MSV/EphA2) with murine orthotopic models of metastatic ovarian cancers as a first step toward development of a new class of nanotherapeutics for the treatment of ovarian cancer. Experimental Design: Tumor accumulation of MSV/EphA2 and sustained release of siRNA from MSV were analyzed after intravenous administration of MSV/siRNA. Nude mice with metastatic SKOV3ip2 tumors were treated with MSV/EphA2 and paclitaxel, and therapeutic efficacy was assessed. Mice with chemotherapy-resistant HeyA8 ovarian tumors were treated with a combination of MSV/EphA2 and docetaxel, and enhanced therapeutic efficacy was evaluated. Results: Treatment of SKOV3ip2 tumor mice with MSV/EphA2 biweekly for 6 weeks resulted in dose-dependent (5, 10, and 15 μg/mice) reduction of tumor weight (36%, 64%, and 83%) and number of tumor nodules compared with the control groups. In addition, tumor growth was completely inhibited when mice were treated with MSV/EphA2 in combination with paclitaxel. Furthermore, combination treatment with MSV/EphA2 and docetaxel inhibited growth of HeyA8-MDR tumors, which were otherwise resistant to docetaxel treatment. Conclusion: These findings indicate that MSV/EphA2 merits further development as a novel therapeutic agent for ovarian cancer.
AB - Purpose: RNA interference has the potential to specifically knockdown the expression of target genes and thereby transform cancer therapy. However, lack of effective delivery of siRNA has dramatically limited its in vivo applications. We have developed a multistage vector (MSV) system, composed of discoidal porous silicon particles loaded with nanotherapeutics, that directs effective delivery and sustained release of siRNA in tumor tissues. In this study, we evaluated therapeutic efficacy of MSV-loaded EphA2 siRNA (MSV/EphA2) with murine orthotopic models of metastatic ovarian cancers as a first step toward development of a new class of nanotherapeutics for the treatment of ovarian cancer. Experimental Design: Tumor accumulation of MSV/EphA2 and sustained release of siRNA from MSV were analyzed after intravenous administration of MSV/siRNA. Nude mice with metastatic SKOV3ip2 tumors were treated with MSV/EphA2 and paclitaxel, and therapeutic efficacy was assessed. Mice with chemotherapy-resistant HeyA8 ovarian tumors were treated with a combination of MSV/EphA2 and docetaxel, and enhanced therapeutic efficacy was evaluated. Results: Treatment of SKOV3ip2 tumor mice with MSV/EphA2 biweekly for 6 weeks resulted in dose-dependent (5, 10, and 15 μg/mice) reduction of tumor weight (36%, 64%, and 83%) and number of tumor nodules compared with the control groups. In addition, tumor growth was completely inhibited when mice were treated with MSV/EphA2 in combination with paclitaxel. Furthermore, combination treatment with MSV/EphA2 and docetaxel inhibited growth of HeyA8-MDR tumors, which were otherwise resistant to docetaxel treatment. Conclusion: These findings indicate that MSV/EphA2 merits further development as a novel therapeutic agent for ovarian cancer.
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U2 - 10.1158/1078-0432.CCR-12-2764
DO - 10.1158/1078-0432.CCR-12-2764
M3 - Article
C2 - 23386691
AN - SCOPUS:84877092185
SN - 1078-0432
VL - 19
SP - 1806
EP - 1815
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -