title: Enhancing chemotherapy response with sustained EphA2 silencing using multistage vector delivery.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  These findings indicate that MSV/EphA2 merits further development as a novel therapeutic agent for ovarian cancer.
authors: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX 77030, USA. hshen@tmhs.org
authors: Haifa
authors: H
authors: Shen
authors: Cristian
authors: C
authors: Rodriguez-Aguayo
authors: Rong
authors: R
authors: Xu
authors: Vianey
authors: V
authors: Gonzalez-Villasana
authors: Junhua
authors: J
authors: Mai
authors: Yi
authors: Y
authors: Huang
authors: Guodong
authors: G
authors: Zhang
authors: Xiaojing
authors: X
authors: Guo
authors: Litao
authors: L
authors: Bai
authors: Guoting
authors: G
authors: Qin
authors: Xiaoyong
authors: X
authors: Deng
authors: Qingpo
authors: Q
authors: Li
authors: Donald R
authors: DR
authors: Erm
authors: Burcu
authors: B
authors: Aslan
authors: Xuewu
authors: X
authors: Liu
authors: Jason
authors: J
authors: Sakamoto
authors: Arturo
authors: A
authors: Chavez-Reyes
authors: Hee-Dong
authors: HD
authors: Han
authors: Anil K
authors: AK
authors: Sood
authors: Mauro
authors: M
authors: Ferrari
authors: Gabriel
authors: G
authors: Lopez-Berestein
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008081:Liposomes; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage; D036104:Receptor, EphA2 / Q000235:genetics*; D012825:Silicon / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D034741:RNA, Small Interfering; D036104:Receptor, EphA2; D012825:Silicon
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