title: Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer.
abstract: OBJECTIVE
  Intravenous (IV) delivery of siRNA incorporated into neutral liposomes allows efficient delivery to tumor tissue, and has therapeutic efficacy in preclinical proof-of-concept studies using EphA2-targeting siRNA. We sought to determine whether intraperitoneal (IP) delivery of these siRNA complexes was as effective at delivery and therapy as IV delivery.
  
  
  METHODS
  SiRNA was incorporated into the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). Alexa555-siRNA-DOPC was injected IP into nude mice bearing established ovarian tumors, and organs were collected for microscopic fluorescent examination. Subsequently, therapeutic efficacy of the IP versus IV routes was directly compared.
  
  
  RESULTS
  Alexa555-siRNA in DOPC liposomes injected IP was diffusely distributed into intraperitoneal ovarian tumors. Delivery was also seen deeply into the liver and kidney parenchyma, suggesting that the predominant means of distribution was through the vasculature, rather than direct diffusion from the peritoneal cavity. In mice with orthotopic ovarian tumors, treatment with combined paclitaxel and IP EphA2-targeting siRNA-DOPC reduced tumor growth by 48-81% compared to paclitaxel/control siRNA-DOPC IP (HeyA8: 0.34 g v 0.66 g; SKOV3ip1: 0.04 v 0.21, p<0.01). This reduction was comparable to concurrently-treated mice with paclitaxel and EphA2 siRNA-DOPC injected IV, which showed a reduction in growth by 45-69% compared to paclitaxel/control siRNA-DOPC injected IV (HeyA8: 0.23g v. 0.42g; SKOV3ip1: 0.04 v. 0.13 g).
  
  
  CONCLUSIONS
  IP injection of siRNA incorporated in DOPC allows intra-tumoral delivery and has therapeutic efficacy in orthotopic ovarian tumors. These findings may have therapeutic implications for siRNA-based strategies.
authors.affiliation: Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
authors.forename: William M
authors.initials: WM
authors.lastname: Merritt
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.forename: Angela M
authors.initials: AM
authors.lastname: Sanguino
authors.forename: Corazon
authors.initials: C
authors.lastname: Bucana
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Lin
authors.forename: Liz Y
authors.initials: LY
authors.lastname: Han
authors.forename: Aparna A
authors.initials: AA
authors.lastname: Kamat
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Schmandt
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: David M
authors.initials: DM
authors.lastname: Gershenson
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000628:therapy*; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering / Q000235:genetics* / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D008081:Liposomes; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; C017251:1,2-oleoylphosphatidylcholine