Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer

Charles N. Landen, William M. Merritt, Lingegowda S. Mangala, Angela M. Sanguino, Corazon Bucana, Chunhua Lu, Yvonne G. Lin, Liz Y. Han, Aparna A. Kamat, Rosemarie Schmandt, Robert L. Coleman, David M. Gershenson, Gabriel Lopez-Berestein, Anil K. Sood

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Purpose: 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. Experimental design: 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.

Original languageEnglish (US)
Pages (from-to)1708-1713
Number of pages6
JournalCancer Biology and Therapy
Volume5
Issue number12
DOIs
StatePublished - Dec 2006

Keywords

  • DOPC
  • EphA2
  • Intraperitoneal
  • Liposomes
  • Ovarian cancer
  • siRNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer'. Together they form a unique fingerprint.

Cite this