Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer.
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.
Landen
Charles N
CN
Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Merritt
William M
WM
Mangala
Lingegowda S
LS
Sanguino
Angela M
AM
Bucana
Corazon
C
Lu
Chunhua
C
Lin
Yvonne G
YG
Han
Liz Y
LY
Kamat
Aparna A
AA
Schmandt
Rosemarie
R
Coleman
Robert L
RL
Gershenson
David M
DM
Lopez-Berestein
Gabriel
G
Sood
Anil K
AK
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
D008081:Liposomes; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; C017251:1,2-oleoylphosphatidylcholine