RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy.
RNA interference (RNAi) entails the potential for novel therapeutic strategies through the silencing of disease-causing genes in vivo. However, recent studies have raised an issue regarding applicable routes of administration for small interfering RNA (siRNA) molecules as therapeutics. In this study, we demonstrate that liposomally formulated siRNA molecules, the so-called siRNA-lipoplexes, but not naked siRNAs, are delivered to the tumor endothelial cells in vivo by microscopy. In addition, functional intracellular delivery of formulated siRNA targeting the tumor suppressor PTEN is shown in endothelial cells of the liver and tumor. Finally, the therapeutic potential of systemically administered siRNA(CD31)-lipoplexes is established by inhibition of tumor growth in two different xenograft mouse models. Our findings corroborate the applicability of this liposomal siRNA delivery technology for inducing RNAi to modulate gene expression levels in angiogenesis-dependent processes. In addition, our results advocate CD31 as a promising therapeutic target for antiangiogenic intervention. Therefore, our study provides a basis for the development of antiangiogenic cancer therapies based on RNAi.
Santel
A
A
Atugen AG (SR Pharma plc subsidiary), Berlin, Germany.
Aleku
M
M
Keil
O
O
Endruschat
J
J
Esche
V
V
Durieux
B
B
Löffler
K
K
Fechtner
M
M
Röhl
T
T
Fisch
G
G
Dames
S
S
Arnold
W
W
Giese
K
K
Klippel
A
A
Kaufmann
J
J
D016475:3T3 Cells; D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014183:Transplantation, Heterologous
D018952:Antigens, CD34; D008081:Liposomes; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D034741:RNA, Small Interfering; D051059:PTEN Phosphohydrolase