Intravenous delivery of anti-RhoA small interfering RNA loaded in nanoparticles of chitosan in mice: safety and efficacy in xenografted aggressive breast cancer.
Overexpression of RhoA in cancer indicates a poor prognosis, because of increased tumor cell proliferation and invasion and tumor angiogenesis. We showed previously that anti-RhoA small interfering RNA (siRNA) inhibited aggressive breast cancer more effectively than conventional blockers of Rho-mediated signaling pathways. This study reports the efficacy and lack of toxicity of intravenously administered encapsulated anti-RhoA siRNA in chitosan-coated polyisohexylcyanoacrylate (PIHCA) nanoparticles in xenografted aggressive breast cancers (MDA-MB-231). The siRNA was administered every 3 days at a dose of 150 or 1500 microg/kg body weight in nude mice. This treatment inhibited the growth of tumors by 90% in the 150-microg group and by even more in the 1500-microg group. Necrotic areas were observed in tumors from animals treated with anti-RhoA siRNA at 1500 microg/kg, resulting from angiogenesis inhibition. In addition, this therapy was found to be devoid of toxic effects, as evidenced by similarities between control and treated animals for the following parameters: body weight gain; biochemical markers of hepatic, renal, and pancreatic function; and macroscopic appearance of organs after 30 days of treatment. Because of its efficacy and the absence of toxicity, it is suggested that this strategy of anti-RhoA siRNA holds significant promise for the treatment of aggressive cancers.
Pillé
J-Y
JY
Laboratoire de Recherche MERCI (Micro-Environnement et Régulation Cellulaire Intégrée), Faculté de Médecine et Pharmacie, Rouen, France. pillejea@etu.univ-rouen.fr
Li
H
H
Blot
E
E
Bertrand
J-R
JR
Pritchard
L-L
LL
Opolon
P
P
Maksimenko
A
A
Lu
H
H
Vannier
J-P
JP
Soria
J
J
Malvy
C
C
Soria
C
C
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000628:therapy*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D007260:Infusion Pumps; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D009368:Neoplasm Transplantation / Q000379:methods / Q000592:standards*; D009369:Neoplasms / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000628:therapy; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
D034741:RNA, Small Interfering; D048271:Chitosan; D020742:rhoA GTP-Binding Protein