Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo.
Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery for siRNAs toward treatment of bone-metastatic cancer. Accordingly, we report here that i.v. injection of GL3 luciferase siRNA complexed with atelocollagen showed effective reduction of luciferase expression from bone-metastatic prostate tumor cells developed in mouse thorax, jaws, and/or legs. We also show that the siRNA/atelocollagen complex can be efficiently delivered to tumors 24 h after injection and can exist intact at least for 3 days. Furthermore, atelocollagen-mediated systemic administration of siRNAs such as enhancer of zeste homolog 2 and phosphoinositide 3'-hydroxykinase p110-alpha-subunit, which were selected as candidate targets for inhibition of bone metastasis, resulted in an efficient inhibition of metastatic tumor growth in bone tissues. In addition, upregulation of serum IL-12 and IFN-alpha levels was not associated with the in vivo administration of the siRNA/atelocollagen complex. Thus, for treatment of bone metastasis of prostate cancer, an atelocollagen-mediated systemic delivery method could be a reliable and safe approach to the achievement of maximal function of siRNA.
Takeshita
Fumitaka
F
Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Minakuchi
Yoshiko
Y
Nagahara
Shunji
S
Honma
Kimi
K
Sasaki
Hideo
H
Hirai
Kotaro
K
Teratani
Takumi
T
Namatame
Nachi
N
Yamamoto
Yusuke
Y
Hanai
Koji
K
Kato
Takashi
T
Sano
Akihiko
A
Ochiya
Takahiro
T
D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary* / Q000628:therapy*; D045744:Cell Line, Tumor; D003094:Collagen / Q000008:administration & dosage*; D004268:DNA-Binding Proteins / Q000235:genetics; D004337:Drug Carriers / Q000627:therapeutic use; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D063151:Polycomb Repressive Complex 2; D011471:Prostatic Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D004337:Drug Carriers; D034741:RNA, Small Interfering; D014157:Transcription Factors; C059821:atelocollagen; D003094:Collagen; D008156:Luciferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D019869:Phosphatidylinositol 3-Kinases