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PMID: 16091473 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 34 ·2005-08-23 ·Pages 12177-82

Takeshita F, Minakuchi Y, Nagahara S, Honma K, Sasaki H, Hirai K, Teratani T, Namatame N, Yamamoto Y, Hanai K, Kato T, Sano A, Ochiya T

Abstract

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.

MeSH Terms
Animals Bone Neoplasms/secondary,therapy Cell Line, Tumor Collagen/administration & dosage DNA-Binding Proteins/genetics Drug Carriers/therapeutic use Enhancer of Zeste Homolog 2 Protein Gene Expression Regulation, Neoplastic/genetics Genetic Therapy/methods Humans Luciferases/metabolism Male Mice Phosphatidylinositol 3-Kinases/genetics Polycomb Repressive Complex 2 Prostatic Neoplasms/pathology RNA, Small Interfering/administration & dosage,genetics,therapeutic use Reverse Transcriptase Polymerase Chain Reaction Transcription Factors/genetics
Chemicals
DNA-Binding Proteins Drug Carriers RNA, Small Interfering Transcription Factors atelocollagen Collagen Luciferases EZH2 protein, human Enhancer of Zeste Homolog 2 Protein Polycomb Repressive Complex 2 Phosphatidylinositol 3-Kinases
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Takeshita Fumitaka
Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Minakuchi Yoshiko
Nagahara Shunji
Honma Kimi
Sasaki Hideo
Hirai Kotaro
Teratani Takumi
Namatame Nachi
Yamamoto Yusuke
Hanai Koji
Kato Takashi
Sano Akihiko
Ochiya Takahiro
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0501753102
Published
2005-08-23
Epub
2005-00-09
Pages
12177-82
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1183487
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0501753102 PMC Full Text View journal details
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