Takeshita, F. et al. Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. Proc. Natl Acad. Sci. USA 102, 12177-12182

Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2005; 102(34):12177-82. DOI: 10.1073/pnas.0501753102
Source: PubMed

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.

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Available from: Fumitaka Takeshita, Jul 27, 2015
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    • "Ziyan et al. (2011) demonstrated that miR-21 was overexpressed in OS, and that the suppression of miR- 21 inhibits migration in OS cell lines. Moreover, it has been found that the injection of miR-143 in mice led to the suppression of OS lung metastasis (Osaki et al., 2011; Takeshita et al., 2005). "
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    ABSTRACT: A better understanding of pediatric tumor biology is needed to allow the development of less toxic and more efficient therapies, as well as to provide novel reliable biomarkers for diagnosis and risk stratification. The emerging role of microRNAs in controlling key pathways implicated in tumorigenesis makes their use in diagnostics a powerful novel tool for the early detection, risk assessment and prognosis, as well as for the development of innovative anticancer therapies. This perspective would be more urgent for the clinical management of pediatric cancer. In this review, we focus on the involvement of microRNAs in the biology of the main childhood tumors, describe their clinical significance and discuss their potential use as novel therapeutic tools and targets. Copyright © 2015 Elsevier GmbH. All rights reserved.
    Acta Histochemica 03/2015; 117(4-5). DOI:10.1016/j.acthis.2015.02.007 · 1.76 Impact Factor
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    • "A recent report showed the potential for atelocollagenmediated systemic antisense therapeutics in a mouse model of bone metastasis without any side effects. Therefore, we believe that targeting YB-1 with siRNA and atelocollagen could be a novel and effective treatment for OS (Takeshita et al, 2005). We previously found that nuclear expression of YB-1 is closely associated with P-gp expression in human OS samples (Oda et al, 1998). "
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    ABSTRACT: Background: Prognosis of osteosarcoma (OS) with distant metastasis and local recurrence is still poor. Y-box binding protein-1 (YB-1) is a multifunctional protein that can act as a regulator of transcription and translation and its high expression of YB-1 protein was observed in OS, however, the role of YB-1 in OS remains unclear. Methods: Y-box binding protein-1 expression in OS cells was inhibited by specific small interfering RNAs to YB-1 (si-YB-1). The effects of si-YB-1 in cell proliferation and cell cycle transition in OS cells were analysed in vitro and in vivo. The association of nuclear expression of YB-1 and clinical prognosis was also investigated by immunohistochemistry. Results: Proliferation of OS cell was suppressed by si-YB-1 in vivo and in vitro. The expression of cyclin D1 and cyclin A were also decreased by si-YB-1. In addition, si-YB-1 induced G1/S arrest with decreased cyclin D1 and cyclin A in OS cell lines. Direct binding of YB-1 in OS cell lines was also observed. Finally, the nuclear expression of YB-1 was significantly related to the poorer overall survival in OS patients. Conclusion: Y-box binding protein-1 would regulate cell cycle progression at G1/S and tumour growth in human OS cells in vitro and in vivo. Nuclear expression of YB-1 was closely associated with the prognosis of OS, thus, YB-1 simultaneously could be a potent molecular target and prognostic biomarker for OS.
    British Journal of Cancer 03/2013; 108(4):836-47. DOI:10.1038/bjc.2012.579 · 4.82 Impact Factor
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    • "Many studies, including some involving in vivo tumor models, have evidenced the contribution of atelocollagen to the enhancement of drugs' antitumor activities, and some of them described the mechanisms. For example, nucleic acids delivered by atelocollagen are protected against degradation by host nucleases [8] [14] [24], and it has also been shown to improve the delivery efficiency of oligonucleotides to tumors [15] [16]. However, the biological functions of atelocollagen and the mechanism by which it enhances delivery efficiency are still not fully understood. "
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    ABSTRACT: Atelocollagen is a major animal protein that is used as a highly biocompatible biomaterial. To date, atelocollagen has been used as an effective drug delivery technology to sustain the release of antitumor proteins and to enhance the antitumor activity of oligonucleotides in in vivo models. However, the biological effects of this technology are not fully understood. In the present study, we investigated the effects of atelocollagen on endothelial paracellular barrier function. An atelocollagen formulation containing oligonucleotides specifically increased the permeability of two types of endothelial cells, and the change was dependent on the molecular size, structure of the oligonucleotides used and the concentrations of the oligonucleotide and atelocollagen in the formulation. An immunohistochemical examination revealed that the formulation had effects on the cellular skeleton and intercellular structure although it did not affect the expression of adherens junction or tight junction proteins. These changes were induced through p38 MAP kinase signaling. It is important to elucidate the biological functions of atelocollagen in order to be able to exploit its drug delivery properties.
    03/2012; 2012:245835. DOI:10.1155/2012/245835
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