Publications by authors named "Satoru Sonoke"

9 Publications

  • Page 1 of 1

Therapeutic effects of microRNA-582-5p and -3p on the inhibition of bladder cancer progression.

Mol Ther 2013 Mar 8;21(3):610-9. Epub 2013 Jan 8.

National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

Many reports have indicated that the abnormal expression of microRNAs (miRNAs) is associated with the progression of disease and have identified miRNAs as attractive targets for therapeutic intervention. However, the bifunctional mechanisms of miRNA guide and passenger strands in RNA interference (RNAi) therapy have not yet been clarified. Here, we show that miRNA (miR)-582-5p and -3p, which are strongly decreased in high-grade bladder cancer clinical samples, regulate tumor progression in vitro and in vivo. Significantly, the overexpression of miR-582-5p or -3p reduced the proliferation and invasion of UM-UC-3 human bladder cancer cells. Furthermore, transurethral injections of synthetic miR-582 molecule suppressed tumor growth and metastasis in an animal model of bladder cancer. Most interestingly, our study revealed that both strands of miR-582-5p and -3p suppressed the expression of the same set of target genes such as protein geranylgeranyltransferase type I beta subunit (PGGT1B), leucine-rich repeat kinase 2 (LRRK2) and DIX domain containing 1 (DIXDC1). Knockdown of these genes using small interfering RNA (siRNA) resulted in the inhibition of cell growth and invasiveness of UM-UC-3. These findings uncover the unique regulatory pathway involving tumor suppression by both strands of a single miRNA that is a potential therapeutic target in the treatment of invasive bladder cancer.
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http://dx.doi.org/10.1038/mt.2012.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589153PMC
March 2013

Galactose-modified cationic liposomes as a liver-targeting delivery system for small interfering RNA.

Biol Pharm Bull 2011 ;34(8):1338-42

Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Tsukuba, Ibaraki 305–0003, Japan.

We have developed a galactose-modified cationic liposome for delivery of small interfering RNA (siRNA) to the liver. The liposomes were designed to be transported into hepatocytes via the asialoglycoprotein receptor, which recognizes galactose residues. The liposomes contained a novel galactose-modified lipid, 1,2-dioleoyl-sn-glycerol-3-phosphatidyl-N-(1-deoxylactito-1-yl)ethanolamine (GDOPE). Delivery of siRNA to hepatocytes by the liposomes was evaluated by measuring the gene-silencing activity of liposome : siRNA complexes in two human hepatoma cell lines. A formulation with a cationic lipid : GDOPE ratio of 3 : 5 by weight, LIC-G5, showed the strongest activity. In mice, intravenous injection of LIC-G5 complexed with (3)H-labeled siRNA led to accumulation of radioactivity in the liver. When the hepatic cellular uptake was determined after intravenous injection into mice followed by collagenase liver perfusion, the distribution of siRNA to parenchymal cells was 1.9 times higher when LIC-G5 rather than nongalactosylated LIC was used as the carrier. The concentration of siRNA accumulated was 45 µg/ml, 30 times the concentration that produced strong gene silencing in vitro and therefore presumably sufficient for a therapeutic effect. Because increasing the cationic-lipid content of a liposome carrier generally enhances the uptake of siRNA by the liver at the expense of increased cell toxicity, we used only a moderate amount of cationic lipid in our galactose-modified carrier. LIC-G5 enhanced the uptake of siRNA by the liver without cytotoxic effects and is a promising candidate delivery system for liver-targeted siRNA therapy.
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http://dx.doi.org/10.1248/bpb.34.1338DOI Listing
February 2012

Tumor regression in mice by delivery of Bcl-2 small interfering RNA with pegylated cationic liposomes.

Cancer Res 2008 Nov;68(21):8843-51

Discovery Research Laboratories, Nippon Shinyaku Co Ltd, Tsukuba, Japan.

The pharmacokinetics and antitumor activity of pegylated small interfering RNA (siRNA)/cationic liposome complexes were studied after systemic administration to mice. We designed pegylated-lipid carriers for achieving increased plasma concentrations of RNA and hence improved accumulation of RNA in tumors by the enhanced permeability and retention effect. We compared the pharmacokinetics of siRNA complexed with liposomes incorporating pegylated lipids with longer (C-17 or C-18), shorter (C-12 to C-16), or unsaturated (C-18:1) acyl chains. When longer acyl chains were used, the plasma concentrations of siRNA obtained were dramatically higher than when shorter or unsaturated chains were used. This may be explained by the higher gel-to-liquid-crystalline phase-transition temperature (Tc) of lipids with longer acyl chains, which may form more rigid liposomes with reduced uptake by the liver. We tested a siRNA that is sequence specific for the antiapoptotic bcl-2 mRNA complexed with a pegylated liposome incorporating a C-18 lipid (PEG-LIC) by i.v. administration in a mouse model of human prostate cancer. Three-fold higher accumulation of RNA in the tumors was achieved when PEG-LIC rather than nonpegylated liposomes was used, and sequence-specific antitumor activity was observed. Our siRNA/PEG-LIC complex showed no side effects on repeated administration and the strength of its antitumor activity may be attributed to its high uptake by the tumors. Pegylation of liposomes improved the plasma retention, uptake by s.c. tumors, and antitumor activity of the encapsulated siRNA. PEG-LIC is a promising candidate for siRNA cancer therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-0127DOI Listing
November 2008

Liver target delivery of small interfering RNA to the HCV gene by lactosylated cationic liposome.

J Hepatol 2007 Dec 26;47(6):744-50. Epub 2007 Jul 26.

Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.

Background/aims: RNA interference has considerable therapeutic potential, particularly for anti-viral therapy. We previously reported that hepatitis C virus (HCV)-directed small interfering RNA (siRNA; siE) efficiently inhibits HCV replication, using HCV replicon cells. To employ the siRNA as a therapeutic strategy, we attempted in vivo silencing of intrahepatic HCV gene expression by siE using a novel cationic liposome.

Methods: The liposomes consisted of conjugated lactose residues, based on the speculation that lactose residues would effectively deliver siRNA to the liver via a liver specific receptor. The lactosylated cationic liposome 5 (CL-LA5) that contained the most lactose residues introduced the most siRNA into a human hepatoma cell line, which then inhibited replication of HCV replicons.

Results: In mice, the siRNA/CL-LA5 complexes accumulated primarily in the liver and were widespread throughout the hepatic parenchymal cells. Moreover, siE/CL-LA5 specifically and dose-dependently suppressed intrahepatic HCV expression in transgenic mice without an interferon response.

Conclusions: The present results indicate that the CL-LA5 we developed is a good vehicle to lead siRNA to the liver. Hence, CL-LA5 will be helpful for siRNA therapy targeting liver diseases, especially hepatitis C.
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http://dx.doi.org/10.1016/j.jhep.2007.06.015DOI Listing
December 2007

Lipid transfer protein transports compounds from lipid nanoparticles to plasma lipoproteins.

Int J Pharm 2004 May;275(1-2):239-48

Pharmacy Laboratories, Nippon Shinyaku Co. Ltd., 14, Nishinosho-Monguchicho, Kissyoin, Minami-Ku, Kyoto 601-8550, Japan.

Nanometer-sized lipid emulsion particles with a diameter of 25-50 nm, called Lipid Nano-Sphere (LNS), are expected as a promising drug carrier to show prolonged plasma half-life of an incorporating drug. In terms of successful drug delivery using LNS, a drug should be incorporated into the lipid particles and remain within the particle, not only in the formulation in vitro but also after administration into the systemic blood circulation. In this study, we showed that phospholipids and some water-insoluble molecules also moved from lipid particles to plasma lipoproteins or albumin in serum and plasma half-lives of these compounds did not reflect that of the drug carriers. It was suggested that phospholipid or its derivative were transferred from LNS particles to plasma lipoproteins by lipid transfer proteins (LTP) in the circulation. These phenomena leaded to unsuccessful delivery of the drug with lipid-particulate drug carriers. On the other hand, lipophilic derivatives with cholesterol pro-moiety tested in this study were not released from LNS particles and showed prolonged plasma half-lives. Lipophilicity is known to be an important parameter for incorporating drugs into lipid particles but substrate specificity for LTP seems to be another key to success promising drug design using lipid emulsion particulate delivery system.
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http://dx.doi.org/10.1016/j.ijpharm.2004.02.008DOI Listing
May 2004

A nanometer lipid emulsion, lipid nano-sphere (LNS), as a parenteral drug carrier for passive drug targeting.

Int J Pharm 2004 Apr;273(1-2):75-83

Pharmacy Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-Monguchicho, Kissyoin, Minami-Ku, Kyoto 601-8550, Japan.

We attempted to develop an artificial lipoprotein-like particle, lipid nano-sphere (LNS), incorporating dexamethasone palmitate (DMP). LNS is 25-50 nm in diameter and is composed of soybean oil and egg lecithin. Potential drug carriers were compared with a conventional fat emulsion for intravenous nutrition, lipid microsphere (LM, d=200-300 nm), which is already used clinically. LM easily entered reticuloendothelial systems, such as the liver, and was rapidly cleared from the circulation. However, LNS showed much higher plasma levels of DMP after intravenous administration to rats and recovered more than 80% of the injected dose in the perfusate in single-pass rat liver perfusion. The calculated volume for the distribution of the lipid emulsion within the liver showed that LNS underwent fenestration and was distributed into the Disse space in the liver. Because of the lower uptake of LNS particles by the liver, LNS showed good recovery from the liver and prolonged the plasma half-life of DMP after intravenous injection. In addition, higher efficiency in the targeting of DMP into inflammation sites and higher anti-inflammatory efficacy were observed in LNS. Thus, LNS easily and selectively passed through the leaky capillary wall by passive diffusion depending on the plasma concentration. Nanometer-sized lipid emulsion particles, LNS, seem to be a promising carrier system for passive drug targeting of lipophilic drugs.
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http://dx.doi.org/10.1016/j.ijpharm.2003.12.022DOI Listing
April 2004

Comparison of LNS-AmB, a novel low-dose formulation of amphotericin B with lipid nano-sphere (LNS), with commercial lipid-based formulations.

Int J Pharm 2003 Nov;267(1-2):101-12

R&D Administration Department, Nippon Shinyaku Co. Ltd., 14 Nishinosho-Monguchi-cho Kisshoin, Minami-ku, Kyoto 601-8550, Japan.

Three lipid-based delivery systems (AmBisome, Amphocil, and Abelcet) for amphotericin B (AmB) have been marketed to overcome the disadvantages associated with the clinical use of AmB. However, to show their efficacy, they need to be administered at higher doses than the conventional dosage form, Fungizone. In this study, we compared LNS-AmB, our new low-dose therapeutic system for AmB using lipid nano-sphere (LNS), with these commercial formulations in terms of their pharmacokinetics and efficacy. The plasma AmB levels yielded by LNS-AmB after intravenous administration to rats were much higher than those yielded by Amphocil or Abelcet, and similar to those yielded by AmBisome, but in dogs LNS-AmB yielded plasma AmB concentrations about three times higher than did AmBisome. In a carrageenin-induced pleurisy model in rats, LNS-AmB yielded AmB levels in the pleural exudate over 20 times those yielded by Amphocil or Abelcet, and similar to those yielded by AmBisome. From these pharmacokinetic results, it is clear that Amphocil and Abelcet are based on a quite distinct drug-delivery concept from LNS-AmB. In a rat model of localized candidiasis, LNS-AmB significantly inhibited the growth of Candida albicans in the pouch, whereas AmBisome did not, even though the AmB concentrations in the pouch were similar. This difference in antifungal activity between LNS-AmB and AmBisome was also found in vitro. That is, the antifungal activity of LNS-AmB against C. albicans was similar to that of Fungizone and dimethyl sulfoxide-solubilized AmB, while AmBisome showed weaker antifungal activity than did other formulations. Based on these results, the release of AmB from AmBisome was judged to be slow and slight. In a mouse model of systemic candidiasis, LNS-AmB (1.0mg/kg) was much more effective than AmBisome (8.0mg/kg) or Fungizone (1.0mg/kg). These results suggest that LNS-AmB maintained the potent activity of AmB against fungal cells even though the AmB was incorporated into LNS particles. We conclude that LNS-AmB may offer an improved therapeutic profile at lower doses than Fungizone and commercial lipid-based formulations.
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http://dx.doi.org/10.1016/j.ijpharm.2003.08.002DOI Listing
November 2003

A novel delivery system for amphotericin B with lipid nano-sphere (LNS).

Int J Pharm 2003 Oct;265(1-2):37-45

R&D Administration Department, Nippon Shinyaku Co. Ltd., 14, Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.

A low-dose therapeutic system with a lipid emulsion for amphotericin B (AmB), a potent antifungal drug, was studied. Lipid nano-sphere (LNS), a small-particle lipid emulsion, was taken up by the liver to a lesser extent than was a conventional lipid emulsion. As a result, LNS yielded higher plasma concentrations of a radiochemical tracer than did the conventional lipid emulsion. LNS was therefore judged to be a suitable carrier for a low-dose therapeutic system for AmB, and LNS incorporating AmB (LNS-AmB) was prepared. LNS-AmB was found to be a homogeneous emulsion with mean particle diameters ranging from 25 to 50 nm. LNS-AmB yielded higher plasma concentrations of AmB than did Fungizone, a conventional intravenous dosage form of AmB, after intravenous administration to mice, rats, dogs, and monkeys. This difference between LNS-AmB and Fungizone was also observed for constant intravenous infusion. In contrast to Fungizone, LNS-AmB showed a linear relationship between dose and AUC. These pharmacokinetic characteristics of LNS-AmB make it a suitable candidate for an effective low-dose therapeutic system for AmB.
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http://dx.doi.org/10.1016/s0378-5173(03)00404-6DOI Listing
October 2003

Evaluation of the efficacy and toxicity of amphotericin B incorporated in lipid nano-sphere (LNS).

Int J Pharm 2003 Sep;263(1-2):51-60

R&D Administration Department, Nippon Shinyaku Co. Ltd., 14, Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.

To develop a low-dose therapeutic system for amphotericin B (AmB), the efficacy and toxicity of lipid nano-sphere (LNS) incorporating AmB (LNS-AmB) were evaluated and compared with those of Fungizone, the conventional dosage form of AmB with sodium deoxycholate. LNS-AmB and Fungizone showed nearly equal activity against fungal cells both in vitro and in vivo. In contrast to Fungizone, however, LNS-AmB did not cause significant hemolysis. In addition, the vomiting toxicity of Fungizone was largely avoided by the use of LNS-AmB in dogs, in spite of the higher plasma AmB concentrations achieved by LNS-AmB. Therefore, LNS-AmB may be selective for fungal cells over mammalian cells. In a study of its toxicity and toxicokinetics in a regimen of daily 2-h intravenous infusions for 14 consecutive days, LNS-AmB showed less toxicity to the kidney than did Fungizone in spite of the higher plasma AmB concentrations achieved. LNS-AmB, therefore, allows the treatment of systemic fungal infections at low doses without the severe nephrotoxicity of Fungizone. Size-exclusion chromatography provided evidence that, when LNS-AmB was administered to rats, AmB was retained in the LNS particles in the blood circulation, but that when Fungizone was administered, AmB was transferred to high-density lipoproteins (HDL). AmB retained in LNS particles seemed to be less toxic to the kidney than was AmB associated with HDL. Consequently, LNS-AmB has the potential to become a low-dose therapeutic system for AmB, minimizing most of the severe side effects of AmB by decreasing the total dose required.
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http://dx.doi.org/10.1016/s0378-5173(03)00342-9DOI Listing
September 2003