6. Cationic Solid Lipid Nanoparticles Dered Apolipoprotent of Liver Fibrosis

Biomaterials 34(2013)542e 551

Contents lists available at SciVerse ScienceDirect

Biomaterials

journal h omepage:

6. Cationic Solid Lipid Nanoparticles Dered Apolipoprotent of Liver Fibrosis

http://www.360docs.net/doc/info-6613c157866fb84ae45c8da3.html /locate/biomaterials

Cationic solid lipid nanoparticles derived from apolipoprotein-free LDLs for target speci fic systemic treatment of liver fibrosis

Won Ho Kong a , Kitae Park b , Min-Young Lee a , Hwiwon Lee a , Dong Kyung Sung c , Sei Kwang Hahn a , b , *

Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH),San 31, Hyoja-dong, Nam-gu, Pohang, Kyungbuk 790-784, Republic of Korea b

School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH),San 31, Hyoja-dong, Nam-gu, Pohang, Kyungbuk 790-784, Republic of Korea c

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul 135-710, Republic of Korea

a

a r t i c l e i n f o

Article history:

Received 6September 2012Accepted 26September 2012Available online 22October 2012Keywords:

Cationic solid lipid nanoparticles Connective tissue growth factor siRNA

Targeted delivery Liver fibrosis

a b s t r a c t

Low density lipoprotein (LDL)plays an important role in transporting fat molecules including choles-terols in the body. In this work, cationic solid lipid nanoparticles (CSLNs),bioinspired and reconstituted from natural LDLs, were designed and applied to target speci fic systemic delivery of connective tissue growth factor siRNA (siCTGF)for the treatment of liver fibrosis. They could form a nuclease-resistant stable nano-complex with siRNA, which was ef ficiently internalized into cells achieving targeted gene silencing in the presence of serum with a remarkably low cytotoxicity. After intravenous injection, CSLN/siCTGF complex was target speci fically delivered to the liver and resulted in a signi ficant reduction in collagen content and pro-fibrogenic factors like tumor necrosis factor alpha (TNF-a ), transforming growth factor beta (TGF-b ), interleukin-6(IL-6),and CTGF with the dramatic improvement of patho-physiological symptoms in liver fibrosis model rats. The bio-distribution study by fluorescence bio-imaging and single-photon emission computed tomography (SPECT)con firmed the target speci fic delivery and accumulation of CSLN/siCTGFcomplexes to the liver tissues.

Ó2012Elsevier Ltd. All rights reserved.

1. Introduction

Chronic liver injury and persistent wound healing in the liver can lead to a fibrogenic process with the imbalance of parenchymal and non-parenchymal cell population, and the activation of hepatic stellate cells (HSCs)[1,2]. The increased production and deposition of hepatic extracellular matrix (ECM)components constitute the fibrous scars in the liver reducing its physiological performance [3,4]. Hepatitis virus infection is one of the major causes of chronic liver diseases like liver fibrosis and cirrhosis [5,6]. The hepatic fibrosis can be reversed by new anti fibrotic therapeutics on the cellular and molecular basis of fibrogenesis [7]. Recently, various small interfering RNAs (siRNAs)have shown a therapeutic potential for liver diseases by hepatotropic viruses [8e 10]. Several pioneer-ing studies have demonstrated the anti fibrotic effect of siRNA on down-regulating pro-fibrogenic growth factors such as connective

*Corresponding author. Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH),San 31, Hyoja-dong, Nam-gu, Pohang, Kyungbuk 790-784, Republic of Korea. Tel.:þ82542792159; fax:þ82542792399.

E-mail address:skhanb@postech.ac.kr(S.K.

6. Cationic Solid Lipid Nanoparticles Dered Apolipoprotent of Liver Fibrosis

Hahn). 0142-9612/$e see front matter Ó2012Elsevier Ltd. All rights reserved. http://www.360docs.net/doc/info-6613c157866fb84ae45c8da3.html /10.1016/j.biomaterials.2012.09.067

tissue growth factor (CTGF)and transforming growth factor beta (TGF-b ) in the liver [11,12]. Especially, the cooperative interaction of CTGF in TGF-b signaling pathway was reported to be highly related with the HSC activation and hepatic fibrosis in the damaged liver [13e 16]. Consequently, much of attention has been devoted to CTGF as an emerging target gene for anti fibrotic therapy [12,17]. The clinical progress of siRNA therapeutics has relied on the development of siRNA delivery carriers. In particular, a great effort has been directed toward the development of lipid-based siRNA delivery systems including liposomes [18,19], micelles [20,21], emulsions [22,23], and solid lipid nanoparticles (SLNs)[24,25]due to their high transfection ef ficiency, improved pharmacokinetic characteristics, and relatively low cytotoxicity [26,27]. Among them, lipoprotein-like lipid nanoparticles have emerged as a promising candidate for the delivery of siRNA [28e 31]. Lipoproteins are endogenous particles that transport lipids to various cell types in the liver. Since the liver plays a major role in their metabolism, they are recognized and taken up via speci fic receptors in the liver [32]. Their endogenous nature allows them to be biodegradable and non-cytotoxic without triggering the reticuloendothelial system (RES)and the immune responses during the systemic circulation [32]. Accordingly, recombinant and reconstituted lipoprotein-like lipid nanoparticles have been developed for targeted siRNA delivery

6. Cationic Solid Lipid Nanoparticles Dered Apolipoprotent of Liver Fibrosis的相关文档搜索

相关文档