Báo cáo khoa học: Efficient and targeted delivery of siRNA in vivo pdf

MINIREVIEW

Efficient and targeted delivery of siRNA in vivo

Min Suk Shim1 and Young Jik Kwon1,2,3

1 Department of Chemical Engineering and Materials Science, University of California, Irvine, CA, USA

2 Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA

3 Department of Biomedical Engineering, University of California, Irvine, CA, USA

Introduction

RNA interference (RNAi) is a highly conserved biologi￾cal process among yeasts, worms, insects, plants and

humans [1]. A single strand of exogenously introduced

double-stranded small interfering RNA (siRNA; 20–30

nucleotides) guides an RNA-inducing silencing protein

complex to degrade the mRNA with the matching

sequence; thus, translation into the target proteins is

silenced [2–4]. RNAi has been of great interest not only

as a powerful research tool to suppress the expression of

a target gene, but also as an emerging therapeutic strat￾egy to silence disease genes [5]. Theoretically, siRNA

can interfere with the translation of almost any mRNA,

as long as the mRNA has a distinctive sequence,

whereas the targets of traditional drugs are limited by

types of cellular receptors and enzymes [6].

Cancer, viral infections, autoimmune diseases and

neurodegenerative diseases have been explored as

promising disease targets of RNAi [7,8]. Recent pro￾gress in clinical trials using siRNA to cure age-related

macular degeneration (bevasiranib; Opko Health, Inc.,

Miami, FL, USA; phase III) and respiratory syncytial

virus infection (ALN-RSV01; Alnylam, Cambridge,

MA, USA; phase II) have demonstrated the therapeu￾tic potential of RNAi [9]. Moreover, the first evidence

Keywords

administration routes; barriers in siRNA

delivery; chemically modified RNA; in vivo

disease models; nanoparticles; nonviral

carriers; nucleic acid therapeutics; RNA

interference; targeted delivery in vivo;

viral vectors

Correspondence

Y. J. Kwon, Department of Pharmaceutical

Sciences, 916 Engineering Tower,

University of California, Irvine, CA 92697,

USA

Fax: +1 949 824 2541

Tel: +1 949 824 8714

E-mail: [email protected]

(Received 7 July 2010, accepted

26 August 2010)

doi:10.1111/j.1742-4658.2010.07904.x

RNA interference (RNAi) has been regarded as a revolutionary tool for

manipulating target biological processes as well as an emerging and prom￾ising therapeutic strategy. In contrast to the tangible and obvious effective￾ness of RNAi in vitro, silencing target gene expression in vivo using small

interfering RNA (siRNA) has been a very challenging task due to

multiscale barriers, including rapid excretion, low stability in blood serum,

nonspecific accumulation in tissues, poor cellular uptake and inefficient

intracellular release. This minireview introduces major challenges in achiev￾ing efficient siRNA delivery in vivo and discusses recent advances in over￾coming them using chemically modified siRNA, viral siRNA vectors and

nonviral siRNA carriers. Enhanced specificity and efficiency of RNAi

in vivo via selective accumulations in desired tissues, specific binding to

target cells and facilitated intracellular trafficking are also commonly

attempted utilizing targeting moieties, cell-penetrating peptides, fusogenic

peptides and stimuli-responsive polymers. Overall, the crucial roles of the

interdisciplinary approaches to optimizing RNAi in vivo, by efficiently and

specifically delivering siRNA to target tissues and cells, are highlighted.

Abbreviations

ApoB, apolipoprotein B; CPP, cell-penetrating peptide; FA, folic acid; GFP, green fluorescent protein; HER-2, human epidermal growth

factor 2; i.p., intraperitoneal; i.t., intratumoral; i.v., intravenous; 9R, nonamer arginine residues; RGD, Arg-Gly-Asp peptide; RNAi,

RNA interference; siRNA, small interfering RNA; VEGF, vascular endothelial growth factor.

4814 FEBS Journal 277 (2010) 4814–4827 ª 2010 The Authors Journal compilation ª 2010 FEBS