Lipid-based systemic delivery of siRNA

Tseng, Yu Cheng; Mozumdar, Subho; Huang, Leaf

doi:10.1016/j.addr.2009.03.003

Cited by 430 publications

(336 citation statements)

References 189 publications

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“…Several reviews have discussed viral and nonviral delivery systems for efficient delivery of siRNA to tissue cells. 17,[19][20][21] Here, we report on the use of a poly(lactic-co-glycolic) acid (PLGA) microparticle-based delivery system for efficient and sustained delivery of siRNA to MSC. PLGA microparticles are biocompatible and biodegradable and have been approved by the Food and Drug Administration.…”

Section: Introductionmentioning

confidence: 99%

Effects of Glucocorticoid Receptor Small Interfering RNA Delivered Using Poly Lactic-Co-Glycolic Acid Microparticles on Proliferation and Differentiation Capabilities of Human Mesenchymal Stromal Cells

Hong

Wei

Joshi

et al. 2012

Tissue Engineering Part A

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Bone marrow-derived mesenchymal stem cells (MSC) are a potential attractive source of cells for stem cellbased tissue regeneration, but the small number and reduced capabilities of MSC proliferation and differentiation due to in vitro replicative senescence and donor-associated pathophysiological factors, including age and estrogen depletion, severely restrict their potential usefulness in clinical applications. Glucocorticoids (GC) are well-known steroid hormones that regulate MSC proliferation and differentiation, but the defined effects and underlying mechanisms of endogenous glucocorticoids on MSC characteristics are not understood. This study investigated the effects of the blockage of endogenous GC using glucocorticoid receptor (GR) small interfering RNA (siRNA) delivered using biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles on proliferation and differentiation capabilities of human MSC in vitro. The results show that we can prepare PLGA microparticles as a delivery system for GR siRNA and maintain release of siRNA up to 40 days in vitro. Transfection of GR siRNA significantly downregulates GR and upregulates the expression of fibroblast growth factor-2 and Sox-11 of human MSC. MSC that have proliferated with endogenous GC blocked in vitro have greater proliferation rates and exhibit upregulated expression of osteogenic markers (alkaline phosphatase and core binding factor alpha 1) under differentiation stimulation after 1 week. Under adipogenic differentiation, MSC proliferated in vitro with siRNA transfection, resulting in significantly lower adipogenic markers (peroxisome proliferatoractivated receptor and lipoprotein lipase) than controls. In conclusion, PLGA particles can serve as a tool for delivery of GR siRNA to effectively block the effects of endogenous GC on MSC, which has the potential to improve the capabilities of human MSC for clinical application by preventing replicative senescence.

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Section: Introductionmentioning

confidence: 99%

Effects of Glucocorticoid Receptor Small Interfering RNA Delivered Using Poly Lactic-Co-Glycolic Acid Microparticles on Proliferation and Differentiation Capabilities of Human Mesenchymal Stromal Cells

Hong

Wei

Joshi

et al. 2012

Tissue Engineering Part A

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“…This progress, however, is still overshadowed by many challenges, and the greatest is siRNA delivery (Sepp-Lorenzino and Ruddy 2008;Tseng et al 2009). From a pharmacodynamic perspective, the essential destination of therapeutic siRNA is the cellular Ago2 in targeted cells.…”

Section: Introductionmentioning

confidence: 99%

Quantitative evaluation of siRNA delivery in vivo

Pei

Hancock²,

Zhang³

et al. 2010

RNA

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Effective small interfering RNA (siRNA)-mediated therapeutics require the siRNA to be delivered into the cellular RNA-induced silencing complex (RISC). Quantitative information of this essential delivery step is currently inferred from the efficacy of gene silencing and siRNA uptake in the tissue. Here we report an approach to directly quantify siRNA in the RISC in rodents and monkey. This is achieved by specific immunoprecipitation of the RISC from tissue lysates and quantification of small RNAs in the immunoprecipitates by stem-loop PCR. The method, expected to be independent of delivery vehicle and target, is label-free, and the throughput is acceptable for preclinical animal studies. We characterized a lipid-formulated siRNA by integrating these approaches and obtained a quantitative perspective on siRNA tissue accumulation, RISC loading, and gene silencing. The described methodologies have utility for the study of silencing mechanism, the development of siRNA therapeutics, and clinical trial design.

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“…The cationic head group is functional for the binding of siRNA phosphate groups, and the lipid moiety is used as a fusogenic group to enhance penetration into the cells (Li and Szoka, 2007). The evolution of lipid-based vectors including their formulation strategies, cytotoxicity, transfection efficacy, extracellular uptake and intracellular trafficking, have been extensively reviewed ( [Li and Szoka, 2007], [Tseng et al, 2009], and [Schroeder et al, 2010]). …”

Section: Lipids and Liposomesmentioning

confidence: 99%