Biodegradable Nanoparticles With Sustained Release of Functional siRNA in Skin

Jacobson, Gunilla B.; González-González, Emilio; Spitler, Ryan; Shinde, Rajesh; Leake, Devin; Kaspar, Roger L.; Contag, Christopher H.; Zare, Richard N.

doi:10.1002/jps.22147

Cited by 53 publications

(40 citation statements)

References 21 publications

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“…Concurrently, mice (6–7 per group) were injected with 50 µL of PBS suspension containing siSCR- or siHSP47-MSNP-PEI-PEG at the dose of 220 µg nanoparticles and 0.65 nmol as siRNA. The siRNA dose was adapted from the reported intradermally injected siRNA doses to mice [57, 58]. Treatments were done twice a week on alternate days with bleomycin injection for a total of 8 treatments over 4 weeks.…”

Section: Methodsmentioning

confidence: 99%

Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis

Morry¹,

Ngamcherdtrakul²,

Gu³

et al. 2015

Biomaterials

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Fibrotic diseases such as scleroderma have been linked to increased oxidative stress and upregulation of pro-fibrotic genes. Recent work suggests a role of NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) in inducing excessive collagen synthesis, leading to fibrotic diseases. Herein, we elucidate the relationship between NOX4 and HSP47 in fibrogenesis and propose to modulate them altogether as a new strategy to treat fibrosis. We developed a nanoparticle platform consisting of polyethylenimine (PEI) and polyethylene glycol (PEG) coating on a 50-nm mesoporous silica nanoparticle (MSNP) core. The nanoparticles effectively delivered small interfering RNA (siRNA) targeting HSP47 (siHSP47) in an in vitro model of fibrosis based on TGF-β stimulated fibroblasts. The MSNP core also imparted an antioxidant property by scavenging reactive oxygen species (ROS) and subsequently reducing NOX4 levels in the in vitro fibrogenesis model. The nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. In vivo evaluation was performed in a bleomycin-induced scleroderma mouse model, which shares many similarities to human scleroderma disease. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (α-SMA), and collagen type I (COL I), as well as skin thickness of the mice.

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Section: Methodsmentioning

confidence: 99%

Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis

Morry¹,

Ngamcherdtrakul²,

Gu³

et al. 2015

Biomaterials

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“…19, 20, 35 HIP is a technique in which a drug-surfactant complex is formed. This complex increases the lipophilicity of the drug, and allows for incorporation of the drug in the lipid core of SLNP.…”

Section: Resultsmentioning

confidence: 99%

In Vivo Sustained Release of siRNA from Solid Lipid Nanoparticles

et al. 2011

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Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with a challenge of being delivered in a sustained manner. Nanoparticle drug delivery systems allow for incorporating and controlled release of therapeutic payloads. We demonstrate that solid lipid nanoparticles can incorporate and provide sustained release of siRNA. Tristearin solid lipid nanoparticles, made by nanoprecipitation, were loaded with siRNA (4.4–5.5 weight percent loading ratio) using a hydrophobic ion pairing approach that employs the cationic lipid DOTAP. Intradermal injection of these nanocarriers in mouse footpads resulted in prolonged siRNA release over a period of 10–13 days. In vitro cell studies showed that the released siRNA retained its activity. Nanoparticles developed in this study offer an alternative approach to polymeric nanoparticles for encapsulation and sustained delivery of siRNA with the advantage of being prepared from physiologically well-tolerated materials.

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“…SNA constructs are able to penetrate the stratum corneum of intact skin, rapidly enter epidermal and dermal cells, and knock down epidermal targets (17). In contrast to SNAs, other topical siRNAbased therapies require epidermal disruption by physical [e.g., injection, tape stripping (23), laser, or ultrasound] or chemical (e.g., conjugation to peptides or lipoplexes or incorporation into other types of nanoparticle structures, lentiviruses, or gels) means for RNAi penetration through the epidermal barrier and into KCs (24)(25)(26)(27)(28)(29)(30)(31). siRNA SNAs are unique, highly anionic constructs that do not require additional chemical modifications to facilitate transportation through the stratum corneum or entry into cells.…”

Section: Discussionmentioning

confidence: 99%

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

Randeria

Seeger²,

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

194

163

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Spherical nucleic acid (SNA) gold nanoparticle conjugates (13-nmdiameter gold cores functionalized with densely packed and highly oriented nucleic acids) dispersed in Aquaphor have been shown to penetrate the epidermal barrier of both intact mouse and human skin, enter keratinocytes, and efficiently down-regulate gene targets. ganglioside-monosialic acid 3 synthase (GM3S) is a known target that is overexpressed in diabetic mice and responsible for causing insulin resistance and impeding wound healing. GM3S SNAs increase keratinocyte migration and proliferation as well as insulin and insulin-like growth factor-1 (IGF1) receptor activation under both normo-and hyperglycemic conditions. The topical application of GM3S SNAs (50 nM) to splinted 6-mm-diameter full-thickness wounds in diet-induced obese diabetic mice decreases local GM3S expression by >80% at the wound edge through an siRNA pathway and fully heals wounds clinically and histologically within 12 d, whereas control-treated wounds are only 50% closed. Granulation tissue area, vascularity, and IGF1 and EGF receptor phosphorylation are increased in GM3S SNA-treated wounds. These data capitalize on the unique ability of SNAs to naturally penetrate the skin and enter keratinocytes without the need for transfection agents. Moreover, the data further validate GM3 as a mediator of the delayed wound healing in type 2 diabetes and support regional GM3 depletion as a promising therapeutic direction.f 27 million Americans diagnosed with type 2 diabetes (T2D), more than 6 million have chronic, nonhealing skin wounds, particularly on the plantar surface, leading to secondary bacterial infection and costing the healthcare system more than $25 billion (1, 2). In 2010 alone, more than 70,000 individuals in the United States with T2D underwent amputation (3). Improved understanding of diabetic wound pathology and new interventions for impaired wound healing are needed.Ganglioside-monosialic acid 3 (GM3), the predominant sialylated glycosphingolipid in skin, has recently been recognized to be a critical mediator of insulin resistance (4-12). Indeed, we have recently shown three-and fourfold more GM3 synthase (GM3S; also known as SAT-I or ST3Gal-V), which is required for the synthesis of GM3, in diabetic human plantar skin than in site-and age-matched control skin (4). Similarly, skin samples from the backs of diet-induced obese (DIO) and ob/ob mouse diabetic models show increased GM3S mRNA expression and GM3 levels. Knockout (KO) of GM3S improves the insulin resistance induced by a high-fat diet in mouse adipose tissue, muscle (5), and as recently shown, skin of DIO T2D mice, reversing the woundhealing impairment of T2D (4). The acceleration of wound healing by GM3S KO and GM3 depletion in mouse skin is associated with increased epidermal cell migration and proliferation as well as activation of the epidermal insulin-like growth factor-1 receptor (IGF1R) in vivo (4). Isolated cultured mouse GM3S −/− keratinocytes (KCs) migrate and proliferate more rapidly than GM3S +/+ WT l...

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Biodegradable Nanoparticles With Sustained Release of Functional siRNA in Skin

Cited by 53 publications

References 21 publications

Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis

Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis

In Vivo Sustained Release of siRNA from Solid Lipid Nanoparticles

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

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