Nanolayered siRNA Dressing for Sustained Localized Knockdown

Castleberry, Steven; Wang, Mary; Hammond, Paula T.

doi:10.1021/nn401011n

Cited by 42 publications

(41 citation statements)

References 50 publications

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“…Layer-by-Layer (LbL) technology has been demonstrated in a myriad of biomedical applications for delivery from a broad range of material surfaces, including stainless steel and degradable polymer matrices. [19] We have previously demonstrated that LbL incorporation and delivery of siRNA can achieve significant and sustained knockdown of reporter genes in vitro [20] , although the ability to translate these results to a more complex environment in vivo remained unknown. Therefore, developing this technology to effectively deliver siRNA to a localized area in vivo using a meaningful therapeutic gene target presents a significant advancement for the treatment of site-specific disorders, including DFUs as well as cardiovascular diseases, cancers, and transplant rejection.…”

Section: Introductionmentioning

confidence: 99%

Self‐Assembled Wound Dressings Silence MMP‐9 and Improve Diabetic Wound Healing In Vivo

et al. 2015

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The direct local delivery of short interfering RNA (siRNA) to tissues may present solutions to several complex medical conditions. In particular, chronic wound healing is a serious and painful complication of diabetes mellitus (DM) affecting as many as one in four patients with a three year recurrence rate of more than 50% and leaving over 70,000 patients in the United States alone facing amputation. Here we describe the use of siRNA delivered locally into the diabetic ulcer directly and in a sustained fashion to knockdown a chronically upregulated extracellular matrix protease, matrix metalloproteinase-9 (MMP-9), to improve wound healing.

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Section: Introductionmentioning

confidence: 99%

Self‐Assembled Wound Dressings Silence MMP‐9 and Improve Diabetic Wound Healing In Vivo

et al. 2015

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“…2a) [72]. When 25 layers of the [Chi/siRNA] film were assembled onto a [Poly2/DS] 20 coated suture, a total of 2.1 ± 0.3 μg/cm of siRNA was incorporated.…”

Section: Resultsmentioning

confidence: 99%

Nanolayered siRNA delivery platforms for local silencing of CTGF reduce cutaneous scar contraction in third-degree burns

et al. 2016

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Wound healing is an incredibly complex biological process that often results in thickened collagen-enriched healed tissue called scar. Cutaneous scars lack many functional structures of the skin such as hair follicles, sweat glands, and papillae. The absence of these structures contributes to a number of the long-term morbidities of wound healing, including loss of function for tissues, increased risk of re-injury, and aesthetic complications. Scar formation is a pervasive factor in our daily lives; however, in the case of serious traumatic injury, scars can create long-lasting complications due to contraction and poor tissue remodeling. Within this report we target the expression of connective tissue growth factor (CTGF), a key mediator of TGFβ pro-fibrotic response in cutaneous wound healing, with controlled local delivery of RNA interference. Through this work we describe both a thorough in vitro analysis of nanolayer coated sutures for the controlled delivery of siRNA and its application to improve scar outcomes in a third-degree burn induced scar model in rats. We demonstrate that the knockdown of CTGF significantly altered the local expression of αSMA, TIMP1, and Col1a1, which are known to play roles in scar formation. The knockdown of CTGF within the healing burn wounds resulted in improved tissue remodeling, reduced scar contraction, and the regeneration of papillary structures within the healing tissue. This work adds support to a number of previous reports that indicate CTGF as a potential therapeutic target for fibrosis. Additionally, we believe that the controlled local delivery of siRNA from ultrathin polymer coatings described within this work is a promising approach in RNA interference that could be applied in developing improved cancer therapies, regenerative medicine, and fundamental scientific research.

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“…In our experiment, the release profile of the LbL film was gradual and linear within the duration of 1 week, which is consistent with the findings of another report. 31 The electrostatically anchored multilayer structure provided a controlled release of the loading cargo, which is pivotal for local drug delivery in order to obtain a sustained effect. [32][33][34] H1299 originates from epithelial lung cancer and has a prominent ability of endocytosis.…”

Section: Discussionmentioning

confidence: 99%

Chitosan/siRNA functionalized titanium surface via a layer-by-layer approach for in vitro sustained gene silencing and osteogenic promotion

Song¹,

Song²,

Yang³

et al. 2015

IJN

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Titanium surface modification is crucial to improving its bioactivity, mainly its bone binding ability in bone implant materials. In order to functionalize titanium with small interfering RNA (siRNA) for sustained gene silencing in nearby cells, the layer-by-layer (LbL) approach was applied using sodium hyaluronate and chitosan/siRNA (CS/siRNA) nanoparticles as polyanion and polycation, respectively, to build up the multilayered film on smooth titanium surfaces. The CS/siRNA nanoparticle characterization was analyzed first. Dynamic contact angle, atomic force microscopy, and scanning electron microscopy were used to monitor the layer accumulation. siRNA loaded in the film was quantitated and the release profile of film in phosphate-buffered saline was studied. In vitro knockdown effect and cytotoxicity evaluation of the film were investigated using H1299 human lung carcinoma cells expressing green fluorescent protein (GFP). The transfection of human osteoblast-like cell MG63 and H1299 were performed and the osteogenic differentiation of MG63 on LbL film was analyzed. The CS/siRNA nanoparticles exhibited nice size distribution. During formation of the film, the surface wettability, topography, and roughness were alternately changed, indicating successful adsorption of the individual layers. The scanning electron microscope images clearly demonstrated the hybrid structure between CS/siRNA nanoparticles and sodium hyaluronate polymer. The cumulated load of siRNA increased linearly with the bilayer number and, more importantly, a gradual release of the film allowed the siRNA to be maintained on the titanium surface over approximately 1 week. In vitro transfection revealed that the LbL film-associated siRNA could consistently suppress GFP expression in H1299 without showing significant cytotoxicity. The LbL film loading with osteogenic siRNA could dramatically increase the osteogenic differentiation in MG63. In conclusion, LbL technology can potentially modify titanium surfaces with specific gene-regulatory siRNAs to enhance biofunction.

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Nanolayered siRNA Dressing for Sustained Localized Knockdown

Cited by 42 publications

References 50 publications

Self‐Assembled Wound Dressings Silence MMP‐9 and Improve Diabetic Wound Healing In Vivo

Self‐Assembled Wound Dressings Silence MMP‐9 and Improve Diabetic Wound Healing In Vivo

Nanolayered siRNA delivery platforms for local silencing of CTGF reduce cutaneous scar contraction in third-degree burns

Chitosan/siRNA functionalized titanium surface via a layer-by-layer approach for in vitro sustained gene silencing and osteogenic promotion

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