Silencing TNFα with lipidoid nanoparticles downregulates both TNFα and MCP-1 in an in vitro co-culture model of diabetic foot ulcers

Kasiewicz, Lisa N.; Whitehead, Kathryn A.

doi:10.1016/j.actbio.2015.12.023

Cited by 55 publications

(45 citation statements)

References 46 publications

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“…The resulting reduction in MCP-1 chemokine expression then led to a delayed macrophage response in the diabetic wounds. An increase in MCP-1 also supports the recruitment of additional monocytes by the resident macrophages, whereas a downregulation of MCP-1 inhibits the in vivo recruitment of additional macrophages to wounds [64,65]. At the same time, MCP-1 also acts as a stimulant for M2 macrophage polarization [65,66].…”

Section: Discussionmentioning

confidence: 99%

“…An increase in MCP-1 also supports the recruitment of additional monocytes by the resident macrophages, whereas a downregulation of MCP-1 inhibits the in vivo recruitment of additional macrophages to wounds [64,65]. At the same time, MCP-1 also acts as a stimulant for M2 macrophage polarization [65,66]. Khan et al [67] reported that monocyte recruitment in a graded-ischemia wound healing model was severely impaired in MCP-1 knockout mice.…”

Section: Discussionmentioning

confidence: 99%

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Rapid tissue regeneration induced by intracellular ATP delivery—A preliminary mechanistic study

et al. 2017

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We have reported a new phenomenon in acute wound healing following the use of intracellular ATP delivery—extremely rapid tissue regeneration, which starts less than 24 h after surgery, and is accompanied by massive macrophage trafficking, in situ proliferation, and direct collagen production. This unusual process bypasses the formation of the traditional provisional extracellular matrix and significantly shortens the wound healing process. Although macrophages/monocytes are known to play a critical role in the initiation and progression of wound healing, their in situ proliferation and direct collagen production in wound healing have never been reported previously. We have explored these two very specific pathways during wound healing, while excluding confounding factors in the in vivo environment by analyzing wound samples and performing in vitro studies. The use of immunohistochemical studies enabled the detection of in situ macrophage proliferation in ATP-vesicle treated wounds. Primary human macrophages and Raw 264.7 cells were used for an in vitro study involving treatment with ATP vesicles, free Mg-ATP alone, lipid vesicles alone, Regranex, or culture medium. Collagen type 1α 1, MCP-1, IL-6, and IL-10 levels were determined by ELISA of the culture supernatant. The intracellular collagen type 1α1 localization was determined with immunocytochemistry. ATP-vesicle treated wounds showed high immunoreactivity towards BrdU and PCNA antigens, indicating in situ proliferation. Most of the cultured macrophages treated with ATP-vesicles maintained their classic phenotype and expressed high levels of collagen type 1α1 for a longer duration than was observed with cells treated with Regranex. These studies provide the first clear evidence of in situ macrophage proliferation and direct collagen production during wound healing. These findings provide part of the explanation for the extremely rapid tissue regeneration, and this treatment may hold promise for acute and chronic wound care.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rapid tissue regeneration induced by intracellular ATP delivery—A preliminary mechanistic study

et al. 2017

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“…Control experiments showed that the pH-adjusted PBS solutions did not cause gene knockdown ( Figure S1) and previous studies have shown that control LNPs containing off-targeting siRNA do not induce statistically significant changes in gene expression. 3,5,7 At longer time points, the nanoparticles stored at room temperature lost efficacy. Interestingly, no major changes in siRNA entrapment, LNP size, or monodispersity were observed that could explain the loss in potency ( Figure 1B-D).…”

Section: Temperature and Ph Affected The Longterm Stability Of Lnpsmentioning

confidence: 99%

“…[1][2][3][4][5][6][7] Studies in our laboratory and others have demonstrated that these materials mediate potent gene knockdown without inducing toxicity. 1,3,5 One concern for translation of the delivery vehicles into a clinical setting is stability, which would require the identification of conditions appropriate for long-term storage of the nanoparticles. Currently, the best conditions for LNP storage, including pH, temperature, and physical state (eg, in solution, lyophilized powder), are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Achieving long-term stability of lipid nanoparticles: examining the effect of pH, temperature, and lyophilization

Ball¹,

Bajaj

Whitehead

2016

IJN

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208

189

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“…Delivery of siRNA, whether systemically or topically, requires a vehicle that protects the RNA cargo and enables its transport across cell and endosomal membranes into the cytoplasm of target cells . Fortunately, we have previously developed LNPs that potently deliver siRNA in vivo and control inflammatory feedback loops via TNFα silencing in a macrophage‐fibroblast co‐culture model . Herein, we show that LNPs can be topically delivered in solution to nondiabetic and diabetic mouse wounds to silence TNFα and improve wound healing outcomes.…”

Section: Introductionmentioning

confidence: 97%

Lipid nanoparticles silence tumor necrosis factor α to improve wound healing in diabetic mice

Kasiewicz

Whitehead

2018

Bioengineering & Transla Med

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Diabetes mellitus is a mounting concern in the United States, as are the mortality and morbidity that result from its complications. Of particular concern, diabetes patients frequently suffer from impaired wound healing and resultant nonhealing diabetic foot ulcers. These ulcers overproduce tumor necrosis factor α (TNFα), which reduces wound bed cell migration and proliferation while encouraging apoptosis. Herein, we describe the use of siRNA‐loaded lipid nanoparticles (LNPs) as a potential wound treatment to combat an overzealous immune response and facilitate wound closure. LNPs were formulated with an ionizable, degradable lipidoid and siRNA specific for TNFα. Topical application of nanoparticles reduced TNFα mRNA expression in the wound by 40–55% in diabetic and nondiabetic mice. In diabetic mice, this TNFα knockdown accelerated wound healing compared to untreated controls. Together, these results serve as proof‐of‐concept that RNA interference therapy using LNPs can reduce the severity and duration of chronic diabetic wounds.

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Silencing TNFα with lipidoid nanoparticles downregulates both TNFα and MCP-1 in an in vitro co-culture model of diabetic foot ulcers

Cited by 55 publications

References 46 publications

Rapid tissue regeneration induced by intracellular ATP delivery—A preliminary mechanistic study

Rapid tissue regeneration induced by intracellular ATP delivery—A preliminary mechanistic study

Achieving long-term stability of lipid nanoparticles: examining the effect of pH, temperature, and lyophilization

Lipid nanoparticles silence tumor necrosis factor α to improve wound healing in diabetic mice

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