Effective siRNA delivery to inflamed primary vascular endothelial cells by anti-E-selectin and anti-VCAM-1 PEGylated SAINT-based lipoplexes

Leus, Niek G. J.; Talman, Eduard G.; Ramana, Pranov; Kowalski, Piotr S.; Woudenberg-Vrenken, Titia E.; Ruiters, Marcel H. J.; Molema, Grietje; Kamps, Jan A. A. M.

doi:10.1016/j.ijpharm.2013.11.008

Cited by 27 publications

(24 citation statements)

References 29 publications

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“…However, it would simultaneously reduce cellular uptake [56] and endosomal escape [57], which reduces the final gene silencing efficiency. In this section, we will first summarize the effects of PEGylation on general liposomal carriers and then focus on the effect PEGylation on siRNA delivery.…”

Section: Pegylation On Liposomal Sirna Deliverymentioning

confidence: 99%

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Effect of surface properties on liposomal siRNA delivery

2016

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Liposomes are one of the most widely investigated carriers for siRNA delivery. The surface properties of liposomal carriers, including the surface charge, PEGylation, and ligand modification can significantly affect the gene silencing efficiency. Three barriers of systemic siRNA delivery (long blood circulation, efficient tumor penetration and efficient cellular uptake/endosomal escape) are analyzed on liposomal carriers with different surface charges, PEGylations and ligand modifications. Cationic formulations dominate siRNA delivery and neutral formulations also have good performance while anionic formulations are generally not proper for siRNA delivery. The PEG dilemma (prolonged blood circulation vs. reduced cellular uptake/endosomal escape) and the side effect of repeated PEGylated formulation (accelerated blood clearance) were discussed. Effects of ligand modification on cationic and neutral formulations were analyzed. Finally, we summarized the achievements in liposomal siRNA delivery, outlined existing problems and provided some future perspectives.

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Section: Pegylation On Liposomal Sirna Deliverymentioning

confidence: 99%

“…However, this method is only suitable for low degree PEGylation. If the ratio of PEG increases to 4-5%, the resulting lipoplexes would have much lower gene silencing efficiency [56, 76]. This decrease is due to much less siRNA loading, since most siRNAs are bound to the exterior of PEGylated liposomes [77].…”

Section: Pegylation On Liposomal Sirna Deliverymentioning

confidence: 99%

Effect of surface properties on liposomal siRNA delivery

2016

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“…HUVEC (Lonza, Breda, the Netherlands) and human aortic endothelial cells (HAEC; Life Technologies, Bleiswijk, the Netherlands) were cultured as described previously (28,29). Conditionally immortalized human glomerular endothelial cells, a gift from S. Satchell (University of Bristol, Bristol, U.K.), were incubated for 24 h at 33˚C, followed by 5 d at 37˚C at 5% CO 2 /95% air before starting an experiment.…”

Section: Cell Culturementioning

confidence: 99%

Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin

Moser

Heeringa

Jongman

et al. 2016

The Journal of Immunology

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Sepsis is a systemic inflammatory response to infections associated with organ failure that is the most frequent cause of death in hospitalized patients. Exaggerated endothelial activation, altered blood flow, vascular leakage, and other disturbances synergistically contribute to sepsis-induced organ failure. The underlying signaling events associated with endothelial proinflammatory activation are not well understood, yet they likely consist of molecular pathways that act in an endothelium-specific manner. We found that LPS, a critical factor in the pathogenesis of sepsis, is internalized by endothelial cells, leading to intracellular signaling without the need for priming as found recently in immune cells. By identifying a novel role for retinoic acid-inducible gene-I (RIG-I) as a central regulator of endothelial activation functioning independent of TLR4, we provide evidence that the current paradigm of TLR4 solely being responsible for LPS-mediated endothelial responses is incomplete. RIG-I, as well as the adaptor protein mitochondrial antiviral signaling protein, regulates NF-kB-mediated induction of adhesion molecules and proinflammatory cytokine expression in response to LPS. Our findings provide essential new insights into the proinflammatory signaling pathways in endothelial cells and suggest that combined endothelial-specific inhibition of RIG-I and TLR4 will provide protection from aberrant endothelial responses associated with sepsis.

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“…Cell culture affords the amplification of cell numbers and preservation of samples for extended time periods (>1 day) and is thereby feasible for obtaining abundance of sample and flexibility for experimental coordination. This method is also amenable to gene-silencing approaches using transfection (59, 60). However, with culture, morphological changes [“cobblestone” monolayers (61, 62)] occur as well as loss of M 3 receptors (63) and connexin 40 (Cx40; composes native gap junctions) (64) while gaining voltage-sensitive transmembrane proteins such as large-conductance Ca 2+ -activated K + (BK Ca ) channels (65).…”

Section: Introductionmentioning

confidence: 99%

Calcium and electrical signaling in arterial endothelial tubes: New insights into cellular physiology and cardiovascular function

Behringer

2017

Microcirculation

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The integral role of the endothelium during the coordination of blood flow throughout vascular resistance networks has been recognized for several decades now. Early examination of the distinct anatomy and physiology of the endothelium as a signaling conduit along the vascular wall has prompted development and application of an intact endothelial “tube” study model isolated from rodent skeletal muscle resistance arteries. Vasodilatory signals such as increased endothelial cell (EC) Ca2+ ([Ca2+]i) and hyperpolarization take place in single ECs while shared between electrically coupled ECs through gap junctions up to distances of millimeters (≥ 2 mm). The small- and intermediate-conductance Ca2+ activated K+ (SKCa/IKCa or KCa2.3/KCa3.1) channels function at the interface of Ca2+ signaling and hyperpolarization; a bidirectional relationship whereby increases in [Ca2+]i activate SKCa/IKCa channels to produce hyperpolarization and vice versa. Further, the spatial domain of hyperpolarization among electrically coupled ECs can be finely tuned via incremental modulation of SKCa/IKCa channels to balance the strength of local and conducted electrical signals underlying vasomotor activity. Multifunctional properties of the voltage-insensitive SKCa/IKCa channels of resistance artery endothelium may be employed for therapy during the aging process and development of vascular disease.

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Effective siRNA delivery to inflamed primary vascular endothelial cells by anti-E-selectin and anti-VCAM-1 PEGylated SAINT-based lipoplexes

Cited by 27 publications

References 29 publications

Effect of surface properties on liposomal siRNA delivery

Effect of surface properties on liposomal siRNA delivery

Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin

Calcium and electrical signaling in arterial endothelial tubes: New insights into cellular physiology and cardiovascular function

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