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siRNA Delivery Impedes the Temporal Expression of Cytokine-Activated VCAM1 on Endothelial Cells

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Abstract

Leukocyte recruitment plays a key role in chronic inflammatory diseases such as cardiovascular disease, rheumatoid arthritis, and cancer. Leukocyte rolling and arrest are mediated in part by the temporally-regulated surface expression of vascular cell adhesion molecule-1 (VCAM1) on endothelial cells (ECs). In this paper, we engineered a pH-responsive vehicle comprised of 30 mol% dimethylaminoethyl methacrylate (30D) and 70 mol% hydroxyethyl methacrylate (70H) to encapsulate, protect, and deliver VCAM1 small interfering RNA (siRNA). The ability of siRNA to reduce VCAM1 gene expression is in direct opposition to its activation by cytokines. At 12 h post-activation, VCAM1 gene knockdown was 90.1 ± 7.5% when delivered via 30D/70H nanoparticles, which was on par with a leading commercial transfection agent. This translated into a 68.8 ± 6.7% reduction in the surface density of VCAM1 on cytokine-activated ECs. The pH-responsive delivery of VCAM1 siRNA efficiently reduced temporal surface protein expression, which may be used to avert leukocyte recruitment.

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Abbreviations

VCAM1:

Vascular cell adhesion molecule-1

ECs:

Endothelial cells

30D:

30 mol% dimethylaminoethyl methacrylate

70H:

70 mol% hydroxyethyl methacrylate

siRNA:

Small interfering RNA

ICAM1:

Intercellular cell adhesion molecule-1

TNFα :

Tumor necrosis factor-α

DMAEMA:

Dimethylaminoethyl methacrylate

HEMA:

Hydroxyethyl methacrylate

IL-1α :

Interleukin 1α

TEM:

Transmission electron microscopy

PECAM1 or CD31:

Platelet endothelial cell adhesion molecule or cluster of differentiation 31

TEGDMA:

Tetraethylene glycol dimethacrylate

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Acknowledgments

This work was funded in part by the National Science Foundation under NSF Award No. DMR 1406271. This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Infrastructure Network (NNIN), which is supported by NSF Award No. ECS-0335765. CNS is part of the Faculty of Arts and Sciences at Harvard University.

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Author notes

  1. Theodore T. Ho

    Present address: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA, 94143, USA

  2. Jin-Oh You

    Present address: Department of Engineering Chemistry, Chungbuk National University, Cheongju, 361-763, Republic of Korea

  3. Debra T. Auguste

    Present address: Grove School of Engineering, The City College of New York, 160 Convent Avenue, New York, NY, 10031, USA

Authors and Affiliations

  1. School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA

    Theodore T. Ho, Jin-Oh You & Debra T. Auguste

  2. Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Debra T. Auguste

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  1. Theodore T. Ho
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Correspondence to Debra T. Auguste.

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Associate Editor Michael Gower oversaw the review of this article.

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Ho, T.T., You, JO. & Auguste, D.T. siRNA Delivery Impedes the Temporal Expression of Cytokine-Activated VCAM1 on Endothelial Cells. Ann Biomed Eng 44, 895–902 (2016). https://doi.org/10.1007/s10439-015-1364-x

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  • DOI: https://doi.org/10.1007/s10439-015-1364-x

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