Tissue factor targeting peptide enhances nanoparticle binding and delivery of a synthetic specialized pro-resolving lipid mediator to injured arteries

Elizabeth S. Levy, PhD; Alexander S. Kim, MD; Evan Werlin, MD; Mian Chen, MD; Brian E. Sansbury, PhD; Matthew Spite, PhD; Tejal A. Desai, PhD; Michael S. Conte, MD

JVS - Vascular Science (Jan 2023)

Tissue factor targeting peptide enhances nanoparticle binding and delivery of a synthetic specialized pro-resolving lipid mediator to injured arteries

Elizabeth S. Levy, PhD,
Alexander S. Kim, MD,
Evan Werlin, MD,
Mian Chen, MD,
Brian E. Sansbury, PhD,
Matthew Spite, PhD,
Tejal A. Desai, PhD,
Michael S. Conte, MD

Affiliations

Elizabeth S. Levy, PhD: Department of Bioengineering and Therapeutics, University of California San Francisco, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham, San Francisco, CA; Small Molecules Pharmaceutics, Genentech, South San Francisco, CA
Alexander S. Kim, MD: Department of Surgery and Cardiovascular Institute, University of California San Francisco, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham, San Francisco, CA
Evan Werlin, MD: Department of Surgery and Cardiovascular Institute, University of California San Francisco, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham, San Francisco, CA
Mian Chen, MD: Department of Surgery and Cardiovascular Institute, University of California San Francisco, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham, San Francisco, CA
Brian E. Sansbury, PhD: Women's Hospital and Harvard Medical School, Boston, MA
Matthew Spite, PhD: Women's Hospital and Harvard Medical School, Boston, MA
Tejal A. Desai, PhD: Department of Bioengineering and Therapeutics, University of California San Francisco, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham, San Francisco, CA; Correspondence: Tejal A. Desai, PhD, Brown University School of Engineering, 184 Hope St, Providence, RI 02912
Michael S. Conte, MD: Department of Surgery and Cardiovascular Institute, University of California San Francisco, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham, San Francisco, CA

Journal volume & issue: Vol. 4
p. 100126

Abstract

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Background: Specialized pro-resolving lipid mediators (SPM) such as resolvin D1 (RvD1) attenuate inflammation and exhibit vasculo-protective properties. Methods: We investigated poly-lactic-co-glycolic acid (PLGA)-based nanoparticles (NP), containing a peptide targeted to tissue factor (TF) for delivery of 17R-RvD1 and a synthetic analog 17-R/S-benzo-RvD1 (benzo-RvD1) using in vitro and in vivo models of acute vascular injury. NPs were characterized in vitro by size, drug loading, drug release, TF binding, and vascular smooth muscle cell migration assays. NPs were also characterized in a rat model of carotid angioplasty. Results: PLGA NPs based on a 75/25 lactic to glycolic acid ratio demonstrated optimal loading (507.3 pg 17R-RvD1/mg NP; P = ns) and release of RvD1 (153.1 pg 17R-RvD1/mg NP; P < .05). NPs incorporating the targeting peptide adhered to immobilized TF with greater avidity than NPs with scrambled peptide (50 nM: 41.6 ± 0.52 vs 32.66 ± 0.34; 100 nM: 35.67 ± 0.95 vs 23.5 ± 0.39; P < .05). NPs loaded with 17R-RvD1 resulted in a trend toward blunted vascular smooth muscle cell migration in a scratch assay. In a rat model of carotid angioplasty, 16-fold more NPs were present after treatment with TF-targeted NPs compared with scrambled NPs (P < .01), with a corresponding trend toward higher tissue levels of 17R-RvD1 (P = .06). Benzo-RvD1 was also detectable in arteries treated with targeted NP delivery and accumulated at 10 times higher levels than NP loaded with 17R-RvD1. There was a trend toward decreased CD45 immunostaining in vessels treated with NP containing benzo-RvD1 (0.76 ± 0.38 cells/mm2 vs 122.1 ± 22.26 cells/mm2; P = .06). There were no significant differences in early arterial inflammatory and cytokine gene expression by reverse transcription-polymerase chain reaction. Conclusions: TF-targeting peptides enhanced NP-mediated delivery of SPM to injured artery. TF-targeted delivery of SPMs may be a promising therapeutic approach to attenuate the vascular injury response.

Published in JVS - Vascular Science

ISSN: 2666-3503 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the circulatory (Cardiovascular) system
Website: https://www.journals.elsevier.com/jvs-vascular-science

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