Title

Development of Mannose Functionalized Dendrimeric Nanoparticles for Targeted Delivery to Macrophages: Use of This Platform to Modulate Atherosclerosis

Abstract

Dysfunctional macrophages underlie the development of several diseases including atherosclerosis where accumulation of cholesteryl esters and persistent inflammation are 2 of the critical macrophage processes that regulate the progression as well as stability of atherosclerotic plaques. Ligand-dependent activation of liver-x-receptor (LXR) not only enhances mobilization of stored cholesteryl ester but also exerts anti-inflammatory effects mediated via trans-repression of proinflammatory transcription factor nuclear factor kappa B. However, increased hepatic lipogenesis by systemic administration of LXR ligands (LXR-L) has precluded their therapeutic use. The objective of the present study was to devise a strategy to selectively deliver LXR-L to atherosclerotic plaque-associated macrophages while limiting hepatic uptake. Mannose-functionalized dendrimeric nanoparticles (mDNP) were synthesized to facilitate active uptake via the mannose receptor expressed exclusively by macrophages using polyamidoamine dendrimer. Terminal amine groups were used to conjugate mannose and LXR-L T091317 via polyethylene glycol spacers. mDNP-LXR-L was effectively taken up by macrophages (and not by hepatocytes), increased expression of LXR target genes (ABCA1/ABCG1), and enhanced cholesterol efflux. When administered intravenously to LDLR−/− mice with established plaques, significant accumulation of fluorescently labeled mDNP-LXR-L was seen in atherosclerotic plaque-associated macrophages. Four weekly injections of mDNP-LXR-L led to significant reduction in atherosclerotic plaque progression, plaque necrosis, and plaque inflammation as assessed by expression of nuclear factor kappa B target gene matrix metalloproteinase 9; no increase in hepatic lipogenic genes or plasma lipids was observed. These studies validate the development of a macrophage-specific delivery platform for the delivery of anti-atherosclerotic agents directly to the plaque-associated macrophages to attenuate plaque burden.

Department(s)

Chemical and Biochemical Engineering

Comments

This work was supported in part by VCU's CTSA (UL1TR000058 from the National Institutes of Health's National Center for Advancing Translational Science) and the Center for Clinical and Translational Research (CCTR) Endowment Fund of the Virginia Commonwealth University to HY and SG as well as VA MERIT award (IO1 BX002297) to SG.

Keywords and Phrases

ABC transporter A1; ABC transporter G1; antiinflammatory agent; cholesterol; dendrimer; gelatinase B; immunoglobulin enhancer binding protein; lipid; liver X receptor; macrogol; mannose receptor; nanoparticle; polyamidoamine; t 091317; unclassified drug; dendrimer; liver X receptor; low density lipoprotein receptor; mannose; nanoparticle, animal cell; animal experiment; animal tissue; atherosclerotic plaque; cell activation; cell viability; comparative study; controlled study; cytotoxicity; disease course; drug delivery system; effusion; female; gene expression; gene targeting; immunohistochemistry; in vitro study; in vivo study; limit of quantitation; lipid blood level; lipogenesis; liver cell; macrophage; male; mouse; nonhuman; particle size; priority journal; proton nuclear magnetic resonance; zeta potential; animal; atherosclerosis; cell culture; macrophage; metabolism; physiology, Animals; Atherosclerosis; Cells, Cultured; Dendrimers; Female; Liver X Receptors; Macrophages; Male; Mannose; Mice; Nanoparticles; Receptors, LDL

International Standard Serial Number (ISSN)

1931-5244

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2018 Elsevier Inc., All rights reserved.

Publication Date

01 Mar 2018

PubMed ID

29172034

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