Dynamically enhancing plaque targeting via a positive feedback loop using multifunctional biomimetic nanoparticles for plaque regression

A paradigm shift from preventive therapy to aggressive plaque regression and eventual eradication is much needed to address increasing atherosclerotic burden and risks. Herein, we report a biologically inspired dual-targeting multifunctional recombinant high-density lipoprotein (rHDL)-mimicking core...

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Veröffentlicht in:Journal of controlled release Jg. 308; S. 71 - 85
Hauptverfasser: Jiang, Cuiping, Qi, Zitong, He, Wanhua, Li, Zhuoting, Tang, Yuqi, Wang, Yunbo, Huang, Yilei, Zang, Haojing, Yang, Hu, Liu, Jianping
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Netherlands Elsevier B.V 28.08.2019
Schlagworte:
Atherosclerosis
biomimetics
catalase
cholesterol
Dual-targeting
high density lipoprotein
macrophages
Nanocarrier
nanoparticles
Plaque regression
Plaque targeting
Positive feedback loop
risk
small interfering RNA
therapeutics
Dual-targeting
Nanocarrier
Plaque regression
Positive feedback loop
Atherosclerosis
Plaque targeting
ISSN:0168-3659, 1873-4995, 1873-4995
Online-Zugang:Volltext
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Zusammenfassung:A paradigm shift from preventive therapy to aggressive plaque regression and eventual eradication is much needed to address increasing atherosclerotic burden and risks. Herein, we report a biologically inspired dual-targeting multifunctional recombinant high-density lipoprotein (rHDL)-mimicking core-shell nanoplatform. It is composed of an ATP-responsive ternary polyplexes core for SR-A siRNA and catalase complexation, and a phosphatidylserine-modified rHDL-based outer shell for SR-BI and CD36 targeting, in which pitavastatin is packaged. We demonstrated that dual-targeting biomimetic core-shell nanoparticles dynamically enhanced macrophage CD36 targeting in the plaques by establishing a positive feedback loop via the reciprocal regulation of SR-A and CD36. Positive feedback-enabled accumulation of the nanoparticles in the atherosclerotic plaques increased by 3.3-fold following 4-week repeated administration. A 3-month dosage regimen of the dual-targeting rHDL-mimicking nanoparticles reduced plaque areas by 65.8%, and decreased macrophages by 57.3%. Collectively, this work shows that dynamically enhancing plaque targeting via a positive feedback loop and dual action of cholesterol deposition inhibition and efflux enhancement accomplished with our novel multifunctional biomimetic nanoparticles provides a new way to regress plaques and alleviate the atherosclerotic burden. [Display omitted] •ApoA-I/PS-NP2S/P/C dynamically enhanced plaque targeting via positive feedback loop.•3-month dosage regimen of apoA-I/PS-NP2S/P/C achieved a plaque reduction of 65.8%.•Catalase triggered ROS elimination, ATP generation, and accelerated siRNA release.
Bibliographie:ObjectType-Article-1
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ISSN:0168-3659
1873-4995
1873-4995
DOI:10.1016/j.jconrel.2019.07.007