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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| Published in: | Journal of controlled release Vol. 308; pp. 71 - 85 |
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| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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Netherlands
Elsevier B.V
28.08.2019
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| ISSN: | 0168-3659, 1873-4995, 1873-4995 |
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| Abstract | 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. |
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| AbstractList | 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. 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. 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.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. |
| Author | Jiang, Cuiping Tang, Yuqi He, Wanhua Qi, Zitong Li, Zhuoting Zang, Haojing Yang, Hu Liu, Jianping Huang, Yilei Wang, Yunbo |
| Author_xml | – sequence: 1 givenname: Cuiping surname: Jiang fullname: Jiang, Cuiping organization: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China – sequence: 2 givenname: Zitong surname: Qi fullname: Qi, Zitong organization: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China – sequence: 3 givenname: Wanhua surname: He fullname: He, Wanhua organization: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China – sequence: 4 givenname: Zhuoting surname: Li fullname: Li, Zhuoting organization: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China – sequence: 5 givenname: Yuqi surname: Tang fullname: Tang, Yuqi organization: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China – sequence: 6 givenname: Yunbo surname: Wang fullname: Wang, Yunbo organization: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China – sequence: 7 givenname: Yilei surname: Huang fullname: Huang, Yilei organization: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China – sequence: 8 givenname: Haojing surname: Zang fullname: Zang, Haojing organization: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China – sequence: 9 givenname: Hu surname: Yang fullname: Yang, Hu email: hyang2@vcu.edu organization: Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA 23219, United States – sequence: 10 givenname: Jianping surname: Liu fullname: Liu, Jianping email: jianpingliu1293@163.com organization: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China |
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| Keywords | Dual-targeting Nanocarrier Plaque regression Positive feedback loop Atherosclerosis Plaque targeting |
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| Title | Dynamically enhancing plaque targeting via a positive feedback loop using multifunctional biomimetic nanoparticles for plaque regression |
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