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J Control Release. 2019 Jun 28;304:259-267. doi: 10.1016/j.jconrel.2019.04.044. Epub 2019 May 1.

Poly(amine-co-ester) nanoparticles for effective Nogo-B knockdown in the liver.

Author information

1
Department of Biomedical Engineering, Yale University, New Haven, CT 06511, United States of America.
2
Department of Chemical & Environmental Engineering, Yale University, New Haven, CT 06511, United States of America.
3
Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06511, United States of America; Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China.
4
Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06511, United States of America.
5
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, United States of America.
6
Department of Biomedical Engineering, Yale University, New Haven, CT 06511, United States of America; Department of Chemical & Environmental Engineering, Yale University, New Haven, CT 06511, United States of America; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, United States of America; Department of Dermatology, Yale School of Medicine, New Haven, CT 06510, United States of America. Electronic address: mark.saltzman@yale.edu.

Abstract

Degradable poly(amine-co-ester) (PACE) terpolymers hold tremendous promise for siRNA delivery because these materials can be formulated into delivery vehicles with highly efficient siRNA encapsulation, providing effective knockdown with low toxicity. Here, we demonstrate that PACE nanoparticles (NPs) provide substantial protein knockdown in human embryonic kidney cells (HEK293) and hard-to-transfect primary human umbilical vein endothelial cells (HUVECs). After intravenous administration, NPs of solid PACE (sPACE)-synthesized with high monomer content of a hydrophobic lactone-accumulated in the liver and, to a lesser extent, in other tissues. Within the liver, a substantial fraction of sPACE NPs were phagocytosed by liver macrophages, while a smaller fraction of NPs accumulated in hepatic stellate cells and liver sinusoidal endothelial cells, suggesting that sPACE NPs could deliver siRNA to diverse cell populations within the liver. To test this hypothesis, we loaded sPACE NPs with siRNA designed to knockdown Nogo-B, a protein that has been implicated in the progression of alcoholic liver disease and liver fibrosis. These sPACE:siRNA NPs produced up to 60% Nogo-B protein suppression in the liver after systemic administration. We demonstrate that sPACE NPs can effectively deliver siRNA therapeutics to the liver to mediate protein knockdown in vivo.

KEYWORDS:

Nogo-B; Poly(amine-co-ester) (PACE); Polymeric nanoparticles; siRNA

PMID:
31054286
PMCID:
PMC6613984
[Available on 2020-06-28]
DOI:
10.1016/j.jconrel.2019.04.044

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