期刊
CARDIOVASCULAR ENGINEERING AND TECHNOLOGY
卷 12, 期 1, 页码 114-125出版社
SPRINGER
DOI: 10.1007/s13239-021-00518-x
关键词
Poly(beta-amino ester)s nanoparticle; In vivo siRNA delivery; Endothelial cell; Tissue-specific delivery
资金
- National Institutes of Health [HL119798, HL095070]
- Spanish Ministerio de Ciencia, Innovacion y Universidades [RTI2018-094734-B-C22]
- AGAUR (Generalitat de Catalunya) [2017FI_B200141]
- John and Jan Portman Professorship
- Wallace H. Coulter Distinguished Faculty Professorship
- Grup d'Enginyeria dels Materials (GEMAT)
- Agencia de Gestio d'ajuts Universitaris i de Recerca, Generalitat de Catalunya (SGR 2017) [1559]
This study optimized a polymer formulation based on pBAEs for siRNA delivery to vascular endothelial cells, demonstrating efficacy both in vitro and in vivo. The results showed that C6-KH pBAE nanoparticles were effective in delivering siRNA to arterial endothelial cells, with tissue-specific delivery observed in the artery endothelium, lung, liver, heart, and kidney.
Purpose-Endothelial cell (EC) dysfunction underlies the pathology of multiple disease conditions including cardiovascular and pulmonary diseases. Dysfunctional ECs have a distinctive gene expression profile compared to healthy ECs. RNAi therapy is a powerful therapeutic approach that can be used to silence multiple genes of interests simultaneously. However, the delivery of RNAi to ECs in vivo continues to be a major challenge. Here, we optimized a polymer formulation based on poly(beta-amino ester)s (pBAEs) to deliver siRNA to vascular ECs. Methods-We developed a library of bioinspired oligopeptide-modified pBAE nanoparticles (NPs) with different physicochemical proprieties and screened them for cellular uptake and efficacy of RNAi delivery in vitro using ECs, vascular smooth muscle cells, and THP-1 monocytes. From the screening, the lysine-/histidine-oligopeptide modified pBAE (C6-KH) NP was selected and further tested ex vivo using mouse aorta and in mice to determine efficiency of siRNA delivery in vivo. Results-The in vitro screening study showed that C6-KH was most efficient in delivering siRNA to ECs. Ex vivo study showed that C6-KH nanoparticles containing siRNAs accumulated in the endothelial layer of mouse aortas. In vivo study showed that C6-KH nanoparticles carrying siICAM2 injected via tail-vein in mice significantly reduced ICAM2 level in the artery endothelium (55%), lung (52%), and kidney (31%), but not in the liver, heart, and thymus, indicating a tissue-specific delivery pattern. Conclusions-We demonstrate that C6-KH pBAE can used for delivery of siRNAs to the artery endothelium and lung, while minimizing potential side or toxic effects in the liver and heart.
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