TY - JOUR
T1 - Delivery of Anti-microRNA-712 to Inflamed Endothelial Cells Using Poly(β-amino ester) Nanoparticles Conjugated with VCAM-1 Targeting Peptide
AU - Dosta, Pere
AU - Tamargo, Ian
AU - Ramos, Victor
AU - Kumar, Sandeep
AU - Kang, Dong Won
AU - Borrós, Salvador
AU - Jo, Hanjoong
N1 - Funding Information:
This work was supported by funding from the National Institutes of Health grants HL119798 and HL095070 to H.J. It was also supported by funding from the Spanish Ministerio de Ciencia, Innovación y Universidades for the grant RTI2018‐094734‐B‐C22 to S.B. P.D. received the financial support from AGAUR (Generalitat de Catalunya) 2017FI_B2 00141. I.T. was supported by NIH training grant T32‐GM008602. H.J. was supported by John and Jan Portman Professorship and Wallace H. Coulter Distinguished Faculty Chair Professorship. This study was also funded by Grup d'Enginyeria dels Materials (GEMAT). GEMAT would like to acknowledge Agència de Gestió d'ajuts Universitaris i de Recerca, Generalitat de Catalunya (SGR 2017) n° 1559.
Funding Information:
This work was supported by funding from the National Institutes of Health grants HL119798 and HL095070 to H.J. It was also supported by funding from the Spanish Ministerio de Ciencia, Innovaci?n y Universidades for the grant RTI2018-094734-B-C22 to S.B. P.D. received the financial support from AGAUR (Generalitat de Catalunya) 2017FI_B2 00141. I.T. was supported by NIH training grant T32-GM008602. H.J. was supported by John and Jan Portman Professorship and Wallace H. Coulter Distinguished Faculty Chair Professorship. This study was also funded by Grup d'Enginyeria dels Materials (GEMAT). GEMAT would like to acknowledge Ag?ncia de Gesti? d'ajuts Universitaris i de Recerca, Generalitat de Catalunya (SGR 2017) n? 1559.
Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2021/8/4
Y1 - 2021/8/4
N2 - Endothelial cells (ECs) are an important target for therapy in a wide range of diseases, most notably atherosclerosis. Developing efficient nanoparticle (NP) systems that deliver RNA interference (RNAi) drugs specifically to dysfunctional ECs in vivo to modulate their gene expression remains a challenge. To date, several lipid-based NPs are developed and shown to deliver RNAi to ECs, but few of them are optimized to specifically target dysfunctional endothelium. Here, a novel, targeted poly(β-amino ester) (pBAE) NP is demonstrated. This pBAE NP is conjugated with VHPK peptides that target vascular cell adhesion molecule 1 protein, overexpressed on inflamed EC membranes. To test this approach, the novel NPs are used to deliver anti-microRNA-712 (anti-miR-712) specifically to inflamed ECs both in vitro and in vivo, reducing the high expression of pro-atherogenic miR-712. A single administration of anti-miR-712 using the VHPK-conjugated-pBAE NPs in mice significantly reduce miR-712 expression, while preventing the loss of its target gene, tissue inhibitor of metalloproteinase 3 (TIMP3) in inflamed endothelium. miR-712 and TIMP3 expression are unchanged in non-inflamed endothelium. This novel, targeted-delivery platform may be used to deliver RNA therapeutics specifically to dysfunctional endothelium for the treatment of vascular disease.
AB - Endothelial cells (ECs) are an important target for therapy in a wide range of diseases, most notably atherosclerosis. Developing efficient nanoparticle (NP) systems that deliver RNA interference (RNAi) drugs specifically to dysfunctional ECs in vivo to modulate their gene expression remains a challenge. To date, several lipid-based NPs are developed and shown to deliver RNAi to ECs, but few of them are optimized to specifically target dysfunctional endothelium. Here, a novel, targeted poly(β-amino ester) (pBAE) NP is demonstrated. This pBAE NP is conjugated with VHPK peptides that target vascular cell adhesion molecule 1 protein, overexpressed on inflamed EC membranes. To test this approach, the novel NPs are used to deliver anti-microRNA-712 (anti-miR-712) specifically to inflamed ECs both in vitro and in vivo, reducing the high expression of pro-atherogenic miR-712. A single administration of anti-miR-712 using the VHPK-conjugated-pBAE NPs in mice significantly reduce miR-712 expression, while preventing the loss of its target gene, tissue inhibitor of metalloproteinase 3 (TIMP3) in inflamed endothelium. miR-712 and TIMP3 expression are unchanged in non-inflamed endothelium. This novel, targeted-delivery platform may be used to deliver RNA therapeutics specifically to dysfunctional endothelium for the treatment of vascular disease.
KW - atherosclerosis
KW - endothelial inflammation
KW - microRNA-712
KW - poly(β-amino ester) nanoparticles
KW - vascular cell adhesion molecule 1-targeting VHPK peptides
UR - http://www.scopus.com/inward/record.url?scp=85099381861&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000607541800001&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1002/adhm.202001894
DO - 10.1002/adhm.202001894
M3 - Article
C2 - 33448151
AN - SCOPUS:85099381861
SN - 2192-2640
VL - 10
JO - Advanced Healthcare Materials
JF - Advanced Healthcare Materials
IS - 15
M1 - 2001894
ER -