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Hydrogel-mediated delivery of microRNA-92a inhibitor polyplex nanoparticles induces localized angiogenesis

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Abstract

Localized stimulation of angiogenesis is an attractive strategy to improve the repair of ischemic or injured tissues. Several microRNAs (miRNAs) such as miRNA-92a (miR-92a) have been reported to negatively regulate angiogenesis in ischemic disease. To exploit the clinical potential of miR-92a inhibitors, safe and efficient delivery needs to be established. Here, we used deoxycholic acid-modified polyethylenimine polymeric conjugates (PEI-DA) to deliver a locked nucleic acid (LNA)-based miR-92a inhibitor (LNA-92a) in vitro and in vivo. The positively charged PEI-DA conjugates condense the negatively charged inhibitors into nano-sized polyplexes (135 ± 7.2 nm) with a positive net charge (34.2 ± 10.6 mV). Similar to the 25 kDa-branched PEI (bPEI25) and Lipofectamine RNAiMAX, human umbilical vein endothelial cells (HUVECs) significantly internalized PEI-DA/LNA-92a polyplexes without any obvious cytotoxicity. Down-regulation of miR-92a following the polyplex-mediated delivery of LNA-92a led to a substantial increase in the integrin subunit alpha 5 (ITGA5), the sirtuin-1 (SIRT1) and Krüppel-like factors (KLF) KLF2/4 expression, formation of capillary-like structures by HUVECs, and migration rate of HUVECs in vitro. Furthermore, PEI-DA/LNA-92a resulted in significantly enhanced capillary density in a chicken chorioallantoic membrane (CAM) model. Localized angiogenesis was substantially induced in the subcutaneous tissues of mice by sustained release of PEI-DA/LNA-92a polyplexes from an in situ forming, biodegradable hydrogel based on clickable poly(ethylene glycol) (PEG) macromers. Our results indicate that PEI-DA conjugates efficiently deliver LNA-92a to improve angiogenesis. Localized delivery of RNA interference (RNAi)-based therapeutics via hydrogel-laden PEI-DA polyplex nanoparticles appears to be a safe and effective approach for different therapeutic targets.

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Data availability

All data generated or analyzed during this study are included in this article and its supplementary information file, and are available from the corresponding author upon request.

Code availability

The quantification of tubular structures was done using WimTube software https://www.wimasis.com/en/WimTube.

Abbreviations

bPEI25 :

25 KDa-branched PEI

bPEI1.8 :

1.8 KDa-branched PEI

DA:

Deoxycholic acid

PEI-DA:

Polyethylenimine-deoxycholic acid

PEG:

Poly(ethylene glycol)

DCC:

Dicyclohexylcarbodiimide

NHS:

N-hydroxysuccinimide

THF:

Tetrahydrofuran

DMSO:

Dimethyl sulfoxide

Na2CO3 :

Sodium carbonate

TAE:

Tris-acetate-EDTA

PBS:

Phosphate-buffered saline

DPBS:

Dulbecco's PBS

M199:

Medium 199

Pen/Strep:

Penicillin/streptomycin

FBS:

Fetal bovine serum

BSA:

Bovine serum albumin

BCA:

Bicinchoninic acid

TBS:

Tris-buffered saline

H&E:

Hematoxylin and eosin

HRP:

Horseradish peroxidase

RITC:

Rhodamine B isothiocyanate

FITC:

Fluorescein isothiocyanate

FAM:

Fluorescein amidites

PVDF:

Polyvinylidene difluoride

DAPI:

4,6-Diamino-2-phenylindole

SMA:

Smooth muscle actin

ITGA5:

Integrin subunit alpha 5

SIRT1:

Sirtuin-1

KLF:

Krüppel-like factor

MI:

Myocardial infarction

RNAi:

RNA interference

miRNA:

MicroRNA

cDNA:

Complementary DNA

MFI:

Mean fluorescent intensity

LNA:

Locked-nucleic acid

EC:

Endothelial cells

HUVEC:

Human umbilical vein endothelial cell

CAM:

Chicken chorioallantoic membrane

VSMC:

Vascular smooth muscle cell

RT:

Room temperature

1H NMR:

Proton nuclear magnetic resonance

DLS:

Dynamic light scattering

AFM:

Atomic force microscopy

CLSM:

Confocal laser scanning microscopy

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

IF:

Immunofluorescence

RNase A:

Ribonuclease A

PK:

Pharmacokinetic

PD:

Pharmacodynamic

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Acknowledgements

We express our appreciation to Paria Pooyan for her assistance with preparation of the schematic figures. We also express our appreciation to Poya Tavakol for his assistance in animal handling.

Funding

This work was supported by a grant from Royan Institute; the Iranian Council of Stem Cell Research and Technology; the Iran National Science Foundation (INSF, Grant Number [96001316]); and Iran Science Elites Federation to H.B.

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Authors and Affiliations

  1. Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Fatemeh Radmanesh

  2. Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Babol, Iran

    Hamid Sadeghi Abandansari

  3. Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Fatemeh Radmanesh, Hamid Sadeghi Abandansari & Mohammad Hossein Ghanian

  4. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Sara Pahlavan, Fahimeh Varzideh, Saeed Yakhkeshi, Mehdi Alikhani, Sharif Moradi & Hossein Baharvand

  5. Max-Planck Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, Bad Nauheim, Germany

    Thomas Braun

  6. Department of Developmental Biology, University of Science and Culture, Tehran, Iran

    Hossein Baharvand

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  1. Fatemeh Radmanesh
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Contributions

HB and FR contributed to the design and implementation of the research. FR, HSA, MHG, FV, SY, and MA performed experiments. TB provided all miRNA inhibitor sequences and approved the manuscript. FR, HSA, MHG, SP, and SM contributed to the interpretation of the results and the preparation of the manuscript. HB provided financial and administrative support and approved the manuscript. All authors reviewed and confirmed the manuscript before submission.

Corresponding author

Correspondence to Hossein Baharvand.

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All animal care and procedures were performed according to standards established by the Royan Institutional Review Board and Institutional Ethics Committee (Tehran, Iran).

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Radmanesh, F., Sadeghi Abandansari, H., Ghanian, M.H. et al. Hydrogel-mediated delivery of microRNA-92a inhibitor polyplex nanoparticles induces localized angiogenesis. Angiogenesis 24, 657–676 (2021). https://doi.org/10.1007/s10456-021-09778-6

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