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

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 (bPEI 25 ) 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.

Therapeutic Acellular Scaffolds for Limiting Left Ventricular Remodelling-Current Status and Future Directions

“…Based on the critical role of angiogenesis in the post-MI heart, some authors applied gene therapy to stimulate it, exploiting the miR-17-92 cluster [ 188 ]. miR-92a is one of the components of this cluster that negatively regulates endothelial cells and angiogenesis and its expression in ischemic myocardium is increased after MI [ 188 ].…”

“…Based on the critical role of angiogenesis in the post-MI heart, some authors applied gene therapy to stimulate it, exploiting the miR-17-92 cluster [ 188 ]. miR-92a is one of the components of this cluster that negatively regulates endothelial cells and angiogenesis and its expression in ischemic myocardium is increased after MI [ 188 ]. Systemic administration of antagomiR-92a in infarcted mice heart promotes angiogenesis, repair of infarct tissue, increases cellular protection and impedes inflammation.…”

miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression

“…MicroRNAs regulate cancer development and/or drug resistance by targeting mRNAs. In recent years, numerous studies have shown that microRNAs are involved in the regulation of tumor growth, metastasis and angiogenesis in different cancers [13][14][15][16]. Our previous study showed that miR-199 and miR-497 inhibited tumor growth and attenuated chemoresistance in glioma and lung cancers [17,18].…”

E7-Targeted Nanotherapeutics for Key HPV Afflicted Cervical Lesions by Employing CRISPR/Cas9 and Poly (Beta-Amino Ester)

“…24 Viral vectors are restricted in clinical applications due to their safety issues. Non-viral vectors, which have been widely developed and adopted due to their low virulence and non-immunogenicity, [25][26][27] include cationic liposomes, 28 polyethyleneimine (PEI) 29 and poly (β-amino ester) (PBAE). 30,31 Among non-viral vectors, PBAEs are a widely used type of cationic polymer gene carrier with excellent biocompatibility, good biodegradability, easy production, and low cost.…”