Small‐Sized Cationic miRi‐PCNPs Selectively Target the Kidneys for High‐Efficiency Antifibrosis Treatment

Abstract

Small‐sized cationic miRi (microRNA‐21 inhibitor)‐PCNPs (low molecular weight chitosan (LMWC)‐modified polylactide‐co‐glycoside (PLGA) nanoparticles (PLNPs)) with special kidney‐targeting and high‐efficiency antifibrosis treatment are fabricated through coupling miRi, PLGA, and LMWC. In the miRi‐PCNPs, easily degraded miRi is encapsulated in PCNPs and thus prevented from degradation by nuclease. Cytotoxicity, immunotoxicity, and systemic toxicity assays and in vitro and ex vivo fluorescence imaging suggest that PCNPs possess excellent biocompatibility, higher cellular uptake efficiency, and selective kidney‐targeting capacity. Western blotting, pathological staining, and real‐time polymerase chain reaction analyses show that the therapeutic effect of miRi‐PCNPs on kidney fibrosis is much higher than that of miRi, which is mainly through suppressing transforming growth factor beta‐1/drosophila mothers against decapentaplegic protein 3 (TGF‐β1/Smad3) and extracellular signal–regulated kinases/mitogen‐activated protein kinase signaling pathway by inhibiting the expression of microRNA‐21. For example, the tubule damage index and tubulointerstitial fibrosis area in the miRi‐PCNPs group are ≈2.5‐fold lower than those in the saline and bare miRi groups. The miRi‐PCNPs with special kidney‐targeting and high‐efficiency antifibrosis treatment may represent a promising strategy for designing and developing a therapeutic treatment for kidney fibrosis.

Cilomilast Ameliorates Renal Tubulointerstitial Fibrosis by Inhibiting the TGF-β1-Smad2/3 Signaling Pathway

“…The activation of TGF-β1 triggers the nuclear localization of Smad2/3 in tubular epithelial cells and fibroblasts (42). To exert its profibrotic role in kidney disease, TGF-β1 can act by stimulating Smad2/3 to positively or negatively regulate microRNAs (43,44). Inhibiting Smad2/3 phosphorylation during TGF-β1-mediated epithelial-mesenchymal transition attenuated kidney fibrosis (45).…”

Targeted Drug Delivery Systems for Kidney Diseases

“…Also, HCA-Chi modified with calcium and salvianolic acid B reversed the TGF-β1-induced epithelial-mesenchymal transition in HK-2 cells (an immortalized proximal tubule epithelial cell line), and in vivo imaging showed a kidney-specific biodistribution (Li et al, 2017). Small-sized cationic microRNA inhibitor-LMWCmodified PLGA nanoparticles also possess kidney-targeting capability and high antifibrosis efficiency (Geng et al, 2018). The drug is two times higher in kidney than heart or liver.…”

Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models

“…NRK-52E cells were cultured with Dulbecco's Modified Eagles's Medium containing 10% FBS, 100 U/mL penicillin, and 100 µg/mL streptomycin. Different concentrations of emodin and Em-MNPs solution from 5 to 50 µg/ mL were added to 96-well plates for 12 and 24 h. Finally, the cell viability was evaluated using a cell counting CCK-8 kit and measured by Thermo Fisher Multiskan GO UV/visible spectrophotometer (Shimadzu, Japan) [20].…”