Efficient Delivery of Triptolide Plus a miR-30-5p Inhibitor Through the Use of Near Infrared Laser Responsive or CADY Modified MSNs for Efficacy in Rheumatoid Arthritis Therapeutics.

Xiaonan Zhang,Yanjiao Zhao,Xipeng Wang,Bing Wang,Tao Wang,Xin Zhang,Bin Bai,Yang Yu,Na Zhang

doi:10.3389/fbioe.2020.00170

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease for which treatment focuses on suppressing an overactive immune system and maintaining the physiological balance of synovial fibroblasts (SFs). We found that miR-30-5p was highly expressed in rheumatoid arthritis synovial fibroblasts (RASFs). Subsequently, we predicted that phosphatidylinositol 3-kinase regulatory subunit 2 (PIK3R2) might be a putative target of miR-30-5p. Recent studies have reported that PIK3R2 can maintain the physiological homeostasis of RASFs. Therefore, miR-30-5p inhibitor has the potential to be used in the treatment of RA, but low levels of miR-30-5p inhibitor internalization affect its application. Triptolide (TP) is an effective drug in the treatment of RA but induces severe toxicity and has a narrow therapeutic window. In this study, the cell internalization performance of miR-30-5p inhibitor was improved by loading it into cell membrane penetrating peptide (CADY)-modified mesoporous silica nanoparticles (MSNs), and the toxicity of TP was decreased by loading it into a controlled drug release system based on MSNs. The nanodrug carrier was constructed by filling a phase-change material (PCM) of 1-tetradecanol and drugs into MSNs that could be triggered by an NIR laser with thermo-chemo combination RA therapy. Our results show that the miR-30-5p inhibitor-loaded MSNs@CADY significantly inhibited RASF proliferation and increased apoptosis. In addition, MSNs@PCM@TP under 808 nm laser irradiation were effective in downregulating immune system activation in an RA rat model. Finally, the results of a pharmacodynamics study showed that the combination of MSNs@CADY@miR-30-5p inhibitor and MSNs@PCM@TP under 808 nm laser significantly increased the effectiveness of RA treatment. These findings provide a novel understanding of RA pathogenesis and a theoretical basis for RA treatment.

Highlights

Rheumatoid arthritis (RA) is a complex autoimmune disorder with two main characteristics: hyperactivity of the immune system and abnormal proliferation of synovial fibroblasts (SFs) (Zwerina et al, 2005; Onozaki, 2009; Mullen and Saag, 2015; Collison, 2016)
To analyze the expression levels of miRNAs in RA patients, we screened tissues from 40 RA patients and 15 healthy volunteers, and we identified that miR-30-5p was overexpressed in 32 rheumatoid arthritis synovial fibroblasts (RASFs) (32/40, 80%) compared with expression in the corresponding adjacent tissues (Figure 1A)
Using TargetScan Human 7.2, we found that PIK3R2 was a putative target of miR-30-5p

Summary

Introduction

Rheumatoid arthritis (RA) is a complex autoimmune disorder with two main characteristics: hyperactivity of the immune system and abnormal proliferation of synovial fibroblasts (SFs) (Zwerina et al, 2005; Onozaki, 2009; Mullen and Saag, 2015; Collison, 2016). Current treatment for RA mainly focuses on maintaining the physiological homeostasis of synovial cells and suppressing the activity of the immune system. The PI3K/AKT signaling pathway activity is prominent in SFs, and its abnormal activation can create an imbalance between SF proliferation and apoptosis (Qu et al, 2019). In 2016, Zhao et al reported that miR-126 targeting of PIK3R2 promotes the proliferation of rheumatoid arthritis synovial fibroblasts (RASFs) and resistance to apoptosis by regulating PI3K/AKT (Gao et al, 2016). Downregulation of miR126 may indirectly inhibit the PI3K/AKT signaling pathway by targeting PIK3R2, disrupting the balance between RASF survival and death. It has been suggested that PIK3R2, which maintains the physiological homeostasis of SFs (Gao et al, 2016), may be a potential target for the treatment of RA

Methods

Results

Conclusion