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, Xin Zhang, Xipeng Wang, Tao Wang, Bin Bai, Na Zhang, Yanjiao Zhao, Yang Yu, Bing Wang
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 microRNA-30-5p (miR-30-5p) was highly expressed in the rheumatoid arthritis synovial fibroblasts (RASFs) in clinical patients. Subsequently, by using the Target Scan Human 7.2 database, we predicted that phosphatidylinositol 3-kinase regulatory subunit 2 (PIK3R2) might be a putative target of miR-30-5p, a supposition verified by qRT-PCR and Western blot analyses. Recent studies have reported that PIK3R2 can maintain the physiological homeostasis of RASFs and may be a potential target in the treatment of RA.Therefore, a miR-30-5p inhibitor has potential to be used in the treatment of RA, but the low levels of miR-30-5p inhibitor internalization affects its application, and 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 the miR-30-5p inhibitor was improved by loading it into CADY (cell membrane penetrating peptide) 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 system was constructed by filling a phase-change materials (PCM) of 1-tetradecanol and drugs into MSNs that could be triggered by 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 by targeting PIK3R2 to regulate the PI3K/AKT signaling pathway. In addition, MSNs@PCM@TP under 808nm laser were effective in upregulating the expression levels of protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in the thymus and spleen, and downregulating the expression levels of IL-2, IL-6 and TNF-α in the serum of the RA rats. Finally, the results of the pharmacodynamic study showed that the combination of MSNs@CADY@miR-30-5p inhibitor and MSNs@PCM@TP under 808nm laser significantly increased the effectiveness of the RA treatment. These findings provide a novel understanding of RA pathogenesis and a theoretical basis for RA treatment.