ABSTRACT
Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.
Subject(s)
Arthritis, Rheumatoid , Fibroblasts , Hydrogels , Methotrexate , Synovial Membrane , Fibroblasts/drug effects , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/therapy , Hydrogels/administration & dosage , Synovial Membrane/immunology , Animals , Methotrexate/administration & dosage , Methotrexate/pharmacology , RNA, Small Interfering/administration & dosage , Photochemotherapy/methods , Mice , Humans , Macrophages/drug effects , Macrophages/immunology , RAW 264.7 Cells , Cytokines/metabolism , Antirheumatic Agents/administration & dosage , Cellular Microenvironment/drug effects , NF-kappa B/metabolism , Phototherapy/methods , Peptides/administration & dosageABSTRACT
Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical.
Subject(s)
Arthritis, Rheumatoid , Hydrogels , Humans , Hydrogels/pharmacology , Synovial Membrane/pathology , Macrophages , Methotrexate/pharmacology , Cytokines , FibroblastsABSTRACT
A processing method to enhance thrombolytic effect of Carthamus tinctorius using a fermentation technology with bacillus sp. C2-13 was investigated. The fibrinolysis and anticoagulation activity of thrombolytic extracts from an optimized fermentation process was studied using a carrageenan induced mice model. The fermented extracts resulted in significantly better thrombolytic activity, suggesting that the process was promising for use in the study and preparation of nature medicines.
