Dataset Information

Hybrid micelles containing methotrexate-conjugated polymer and co-loaded with microRNA-124 for rheumatoid arthritis therapy.

ABSTRACT: Purpose: Methotrexate (MTX) is a first-line drug for rheumatoid arthritis (RA)therapy. However, MTX monotherapy often results in irreversible joint damage due to its slow onset of action and long duration. microRNA-124 (miR-124) has shown direct bone protection activity against RA. A co-delivery system for MTX and microRNA combination may provide therapeutic synergy. Methods: Methotrexate-conjugated polymer hybrid micelles (M-PHMs) were prepared by self-assembly of two functional amphiphilic polymers (MTX-PEI-LA and mPEG-LA) at an optimized weight ratio. Incorporation of microRNA was achieved through electrostatic interactions between microRNA and cationic polymer MTX-PEI-LA. Cellular uptake, endosome escape, biodistribution, and therapeutic efficacy of M-PHMs/miR-124 complexes were investigated and evaluated in RAW264.7 cells and a rat adjuvant-induced arthritis (AIA) model. Results: M-PHMs/miR-124 complexes exhibited folate receptor-mediated uptake in activated RAW264.7 cells. miR-124 was able to escape from the endosome and down-regulate nuclear factor of activated T cells cytoplasmic1 (NFATc1). M-PHMs/miR-124 complexes accumulated in inflamed joints of AIA rats and showed superior therapeutic efficacy through both anti-inflammatory effect and direct bone protective effect. Combination of miR-124 and MTX in these micelles induced disease remission. Conclusions: M-PHMs/miR-124 was highly effective against RA through therapeutic synergy. Additional studies are warranted to further investigate its therapeutic potential and delineate its mechanisms of action.

SUBMITTER: Hao F

PROVIDER: S-EPMC6691571 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Hybrid micelles containing methotrexate-conjugated polymer and co-loaded with microRNA-124 for rheumatoid arthritis therapy.

Hao Fei F Lee Robert J RJ Zhong Lihuang L Dong Shiyan S Yang Chunmiao C Teng Lirong L Meng Qingfan Q Lu Jiahui J Xie Jing J Teng Lesheng L

Theranostics 20190709 18

<b>Purpose</b>: Methotrexate (MTX) is a first-line drug for rheumatoid arthritis (RA)therapy. However, MTX monotherapy often results in irreversible joint damage due to its slow onset of action and long duration. microRNA-124 (miR-124) has shown direct bone protection activity against RA. A co-delivery system for MTX and microRNA combination may provide therapeutic synergy. <b>Methods</b>: Methotrexate-conjugated polymer hybrid micelles (M-PHMs) were prepared by self-assembly of two functional a ...[more]

PMID: 31410215

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Project description:Angiogenesis plays an essential role in the progression of rheumatoid arthritis (RA). RGD peptide shows high affinity and selectivity for integrin ?v?3, which is one of the most extensively examined target of angiogenesis. Nimesulide could improve the anti-rheumatic profile of methotrexate. But the clinical application was limited due to water-insolubility of both methotrexate and nimesulide and lacking targeting ability. Therefore, this study aimed to design a targeted drug delivery system of micelles mediated by RGD plus the passive targeting of micelles to solve the application problems of methotrexate and nimesulide (M/N), and thus enhance their combined therapeutic effect on RA. Methods: RGD was conjugated with NHS-PEG-PLA to form RGD-PEG-PLA for the preparation of RGD-modified drug-loaded micelles (R-M/N-PMs). The size and zeta potential of micelles were measured by dynamic light scattering. Morphology was detected by transmission electron microscopy. The inhibition effect of R-M/N-PMs on angiogenesis was assessed by the chick chorioallantoic membrane assay. The real-time fluorescence imaging analysis was conducted to examine the in vivo distribution of the fluorescence-labeled R-M/N-PMs. Rats arthritis model induced by Freund's adjuvant was used to evaluate the in vivo anti-inflammatory efficacy of R-M/N-PMs. Results: The in vitro study indicated successful development of R-M/N-PMs. R-M/N-PMs could markedly suppress the angiogenesis of chick embryos. The fluorescence-labeled R-M/N-PMs mainly accumulated in arthritic joints. RGD enhanced the targeting ability of micelles and thus promoted retention of micelles in arthritic joints. Moreover, R-M/N-PMs significantly alleviated the joint swelling while reducing bone erosion and serum levels of inflammatory cytokines. It helped to recover the bone microstructure of arthritic rats. Conclusion: Our results confirmed that the targeted delivery of the combination of a low dose of methotrexate and nimesulide mediated by RGD-modified polymeric micelles could enhance the therapeutic effect on rheumatoid arthritis. These findings provide a promising potential for the clinical therapy of rheumatoid arthritis.

Project description:BackgroundMethotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but failure of satisfying treatment response occurs in a significant proportion of patients. Here we present a longitudinal multi-omics study aimed at detecting molecular and cellular processes in peripheral blood associated with a successful methotrexate treatment of rheumatoid arthritis.MethodsEighty newly diagnosed patients with RA underwent clinical assessment and donated blood before initiation of MTX, and 3 months into treatment. Flow cytometry was used to describe cell types and presence of activation markers in peripheral blood, the expression of 51 proteins was measured in serum or plasma, and RNA sequencing was performed in peripheral blood mononuclear cells (PBMC). Response to treatment after 3 months was determined using the EULAR response criteria. We assessed the changes in biological phenotypes during treatment, and whether these changes differed between responders and non-responders with regression analysis. By using measurements from baseline, we also tried to find biomarkers of future MTX response or, alternatively, to predict MTX response.ResultsAmong the MTX responders, (Good or Moderate according to EULAR treatment response classification, n = 60, 75%), we observed changes in 29 partly overlapping cell types proportions, levels of 13 proteins and expression of 38 genes during treatment. These changes were in most cases suppressions that were stronger among responders compared to non-responders. Within responders to treatment, we observed a suppression of FOXP3 gene expression, reduction of immunoglobulin gene expression and suppression of genes involved in cell proliferation. The proportion of many HLA-DR expressing T-cell populations were suppressed in all patients irrespective of clinical response, and the proportion of many IL21R+ T-cells were reduced exclusively in non-responders. Using only the baseline measurements we could not detect any biomarkers or prediction models that could predict response to MTX.ConclusionWe conclude that a deep molecular and cellular phenotyping of peripheral blood cells in RA patients treated with methotrexate can reveal previously not recognized differences between responders and non-responders during 3 months of treatment with MTX. This may contribute to the understanding of MTX mode of action and explain non-responsiveness to MTX therapy.

Dataset Information

Hybrid micelles containing methotrexate-conjugated polymer and co-loaded with microRNA-124 for rheumatoid arthritis therapy.

Publications

Hybrid micelles containing methotrexate-conjugated polymer and co-loaded with microRNA-124 for rheumatoid arthritis therapy.

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