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用于类风湿性关节炎大鼠模型中靶向巨噬细胞极化的DS修饰芍药苷pH响应性脂质-聚合物杂化纳米颗粒

DS-Modified Paeoniflorin pH-Responsive Lipid-Polymer Hybrid Nanoparticles for Targeted Macrophage Polarization in a Rat Model of Rheumatoid Arthritis.

作者信息

Zhang Junhao, Yang Jing, Yu Zhoubo, Bai Haotian, Wang Yanhong, Wang Rui

机构信息

College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150040, People's Republic of China.

Basic Medical College, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150040, People's Republic of China.

出版信息

Int J Nanomedicine. 2025 Jul 12;20:8967-8992. doi: 10.2147/IJN.S516434. eCollection 2025.

DOI:10.2147/IJN.S516434
PMID:40671689
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12266063/
Abstract

PURPOSE: Macrophages play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Paeoniflorin, a traditional Chinese medication, reduces inflammation by suppressing immune cell activation and inducing synovial fibroblast apoptosis, attenuating RA disease progression. Despite the potential therapeutic benefits, free paeoniflorin has limitations, including low drug utilization, poor selectivity, and short half-life during administration. We aimed to develop and evaluate dextran sulfate-modified paeoniflorin pH-responsive lipid-polymer hybrid nanoparticles (Pae-PPNPs-DS) for targeted macrophage delivery and improved treatment efficacy in RA. The pH sensitivity is attributed to the incorporation of poly(cyclohexane-1,4-dimethylene ketal), which undergoes hydrolysis-triggered degradation under acidic conditions enabling passive targeting to inflammatory sites through pH-dependent drug release. Simultaneously, dextran sulfate serves as a ligand to actively target Scavenger receptor class A type I overexpressed on activated macrophages in RA synovium, achieving dual-targeted delivery via environmental responsiveness and ligand-receptor interaction. METHODS: We developed dextran sulfate-modified Pae-PPNPs-DS, which exhibits dual capabilities of active macrophage targeting and pH-triggered drug release, to deliver paeoniflorin to macrophages and improve drug delivery at the joint inflammation site. Nanoparticle characterization, in vitro release behavior, stability, macrophage uptake, macrophage polarization pathway, phenotypic polarization, and therapeutic efficacy were evaluated in a rat model of RA. RESULTS: Pae-PPNPs-DS had smooth surfaces, uniform particle sizes, physical stability, and pH-responsive characteristics. RAW264.7 macrophages showed enhanced Pae-PPNPs-DS uptake. Pae-PPNPs-DS effectively modulated the STAT signaling pathway and modulated macrophage polarization. Pae-PPNPs-DS inhibited the expression of /// (pro-inflammatory and M1 markers), while promoting // (anti-inflammatory and M2 markers) secretion. Pathological analysis revealed that Pae-PPNPs-DS prevented synovial tissue proliferation, inhibited inflammatory cell infiltration, and exhibited therapeutic efficacy. CONCLUSION: Pae-PPNPs-DS actively target macrophages, regulate polarization through STAT pathway, and inhibit joint inflammation, suggesting its potential in treating RA. The study highlights the potential of pH-responsive nanocarriers as an innovative approach to treating autoimmune diseases.

摘要

目的：巨噬细胞在类风湿性关节炎（RA）发病机制中起关键作用。芍药苷作为一种传统中药，通过抑制免疫细胞活化和诱导滑膜成纤维细胞凋亡来减轻炎症，从而减缓RA疾病进展。尽管具有潜在的治疗益处，但游离芍药苷存在局限性，包括药物利用率低、选择性差以及给药期间半衰期短。我们旨在开发并评估硫酸葡聚糖修饰的芍药苷pH响应性脂质-聚合物杂化纳米粒（Pae-PPNPs-DS），用于靶向巨噬细胞递送并提高RA的治疗效果。pH敏感性归因于聚（环己烷-1,4-二甲醇缩酮）的掺入，其在酸性条件下会发生水解引发的降解，从而通过pH依赖性药物释放实现对炎症部位的被动靶向。同时，硫酸葡聚糖作为配体，可主动靶向RA滑膜中活化巨噬细胞上过度表达的I型清道夫受体A类，通过环境响应性和配体-受体相互作用实现双靶向递送。 方法：我们开发了具有主动靶向巨噬细胞和pH触发药物释放双重能力的硫酸葡聚糖修饰的Pae-PPNPs-DS，以将芍药苷递送至巨噬细胞并改善关节炎症部位的药物递送。在RA大鼠模型中评估了纳米粒表征、体外释放行为、稳定性、巨噬细胞摄取、巨噬细胞极化途径、表型极化和治疗效果。 结果：Pae-PPNPs-DS表面光滑，粒径均匀，具有物理稳定性和pH响应特性。RAW264.7巨噬细胞对Pae-PPNPs-DS的摄取增强。Pae-PPNPs-DS有效调节STAT信号通路并调节巨噬细胞极化。Pae-PPNPs-DS抑制了///（促炎和M1标志物）的表达，同时促进了//（抗炎和M2标志物）的分泌。病理分析表明，Pae-PPNPs-DS可防止滑膜组织增生，抑制炎性细胞浸润，并显示出治疗效果。 结论：Pae-PPNPs-DS可主动靶向巨噬细胞，通过STAT途径调节极化并抑制关节炎症，表明其在治疗RA方面具有潜力。该研究突出了pH响应性纳米载体作为治疗自身免疫性疾病创新方法的潜力。

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本文引用的文献

[1]
Branched-chain amino acids supplementation induces insulin resistance and pro-inflammatory macrophage polarization via INFGR1/JAK1/STAT1 signal pathway.

Mol Med. 2024-9-12

[2]
Paeoniflorin suppresses kidney inflammation by regulating macrophage polarization via KLF4-mediated mitophagy.

Phytomedicine. 2023-7-25

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Nat Rev Rheumatol. 2023-6

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Formulation development of lipid polymer hybrid nanoparticles of doxorubicin and its and computational evaluation.

Front Pharmacol. 2023-2-7

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Curr Opin Pharmacol. 2022-6

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Ketone body β-hydroxybutyrate ameliorates colitis by promoting M2 macrophage polarization through the STAT6-dependent signaling pathway.

BMC Med. 2022-4-15

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