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Published on: February 5, 2019
DS-Modified Paeoniflorin pH-Responsive Lipid-Polymer Hybrid Nanoparticles for Targeted Macrophage Polarization in a
Junhao Zhang1, Jing Yang2, Zhoubo Yu1
1College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150040, People's Republic of China.
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 TNF-α/IL-1β/iNOS/IL-6 (pro-inflammatory and M1 markers), while promoting IL-10/Arg-1/TGF-β (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.
Insights
This study developed novel pH-responsive lipid-polymer hybrid nanoparticles (Pae-PPNPs-DS) for targeted delivery of paeoniflorin to macrophages, effectively treating rheumatoid arthritis (RA) by reducing inflammation and improving therapeutic outcomes.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Immunology
Background:
- Macrophages are key drivers of rheumatoid arthritis (RA) pathogenesis.
- Paeoniflorin shows anti-inflammatory potential but suffers from poor drug utilization and short half-life.
- Targeted drug delivery systems are needed to overcome paeoniflorin's limitations in RA treatment.
Purpose of the Study:
- To develop and evaluate dextran sulfate-modified paeoniflorin pH-responsive lipid-polymer hybrid nanoparticles (Pae-PPNPs-DS).
- To achieve targeted delivery of paeoniflorin to macrophages in RA synovium.
- To enhance therapeutic efficacy for rheumatoid arthritis through dual-targeted delivery.
Main Methods:
- Characterization of Pae-PPNPs-DS for size, stability, and pH-responsive properties.
- In vitro evaluation of macrophage uptake and drug release kinetics.
- Assessment of macrophage polarization and inflammatory marker modulation in a rat RA model.
Main Results:
- Pae-PPNPs-DS demonstrated favorable physicochemical properties and enhanced macrophage uptake.
- The nanoparticles effectively modulated macrophage polarization via the STAT pathway, reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and increasing anti-inflammatory markers (IL-10).
- In vivo studies showed Pae-PPNPs-DS inhibited synovial proliferation and inflammatory cell infiltration, demonstrating significant therapeutic efficacy in RA.
Conclusions:
- Pae-PPNPs-DS exhibit dual targeting capabilities for active macrophage delivery and pH-responsive drug release.
- These nanoparticles effectively regulate macrophage polarization and inhibit joint inflammation, showing promise for RA treatment.
- pH-responsive nanocarriers represent an innovative strategy for managing autoimmune diseases like RA.
