Chitosan-PLGA biopolymeric nanogel as a platform for enhanced methotrexate delivery and redox-modulated anti-inflammatory activity.

IF 5.1 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2026-10-05 Epub Date: 2026-08-19 DOI:10.1016/j.bioorg.2026.110412

Reem Darwesh, Sarah Alharthi, Nora Hamad Al-Shaalan, Mohamed Mohamady Ghobashy, Fatima M Shaaban, Amal M Hammad, Ehab M Zayed, Rasha E Hassan, Ghadah Alrabghi, Ahmad S Kodous

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引用次数: 0

Abstract

Methotrexate (MTX) is an effective disease-modifying antirheumatic drug for the treatment of chronic inflammatory disorders; however, its clinical application is limited by poor bioavailability, rapid systemic clearance, and dose-dependent adverse effects. In this study, a pH-responsive methotrexate-loaded chitosan/poly(lactic-co-glycolic acid) ((Chit/PLGA)/MTX) nanogel was developed to improve drug delivery and therapeutic performance. The nanogel was fabricated by ionic gelation followed by gamma radiation-induced in situ free-radical polymerization (20 kGy) and subsequently loaded with methotrexate using a pH-triggered swelling-shrinking encapsulation strategy. Physicochemical characterization by TEM, DLS, FTIR, UV-Vis spectroscopy, and zeta potential analysis confirmed the successful formation of spherical nanogel particles with an average hydrodynamic diameter of 125 nm, a polydispersity index of 0.18 ± 0.03, and a zeta potential of -2.5 mV. The nanogel exhibited a high encapsulation efficiency (89.3 ± 2.1%) and drug-loading capacity (15.1 ± 0.8%). In vitro release studies demonstrated pronounced pH-responsive behavior, with cumulative methotrexate release reaching approximately 60% at pH 5.5 compared with 40% at pH 7.4 after 300 s, indicating preferential drug release under acidic inflammatory conditions. Cytotoxicity evaluation showed that the nanogel formulation exhibited improved biocompatibility (IC₅₀ = 422.5 μg/mL) compared with free methotrexate (IC₅₀ = 311.7 μg/mL). The (Chit/PLGA)/MTX nanogel significantly enhanced antioxidant activity, exhibiting 79.1% DPPH radical scavenging, 81.8% membrane stabilization, and 83.3% inhibition of protein denaturation. Furthermore, the formulation effectively suppressed the expression of major inflammatory mediators, including COX-2 (37.2%), iNOS (47.2%), TNF-α (40.3%), and NF-κB (40.9%), while reducing IL-1β (33.5%) and IL-6 (45.0%) production. Collectively, these findings demonstrate that the pH-responsive Chitosan-PLGA nanogel provides efficient methotrexate encapsulation, controlled drug release, enhanced antioxidant activity, and potent anti-inflammatory effects, highlighting its promise as a nanocarrier platform for the treatment of chronic inflammatory diseases.

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壳聚糖- plga生物聚合物纳米凝胶作为增强甲氨蝶呤递送和氧化还原调节抗炎活性的平台。

甲氨蝶呤（MTX）是治疗慢性炎症性疾病的一种有效的抗风湿药物；然而，其临床应用受到生物利用度差、全身清除快和剂量依赖性不良反应的限制。在本研究中，开发了一种ph响应的甲氨蝶呤负载壳聚糖/聚（乳酸-羟基乙酸）（(Chit/PLGA)/MTX）纳米凝胶，以改善药物传递和治疗性能。纳米凝胶是通过离子凝胶和γ辐射诱导的原位自由基聚合（20 kGy）制备的，然后使用ph触发的膨胀收缩封装策略加载甲氨蝶呤。通过TEM、DLS、FTIR、UV-Vis光谱和zeta电位等物理化学表征，成功制备了球形纳米凝胶颗粒，其平均水动力直径为125 nm，多分散性指数为0.18±0.03，zeta电位为-2.5 mV。该纳米凝胶具有较高的包封率（89.3±2.1%）和载药量（15.1±0.8%）。体外释放研究显示出明显的pH响应行为，300 s后，在pH 5.5时甲氨蝶呤的累积释放量约为60%，而在pH 7.4时为40%，表明在酸性炎症条件下药物优先释放。细胞毒性评估表明，与游离甲氨蝶呤（IC₅₀= 311.7 μg/mL）相比，纳米凝胶配方具有更好的生物相容性（IC₅₀= 422.5 μg/mL）。（Chit/PLGA）/MTX纳米凝胶的抗氧化活性显著增强，对DPPH自由基的清除率为79.1%，对膜的稳定性为81.8%，对蛋白质变性的抑制率为83.3%。此外，该制剂有效抑制主要炎症介质的表达，包括COX-2（37.2%）、iNOS（47.2%）、TNF-α(40.3%)和NF-κB(40.9%)，同时降低IL-1β(33.5%)和IL-6（45.0%）的产生。总之，这些发现表明，ph响应壳聚糖- plga纳米凝胶提供有效的甲氨蝶呤包封，控制药物释放，增强抗氧化活性和有效的抗炎作用，突出了其作为治疗慢性炎症性疾病的纳米载体平台的前景。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.