Nanoparticle-mediated local delivery of pioglitazone attenuates bleomycin-induced skin fibrosis
Nanoparticle-mediated local delivery of pioglitazone attenuates bleomycin-induced skin fibrosis
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DOI：
10.1016/j.jdermsci.2018.11.012
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发表时间：
2019-01-01
影响因子：
4.6
通讯作者：
Katoh, Norito
中科院分区：
文献类型：
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作者：
Kanemaru, Mai;Asai, Jun;Katoh, Norito
背景：纳米颗粒载药系统近年来引起了广泛的关注。聚乳酸-羟基乙酸（PLGA）是生物医学应用中最成功的生物可降解聚合物之一。使用缓释药物治疗真皮纤维化的研究很少。过氧化物酶体增殖物激活受体γ (ppar - γ)在内源性抗纤维化防御机制中发挥重要作用。最近的研究表明，吡格列酮是一种合成的ppar - γ激活剂，它的作用不仅限于降低血糖，而且在全身使用时还可以减少纤维化和炎症。目的：我们旨在评估局部注射吡格列酮负载PLGA纳米颗粒（PGN-NP）对实验性硬化症的影响，并证明皮下给药PLGA纳米颗粒的体内药代动力学。方法：制备局部可注射的pgnn - np，并皮下注射给博来霉素（BLM）诱导的硬皮病模型小鼠。用培养成纤维细胞评价吡格列酮的作用。利用香豆素-6负载的荧光PLGA纳米颗粒（FL-NP）和硅萘菁负载的近红外PLGA纳米颗粒（NIR-NP）来证明培养成纤维细胞对其的体外细胞摄取和皮下给药纳米颗粒的体内药代动力学。结果：每周皮下注射pgnn - np可减轻blm诱导的硬皮病模型小鼠的皮肤纤维化。吡格列酮显著抑制培养成纤维细胞的迁移能力和tgf - β介导的肌成纤维细胞分化。FL-NP在60分钟内内化到培养成纤维细胞中，pgn - np引物的成纤维细胞表达抗纤维化表型。皮下注射的NIR-NP在注射部位附近的残留比非颗粒型萘菁硅多。结论：这些结果为开发新的真皮纤维化治疗方法和更好地了解PLGA纳米颗粒在皮肤病学中的潜力提供了基础。(C) 2018年日本皮肤病研究学会。Elsevier B.V.版权所有。
Background: Nanoparticle-loaded delivery systems have attracted much attention recently. Poly(lactic-co-glycolic acid) (PLGA) is one of the most successful biodegradable polymers for biomedical applications. There are only a few studies on the treatment of dermal fibrosis with sustained-release drugs. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays an important role in endogenous anti-fibrotic defense mechanisms. Recent studies have suggested that pioglitazone, a synthetic PPAR-gamma activator, has effects beyond reducing blood sugar and it can reduce fibrosis and inflammation when used systemically.Objective: We aimed to assess the effects of local injections of pioglitazone-loaded PLGA nanoparticles (PGN-NP) on an experimental sclerosis and to demonstrate the in vivo pharmacokinetics of subcutaneously administered PLGA nanoparticles.Methods: Locally injectable PGN-NP were prepared and subcutaneously administered to bleomycin (BLM)-induced scleroderma model mice. The effect of pioglitazone was also evaluated with cultured fibroblasts. Coumarin-6-loaded fluorescent PLGA nanoparticles (FL-NP) and silicon naphthalocyanine-loaded near-infrared PLGA nanoparticles (NIR-NP) were used to demonstrate in vitro cellular uptake by cultured fibroblasts and the in vivo pharmacokinetics of subcutaneously administered nanoparticles.Results: Weekly subcutaneous injections of PGN-NP attenuated skin fibrosis in BLM-induced scleroderma model mice. Pioglitazone significantly suppressed migration ability and TGF-beta-mediated myofibroblast differentiation in cultured fibroblasts. FL-NP were internalized into cultured fibroblasts within 60 min, and PGN-NP-primed fibroblasts expressed anti-fibrotic phenotypes. Subcutaneously injected NIR-NP remained in the vicinity of the injection site more than non-particulate silicon naphthalocyanine.Conclusion: These results provide a basis for the development of new treatments for dermal fibrosis and a better understanding of the potential of PLGA nanoparticles in dermatology. (C) 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.