Development of a nanoparticulate formulation of retinoic acid that suppresses Th17 cells and upregulates regulatory T cells.
Development of a nanoparticulate formulation of retinoic acid that suppresses Th17 cells and upregulates regulatory T cells.
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DOI：
10.4161/self.1.4.13946
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发表时间：
2010-10-01
期刊：
影响因子：
--
通讯作者：
Fahmy, Tarek M
中科院分区：
文献类型：
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作者：
Capurso, Noah A;Look, Michael;Fahmy, Tarek M
视黄酸（RA）是一种小分子，能够将发育中的T细胞从Th 17谱系转向Treg表型，使其成为自身免疫性和炎症性疾病的潜在有用治疗剂。然而，治疗可能因全身毒性和不可预测的生物利用度而复杂化，使得用于局部治疗的靶向药物递送载体成为期望的。一种有前途的方法是使用纳米颗粒，其已被证明在各种疾病模型（包括Th 17介导的疾病）中增加效力并降低治疗的毒性。纳米颗粒还可以通过表面修饰靶向特定细胞类型，进一步提高这种方法的潜在特异性。因此，我们构建了一个纳米颗粒药物输送平台，从聚（乳酸-共-乙醇酸）（PLGA）能够封装和释放RA。在这里，我们报告的制造，表征，并在体外生物活性的这个平台。我们证明，RA含有PLGA纳米颗粒抑制IL-17的生产和ROR-γ（t）的表达在T细胞极化的Th 17表型在体外具有类似的效力，游离药物。此外，我们表明，这些颗粒增强TGF-β依赖性Foxp 3的表达和IL-10的生产T细胞在体外具有类似的效力游离RA。最后，我们证明了在游离和纳米颗粒RA存在下，向Th 17表型极化的T细胞具有类似的抑制成纤维细胞诱导IL-6产生的能力。我们的研究结果证明了通过可生物降解的纳米颗粒递送RA的可行性，并代表了治疗自身免疫性和炎症性疾病的令人兴奋的技术。
Retinoic acid (RA) is a small molecule capable of shunting developing T cells away from the Th17 lineage and towards the Treg phenotype, making it a potentially useful therapeutic for autoimmune and inflammatory diseases. However, therapy can be complicated by systemic toxicity and unpredictable bioavailability, making a targeted drug delivery vehicle for local therapy desirable. A promising approach is the use of nanoparticles, which have been demonstrated to increase potency and decrease toxicity of therapies in a variety of disease models including Th17 mediated diseases. Nanoparticles can also be targeted to specific cell types via surface modification, further increasing the potential specificity of this approach. We therefore constructed a nanoparticulate drug delivery platform from poly(lactic-co-glycolic acid) (PLGA) capable of encapsulating and releasing RA. Here we report the fabrication, characterization, and in vitro bioactivity of this platform. We demonstrate that RA containing PLGA nanoparticles suppress IL-17 production and ROR-gamma(t) expression in T cells polarized towards the Th17 phenotype in vitro with similar potency to that of free drug. Furthermore, we show that these particles enhance TGF-beta dependent Foxp3 expression and IL-10 production of T cells in vitro with similar potency to free RA. Finally, we demonstrate that T cells polarized towards the Th17 phenotype in the presence of free and nanoparticulate RA have similarly suppressed ability to induce IL-6 production by fibroblasts. Our findings demonstrate the feasibility of RA delivery via biodegradable nanoparticles and represent an exciting technology for the treatment of autoimmune and inflammatory diseases.