We previously reported that inorganic-organic hybrid nanoparticles (IOH-NPs) containing the synthetic glucocorticoid (GC) betamethasone show efficient anti-inflammatory activity in mice. Here, we employed IOH-NPs with the chemical composition Gd3+2[AMP]2-3 (AMP: adenosine monophosphate) to determine their in vivo distribution by magnetic resonance imaging after intraperitoneal injection. We show that IOH-NPs distribute throughout the peritoneal cavity from where they get rapidly cleared and then localize to abdominal organs. Our findings were confirmed by analyzing individual mouse organs ex vivo following injection of IOH-NPs with the chemical composition [ZrO]2+[(BMP)0.9(FMN)0.1]2- (BMP: betamethasone phosphate, FMN: flavin mononucleotide) or [ZrO]2+[(HPO4)0.9(FMN)0.1]2- using inductively coupled plasma mass spectrometry and flow cytometry. To characterize the mechanism of cellular uptake in vitro, we tested different cell lines for their ability to engulf IOH-NPs by flow cytometric analysis taking advantage of the incorporated fluorescent dye FMN. We found that IOH-NPs were efficiently taken up by macrophages, to a lesser extent by fibroblasts, epithelial cells, and myoblasts, and hardly at all by both T and B lymphocytes. Characterization of the endocytic pathway further suggested that IOH-NPs were internalized by macropinocytosis, and imaging flow cytometry revealed a strong colocalization of the engulfed IOH-NPs with the lysosomal compartment. Intracellular release of the functional anions from IOH-NPs was confirmed by the ability of the GC betamethasone to downregulate the expression of surface receptors on bone marrow-derived macrophages. Taken together, our findings unveil the mechanistic basis of an anti-inflammatory GC therapy with IOH-NPs, which may entail translational approaches in the future.

中文翻译：

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高度定制的器官分布和无机-有机杂化纳米颗粒的细胞摄取，专门用于糖皮质激素的靶向递送。

我们之前曾报道过，含有合成糖皮质激素（GC）倍他米松的无机-有机杂化纳米颗粒（IOH-NPs）在小鼠中显示出有效的抗炎活性。在这里，我们采用化学成分为Gd3 + 2 [AMP] 2-3（AMP：单磷酸腺苷）的IOH-NP，通过腹腔注射后的磁共振成像确定其体内分布。我们显示IOH-NPs分布在整个腹膜腔中，从那里它们迅速清除，然后定位到腹腔器官。通过以化学成分[ZrO] 2 + [（BMP）0.9（FMN）0.1] 2-（BMP：磷酸倍他米松，FMN：黄素单核苷酸）注射IOH-NP后，离体分析单个小鼠器官，可以证实我们的发现。 [ZrO] 2 + [（（HPO4）0.9（FMN）0.1] 2-使用电感耦合等离子体质谱和流式细胞仪。为了表征体外细胞摄取的机制，我们利用掺入的荧光染料FMN，通过流式细胞术分析了不同细胞系吞噬IOH-NP的能力。我们发现IOH-NPs被巨噬细胞有效地吸收，在较小程度上被成纤维细胞，上皮细胞和成肌细胞吸收，而T和B淋巴细胞几乎都没有。内吞途径的特征进一步表明，IOH-NPs通过巨胞吞作用而被内在化，而流式细胞仪成像显示被吞噬的IOH-NPs与溶酶体区室存在强烈的共定位。GC倍他米松具有下调骨髓来源的巨噬细胞表面受体表达的能力，从而证实了IOH-NPs释放功能性阴离子的能力。在一起