Posaconazole-Loaded Leukocytes as a Novel Treatment Strategy Targeting Invasive Pulmonary Aspergillosis
Posaconazole-Loaded Leukocytes as a Novel Treatment Strategy Targeting Invasive Pulmonary Aspergillosis
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DOI：
10.1093/infdis/jiw513
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发表时间：
2017-06-01
影响因子：
6.4
通讯作者：
Sheppard, Donald C.
中科院分区：
文献类型：
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作者：
Baistrocchi, Shane R.;Lee, Mark J.;Sheppard, Donald C.
背景资料。在侵袭性肺曲霉菌病(IPA)中，抗真菌药物向菌丝输送的障碍被认为是导致治疗失败的原因之一。我们假设，在体外输注携带亲脂性抗真菌药物泊沙康唑的白细胞可以改善抗真菌药物对已建立的感染部位的输送，并改善实验性IPA的结局。将HL-60白血病细胞系分化为中性粒细胞样表型(分化的HL-60[DHL-60]细胞)，然后将其暴露于一定浓度的泊沙康唑。在体外和在IPA小鼠模型中对这些细胞的功能和抗真菌活性进行了评估。在DHL-60细胞中的泊沙康唑水平是暴露浓度的265倍。泊沙康唑负载的细胞是存活的，并保持其经历主动趋化的能力。在体外观察到泊沙康唑从DHL-60细胞向菌丝的接触转移，导致真菌活力下降。在中性粒细胞减少的IPA小鼠模型中，负载泊沙康唑的DHL-60细胞与单独使用DHL-60细胞相比，真菌负荷显著降低。泊沙康唑在DHL-60细胞中高浓度蓄积，在体外和体内均可增强其抗真菌活性。这些发现表明，泊沙康唑负载白细胞可能为IPA的治疗带来希望。
Background. Impaired delivery of antifungals to hyphae within necrotic lesions is thought to contribute to therapeutic failure in invasive pulmonary aspergillosis (IPA). We hypothesized that transfusion of leukocytes loaded ex vivo with the lipophilic antifungal posaconazole could improve delivery of antifungals to the sites of established infection and improve outcome in experimental IPA.Methods. The HL-60 leukemia cell line was differentiated to a neutrophil-like phenotype (differentiated HL-60 [ dHL-60] cells) and then exposed to a range of posaconazole concentrations. The functional capacity and antifungal activity of these cells were assessed in vitro and in a mouse model of IPA.Results. Posaconazole levels in dHL-60 cells were 265-fold greater than the exposure concentration. Posaconazole-loaded cells were viable and maintained their capacity to undergo active chemotaxis. Contact-dependent transfer of posaconazole from dHL-60 cells to hyphae was observed in vitro, resulting in decreased fungal viability. In a neutropenic mouse model of IPA, treatment with posaconazole-loaded dHL-60 cells resulted in significantly reduced fungal burden in comparison to treatment with dHL-60 cells alone.Conclusions. Posaconazole accumulates at high concentrations in dHL-60 cells and increases their antifungal activity in vitro and in vivo. These findings suggest that posaconazole-loading of leukocytes may hold promise for the therapy of IPA.