Development and evaluation of inhalable composite niclosamide-lysozyme particles: A broad-spectrum, patient-adaptable treatment for coronavirus infections and sequalae.
Development and evaluation of inhalable composite niclosamide-lysozyme particles: A broad-spectrum, patient-adaptable treatment for coronavirus infections and sequalae.
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DOI：
10.1371/journal.pone.0246803
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Smyth HDC
中科院分区：
文献类型：
--
作者：
Brunaugh AD;Seo H;Warnken Z;Ding L;Seo SH;Smyth HDC
氯硝柳胺（NIC）已被证明对COVID-19大流行的病原体SARS-CoV-2具有良好的体外抗病毒疗效。尽管NIC已经获得FDA批准，但目前可用的口服制剂的给药导致全身药物水平太低，无法抑制SARS-CoV-2。我们假设NIC与内源性蛋白质人溶菌酶（hLYS）的共制剂可以使药物直接气雾剂递送至呼吸道作为口服递送的替代方案，从而通过靶向SARS-CoV-2获得和传播的主要部位有效治疗COVID-19。为了检验这一假设，我们设计并优化了含有NIC和hLYS的复合颗粒，其适合通过干粉吸入器、雾化器和鼻喷雾器递送到上气道和下气道。这种新的制剂在体外和体内对两种冠状病毒株MERS-CoV和SARS-CoV-2表现出有效的活性，并可能提供对耐甲氧西林金黄色葡萄球菌肺炎和继发于SARS-CoV-2感染的炎性肺损伤的保护。该制剂对疾病所有阶段的适用性和低成本开发方法将确保快速临床开发和广泛应用。
Niclosamide (NIC) has demonstrated promising in vitro antiviral efficacy against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Though NIC is already FDA-approved, administration of the currently available oral formulation results in systemic drug levels that are too low for the inhibition of SARS-CoV-2. We hypothesized that the co-formulation of NIC with an endogenous protein, human lysozyme (hLYS), could enable the direct aerosol delivery of the drug to the respiratory tract as an alternative to oral delivery, thereby effectively treating COVID-19 by targeting the primary site of SARS-CoV-2 acquisition and spread. To test this hypothesis, we engineered and optimized composite particles containing NIC and hLYS suitable for delivery to the upper and lower airways via dry powder inhaler, nebulizer, and nasal spray. The novel formulation demonstrates potent in vitro and in vivo activity against two coronavirus strains, MERS-CoV and SARS-CoV-2, and may offer protection against methicillin-resistance staphylococcus aureus pneumonia and inflammatory lung damage occurring secondary to SARS-CoV-2 infections. The suitability of the formulation for all stages of the disease and low-cost development approach will ensure rapid clinical development and wide-spread utilization.