A macrophage-targeted platform for extending drug dosing with polymer prodrugs for pulmonary infection prophylaxis.
A macrophage-targeted platform for extending drug dosing with polymer prodrugs for pulmonary infection prophylaxis.
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DOI：
10.1016/j.jconrel.2020.11.031
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发表时间：
2021-02-10
期刊：
影响因子：
--
通讯作者：
Stayton PS
中科院分区：
文献类型：
--
作者：
Chavas TEJ;Su FY;Srinivasan S;Roy D;Lee B;Lovelace-Macon L;Rerolle GF;Limqueco E;Skerrett SJ;Ratner DM;West TE;Stayton PS
肺类鼻疽病是一种细菌性疾病，在南亚资源贫乏地区发病率和死亡率可高达40%。这种疾病负担与病原体的内在耐药性和肺泡巨噬细胞中受保护的细胞内定位有关。目前的治疗方案需要几种抗生素，口服和静脉注射数月，这在发展中国家很难实施。在此，我们报告了巨噬细胞靶向的聚环丙沙星前药作为一个令人惊讶的有效的暴露前预防在高度致命的雾化人肺类鼻疽小鼠模型。单剂量的聚合物前药维持高的肺药物水平，并将环丙沙星的细胞内贮库靶向肺泡巨噬细胞隔室，其持续超过最小抑制浓度7天。这种细胞内药代动力学特征在BSL-3模型中提供了完整的暴露前保护，该模型使用了来自泰国的类鼻疽伯克霍尔德氏菌的耐药性、雾化临床分离株。尽管细菌对环丙沙星具有内在耐药性，但仍实现了这种总保护，并且肺部给予等效剂量的环丙沙星无效。我们首次证明，在肺类鼻疽模型中，靶向细胞内巨噬细胞隔室并延长抗生素剂量可以实现暴露前预防。这种完全合成和模块化的治疗平台可能是一种重要的治疗方法，具有用于类鼻疽预防和治疗的新的或重新使用的抗生素，特别是在高风险，资源匮乏的环境中作为便携式吸入装置。
Pulmonary melioidosis is a bacterial disease with high morbidity and a mortality rate that can be as high as 40% in resource-poor regions of South Asia. This disease burden is linked to the pathogen’s intrinsic antibiotic-resistance and protected intracellular localization in alveolar macrophages. Current treatment regimens require several antibiotics with multi-month oral and intravenous administrations that are difficult to implement in the developing world. Herein, we report that a macrophage-targeted polyciprofloxacin prodrug acts as a surprisingly effective pre-exposure prophylactic in highly lethal murine models of aerosolized human pulmonary melioidosis. A single dose of the polymeric prodrug maintained high lung drug levels and targeted an intracellular depot of ciprofloxacin to the alveolar macrophage compartment that was sustained over a period of 7 days above minimal inhibitory concentrations. This intracellular pharmacokinetic profile provided complete pre-exposure protection in a BSL-3 model with a drug-resistant, aerosolized clinical isolate of Burkholderia pseudomallei from Thailand. This total protection was achieved despite the bacteria’s intrinsic resistance to ciprofloxacin and where an equivalent dose of pulmonary-administered ciprofloxacin was ineffective. For the first time, we demonstrate that targeting the intracellular macrophage compartment with extended antibiotic dosing can achieve pre-exposure prophylaxis in a model of pulmonary melioidosis. This fully synthetic and modular therapeutic platform could be an important therapeutic approach with new or re-purposed antibiotics for melioidosis prevention and treatment, especially as portable inhalation devices in high-risk, resource-poor settings.
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影响因子：
3.2
作者：
DeShazer, D;Brett, PJ;Woods, DE
通讯作者：
Woods, DE
影响因子：
4
作者：
Koch A;Cox H;Mizrahi V
通讯作者：
Mizrahi V
影响因子：
4.9
作者：
Barnes, Kay B.;Hamblin, Karleigh A.;Harding, Sarah V.
通讯作者：
Harding, Sarah V.
影响因子：
3.8
作者：
Currie BJ;Ward L;Cheng AC
通讯作者：
Cheng AC
DOI：
10.1073/pnas.1111020108
发表时间：
2011-10-11
影响因子：
11.1
作者：
Chantratita, Narisara;Rholl, Drew A.;Peacock, Sharon J.
通讯作者：
Peacock, Sharon J.