Macrophage-targeted drugamers with enzyme-cleavable linkers deliver high intracellular drug dosing and sustained drug pharmacokinetics against alveolar pulmonary infections.
Macrophage-targeted drugamers with enzyme-cleavable linkers deliver high intracellular drug dosing and sustained drug pharmacokinetics against alveolar pulmonary infections.
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DOI：
10.1016/j.jconrel.2018.08.014
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发表时间：
2018-10-10
期刊：
影响因子：
--
通讯作者：
Stayton PS
中科院分区：
文献类型：
--
作者：
Su FY;Srinivasan S;Lee B;Chen J;Convertine AJ;West TE;Ratner DM;Skerrett SJ;Stayton PS
肺肺泡巨噬细胞（AM）的细胞内细菌感染仍然是抗菌治疗最具挑战性的设置之一。目前的全身性抗生素治疗不能给细胞内的细菌储存库提供持续的剂量，这就需要延长治疗方案。在这里，我们展示了一种新的细胞内酶可切割聚合物前药，具有量身定制的环丙沙星在肺部和AM中的释放谱。靶向聚合前药，被称为“药物玩家”，包含(1)亲水性甘露糖残基，以溶解抗生素货，靶向并增强AM摄取和细胞内递送，以及(2)酶可切割连锁化学，以提供高且持续的细胞内AM药物剂量。从抗生素环丙沙星衍生的前药单体，由细胞内蛋白酶可切割的二肽连接物或水解苯基酯连接物合成。采用RAFT聚合法将前药单体与甘露糖单体共聚，无需聚合后偶联步骤即可合成具有良好定义的药物。除了气管内给药后良好的体内安全性外，单剂量的药物玩家在肺和AMs中维持环丙沙星剂量超过最低抑制浓度（MIC）至少48小时。酶切疗法在AM中实现了持续环丙沙星10倍以上的增加，并保持了显著更高的全肺PK。以相同方式给药的环丙沙星显示出快速清除，半衰期约为30分钟。值得注意的是，吸入甘露糖靶向环丙沙星药物的游戏玩家在高度致命的肺炎兔吸虫病小鼠模型中获得了完全生存率（100%），而使用游离环丙沙星的小鼠的生存率为0%。这些发现证明了drugamer平台在设计细胞内药代动力学特征方面的多功能性，以及它在治疗肺部细胞内感染方面的强大治疗活性。
Intracellular bacterial infections localized to the lung alveolar macrophage (AM) remain one of the most challenging settings for antimicrobial therapy. Current systemic antibiotic treatment fails to deliver sustained doses to intracellular bacterial reservoirs, which necessitates prolonged treatment regimens. Herein, we demonstrate a new intracellular enzyme-cleavable polymeric prodrug with tailored ciprofloxacin release profiles in the lungs and AM. The targeted polymeric prodrug, termed “drugamers”, incorporates (1) hydrophilic mannose residues to solubilize the antibiotic cargo and to target and enhance AM uptake and intracellular delivery, and (2) enzyme-cleavable linkage chemistry to provide high and sustained intracellular AM drug dosing. Prodrug monomers, derived from the antibiotic ciprofloxacin, were synthesized with either an intracellular protease cleavable dipeptide linker or a hydrolytic phenyl ester linker. RAFT polymerization was used to copolymerize the prodrug monomers and mannose monomer to synthesize well-defined drugamers without requiring a post-polymerization conjugation step. In addition to favorable in vivo safety profiles following intratracheal administration, a single dose of the drugamers sustained ciprofloxacin dosing in lungs and AMs above the minimum inhibitory concentration (MIC) over at least a 48 h period. The enzyme-cleavable therapeutic achieved a greater than 10-fold increase in sustained ciprofloxacin in AM, and maintained a significantly higher whole lung PK as well. Ciprofloxacin dosed in identical fashion displayed rapid clearance with a half-life of approximately 30 min. Notably, inhalation of the mannose-targeted ciprofloxacin drugamers achieved full survival (100%) in a highly lethal mouse model of pneumonic tularemia, contrasted with 0% survival using free ciprofloxacin. These findings demonstrate the versatility of the drugamer platform for engineering the intracellular pharmacokinetic profiles and its strong therapeutic activity in treating pulmonary intracellular infections.
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DOI：
10.1016/j.jconrel.2008.10.004
发表时间：
2009-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Convertine AJ;Benoit DS;Duvall CL;Hoffman AS;Stayton PS
通讯作者：
Stayton PS
影响因子：
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影响因子：
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8.9
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影响因子：
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