Glycan targeted polymeric antibiotic prodrugs for alveolar macrophage infections
Glycan targeted polymeric antibiotic prodrugs for alveolar macrophage infections
复制标题
DOI：
10.1016/j.biomaterials.2018.10.017
复制
发表时间：
2019-03-01
期刊：
影响因子：
14
通讯作者：
Ratner, Daniel M.
中科院分区：
文献类型：
--
作者：
Chen, Jasmin;Su, Fang-Yi;Ratner, Daniel M.
肺泡巨噬细胞是肺固有免疫反应的主要吞噬效应细胞，矛盾的是，它也是病原体的诱人港湾。因此，兼性细胞内细菌，如图拉氏方济氏菌，可导致严重的全身疾病和败血症，与肺部感染相关的高发病率和死亡率。目前的临床治疗包括彻底的口服或静脉注射抗生素治疗，具有全身毒性和非靶点效应等局限性。肺部给药是一种很有希望的替代全身给药的方法，可以直接将抗生素输送到肺部。在这里，我们提出了合成的甘露糖化环丙沙星多聚体前药，用于有效的肺部递送、靶向和随后的肺泡巨噬细胞内化，我们在另一种同样致命的空气传播的弗朗西斯菌小鼠模型(F.novicida)中展示了对抗细胞内感染的显著改善。甘露糖化环丙沙星多聚前药预防性给药小鼠肺内时，存活率为50%。在同时感染的治疗方案中，小鼠的存活率提高到87.5%。在这两种情况下，免费的环丙沙星抗生素都无效。这种显著的抗菌效果差异表明，这个基于改善环丙沙星的物理化学、药代动力学和药效学特性的给药平台的影响通过我们的葡聚糖聚合物前药给药。这个模块化的平台为克服免费药物的限制和提高细胞内感染的治疗效果提供了一条途径。
Alveolar macrophages resident in the lung are prominent phagocytic effector cells of the pulmonary innate immune response, and paradoxically, are attractive harbors for pathogens. Consequently, facultative intracellular bacteria, such as Francisella tularensis, can cause severe systemic disease and sepsis, with high morbidity and mortality associated with pulmonary infection. Current clinical treatment, which involves exhaustive oral or intravenous antibiotic therapy, has limitations such as systemic toxicity and off-target effects. Pulmonary administration represents a promising alternative to systemic dosing for delivering antibiotics directly to the lung. Here, we present synthesized mannosylated ciprofloxacin polymeric prodrugs for efficient pulmonary delivery, targeting, and subsequent internalization by alveolar macrophages, We demonstrate significant improvement in efficacy against intracellular infections in an otherwise uniformly lethal airborne Francisella murine model (F. novicida). When administered to the lungs of mice in a prophylactic regimen, the mannosylated ciprofloxacin polymeric prodrugs led to 50% survival. In a treatment regimen that was concurrent with infection, the survival of mice increased to 87.5%. Free ciprofloxacin antibiotic was ineffective in both cases. This significant difference in antibacterial efficacy demonstrates the impact of this delivery platform based on improved physiochemical, pharmacokinetic, and pharmacodynamic properties of ciprofloxacin administered via our glycan polymeric prodrug. This modular platform provides a route for overcoming the limitations of free drug and increasing efficacy in treatment of intracellular infection.