Bio-Orthogonal Chemistry and Reloadable Biomaterial Enable Local Activation of Antibiotic Prodrugs and Enhance Treatments against Staphylococcus aureus Infections
Bio-Orthogonal Chemistry and Reloadable Biomaterial Enable Local Activation of Antibiotic Prodrugs and Enhance Treatments against Staphylococcus aureus Infections
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DOI：
10.1021/acscentsci.8b00344
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发表时间：
2018-12-26
影响因子：
18.2
通讯作者：
Oneto, Jose M. Mejia
中科院分区：
文献类型：
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作者：
Czuban, Magdalena;Srinivasan, Sangeetha;Oneto, Jose M. Mejia
抗生素的全身给药可引起严重的副作用，如肝和肾毒性，破坏健康的肠道细菌，以及多药耐药性。在这里，我们提出了一个生物正交化学为基础的策略，对当地的前药浓度和激活。该策略是基于反式环辛烯和四嗪之间的逆电子需求狄尔斯-阿尔德化学，并涉及一种生物材料，可以在局部部位浓缩和激活多剂量的全身性抗生素治疗前药。我们证明了一种生物材料，由四嗪修饰的藻酸盐水凝胶组成，在体外和体内激活多剂量的万古霉素和达托霉素前药是有效的。这些结果支持药物递送过程是独立的内源性环境标志物。这种方法有望提高治疗效果，减少抗生素对细菌感染的副作用。该平台具有广泛的可能应用范围，如伤口愈合，癌症和免疫治疗。
Systemic administration of antibiotics can cause severe side-effects such as liver and kidney toxicity, destruction of healthy gut bacteria, as well as multidrug resistance. Here, we present a bio-orthogonal chemistry-based strategy toward local prodrug concentration and activation. The strategy is based on the inverse electron-demand Diels-Alder chemistry between trans-cyclooctene and tetrazine and involves a biomaterial that can concentrate and activate multiple doses of systemic antibiotic therapy prodrugs at a local site. We demonstrate that a biomaterial, consisting of alginate hydrogel modified with tetrazine, is efficient at activating multiple doses of prodrugs of vancomycin and daptomycin in vitro as well as in vivo. These results support a drug delivery process that is independent of endogenous environmental markers. This approach is expected to improve therapeutic efficacy with decreased side-effects of antibiotics against bacterial infections. The platform has a wide scope of possible applications such as wound healing, and cancer and immunotherapy.