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.

中文翻译：

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生物正交化学和可重载生物材料能够局部激活抗生素前药并增强对金黄色葡萄球菌感染的治疗

抗生素的全身给药会导致严重的副作用，例如肝肾毒性、健康肠道细菌的破坏以及多重耐药性。在这里，我们提出了一种基于生物正交化学的局部前药浓度和激活策略。该策略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，涉及一种可以在局部部位浓缩和激活多剂量的全身抗生素治疗前药的生物材料。我们证明，由四嗪修饰的藻酸盐水凝胶组成的生物材料能够在体外和体内有效激活多剂量的万古霉素和达托霉素前药。这些结果支持独立于内源性环境标志物的药物递送过程。这种方法有望提高治疗效果，减少抗生素对抗细菌感染的副作用。该平台具有广泛的应用前景，例如伤口愈合、癌症和免疫治疗。