Antibacterial Micelles with Vancomycin-Mediated Targeting and pH/Lipase-Triggered Release of Antibiotics
Antibacterial Micelles with Vancomycin-Mediated Targeting and pH/Lipase-Triggered Release of Antibiotics
复制标题
具有万古霉素介导靶向和 pH/脂肪酶触发抗生素释放的抗菌胶束
DOI：
10.1021/acsami.8b16092
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发表时间：
2018-10-31
影响因子：
9.5
通讯作者：
Li, Xiaohong
中科院分区：
文献类型：
--
作者：
Chen, Maohua;Xie, Songzhi;Li, Xiaohong
抗生素给药系统在提高疗效、降低脱靶毒性和抗生素耐药性方面发挥着重要作用。尽管细菌感染与肿瘤组织具有相似的病理生理学途径，但很少有递送系统实现细菌靶向和按需释放抗生素。在目前的研究中，两亲性聚（乙二醇）-聚（ε-己内酯）（PECL）共聚物与万古霉素（货车）作为靶向配体通过pH可裂解的腙键缀合，以获得胶束载体（Van-hyd-PECL）。其次，将环丙沙星（CIP）包封，得到平均粒径为77 nm、CIP负载量为4.5%的Van-hyd-PECL/Cip胶束。胶束表面的聚乙二醇壳和货车基团的延伸增强了细菌的血液循环和选择性识别。货车壳在酸性条件下的去屏蔽破坏了疏水/亲水平衡，导致胶束尺寸的增加，这促进了感染部位中过表达的脂肪酶对聚（ε-己内酯）的降解，并释放包封的CIP用于细菌破坏。胶束治疗提高了铜绿假单胞菌感染的小鼠的存活率，并减少了肺中的细菌负荷和肺泡损伤，与游离药物和没有接种货车部分的胶束相比。三种剂量的Van-hyd-PECL/Cip胶束进一步延长了动物的存活时间，减少了肺中的细菌定植，并且几乎恢复了正常的肺泡微结构。在这方面，这项研究已经证明了一种通过抗生素（货车）增强胶束的细菌靶向并在感染部位顺序触发抗生素（货车和CIP）释放的策略。
Antibiotic delivery systems play an important role in increasing the efficacy while reducing the off-target toxicity and antibiotic resistance. Though bacterial infections share pathophysiological pathways similar to tumor tissues, few delivery systems have achieved bacterial targeting and on-demand release of antibiotics. In the current study, amphiphilic poly(ethylene glycol)-poly(epsilon-caprolactone) (PECL) copolymers are conjugated with vancomycin (VAN) as targeting ligands via pH-cleavable hydrazone bonds to obtain micelle carriers (Van-hyd-PECL). Sub-sequently, ciprofloxacin (CIP) is encapsulated to obtain Van-hyd-PECL/Cip micelles with an average size of 77 nm and a CIP loading amount of 4.5%. The poly(ethylene glycol) shells and the extension of VAN moieties on the micelle surface enhance the blood circulation and selective recognition of bacteria. The deshielding of VAN shells under acidic conditions disrupts the hydrophobic/hydrophilic balance leading to an increase in micelle sizes, which facilitates the degradation of poly(epsilon-caprolactone) by lipase overexpressed in the infection site and the release of encapsulated CIP for bacterial destruction. The micelle treatment has improved the survival of Pseudomonas aeruginosa-infected mice and reduced the bacterial burdens and alveolar injuries in lungs, compared with free drugs and micelles without inoculation of VAN moieties. Three doses of Van-hyd-PECL/Cip micelles further extend the animal survival, decrease the bacterial colonization in lungs, and almost restore the normal alveolar microstructure. In this regard, this study has demonstrated a strategy to enhance the bacterial targeting of micelles via an antibiotic (VAN) and to sequentially trigger the release of antibiotics (VAN and CIP) at the infection site.