期刊
ACS APPLIED MATERIALS & INTERFACES
卷 10, 期 43, 页码 36814-36823出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.8b16092
关键词
antibiotics-loaded micelle; vancomycin-mediated targeting; acid-liable deshielding; lipase-sensitive release; in vivo antibacterial efficacy
资金
- National Natural Science Foundation of China [31771034, 31470922]
- Key Research and Development Program of Sichuan Province [2018SZ0348]
- Doctoral Innovation Fund Program of Southwest Jiaotong University
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.
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