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 ondemand release of antibiotics. In the current study, amphiphilic poly(ethylene glycol)−poly(ε-caprolactone) (PECL) copolymers are conjugated with vancomycin (VAN) as targeting ligands via pH-cleavable hydrazone bonds to obtain micelle carriers (Van-hyd-PECL). Subsequently, 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(ε-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.

The maintenance of hepatocyte phenotype and functions remains as a great challenge in the generation of functional liver tissue and in vitro model for drug metabolism studies. The use of hepatocyte coculture systems plays essential roles in the establishment of cell-cell and cell-extracellular matrix communications similar to native liver tissues. In the current study, micropatterned electrospun fibrous mats were created to load hepatocytes, fibroblasts, and endothelial cells (ECs), which were precisely assembled to establish their spatially controlled coculture for mimicking the in vivo structure of hepatic lobules. Hepatocytes formed compact polyhedral spheroids with an average diameter of 80-100 μm, reorganized actin filaments in the cell-cell contact regions, and well-developed bile canaliculi. Compared with hepatocytes cultured alone, the coculture of hepatocytes with either fibroblasts or ECs led to significantly higher albumin secretion, urea synthesis and cytochrome P-450 expression, which were dramatically improved by the coculture of hepatocytes with both fibroblasts and ECs. The cocultured ECs well spread on patterned regions with little organized filamentous actin, and significantly higher densities and deeper penetration into patterned scaffolds were determined for ECs after coculture with fibroblasts and hepatocytes compared with those after cultured alone or coculture with either fibroblasts or hepatocytes. A Matrigel overlay assay showed that the capabilities of ECs to form capillary tubes were significantly enhanced by micropatterned coculture with fibroblasts and hepatocytes. Thus, the coculture of hepatocytes, fibroblasts, and ECs on micropatterned fibrous mats helps both hepatocytes in the maintenance of hepatic functions and ECs in the formation of capillary-like structures. It is suggested that the micropatterned coculture model described here not only provides functional hepatic tissues for predictions of drug metabolism profiles, but also will enable investigations on more complex and physiological cell-cell communications.

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Biofilms formed by pathogenic bacteria are one of the most important reasons for multidrug resistance.