CAS Key Laboratory of Soft Matter Chemistry and Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China.
J Am Chem Soc. 2012 Mar 7;134(9):4355-62. doi: 10.1021/ja211279u. Epub 2012 Feb 23.
We report a new strategy for differential delivery of antimicrobials to bacterial infection sites with a lipase-sensitive polymeric triple-layered nanogel (TLN) as the drug carrier. The TLN was synthesized by a convenient arm-first procedure using an amphiphilic diblock copolymer, namely, monomethoxy poly(ethylene glycol)-b-poly(ε-caprolactone), to initiate the ring-opening polymerization of the difunctional monomer 3-oxapentane-1,5-diyl bis(ethylene phosphate). The hydrophobic poly(ε-caprolactone) (PCL) segments collapsed and surrounded the polyphosphoester core, forming a hydrophobic and compact molecular fence in aqueous solution which prevented antibiotic release from the polyphosphoester core prior to reaching bacterial infection sites. However, once the TLN sensed the lipase-secreting bacteria, the PCL fence of the TLN degraded to release the antibiotic. Using Staphylococcus aureus (S. aureus) as the model bacterium and vancomycin as the model antimicrobial, we demonstrated that the TLN released almost all the encapsulated vancomycin within 24 h only in the presence of S. aureus, significantly inhibiting S. aureus growth. The TLN further delivered the drug into bacteria-infected cells and efficiently released the drug to kill intracellular bacteria. This technique can be generalized to selectively deliver a variety of antibiotics for the treatment of various infections caused by lipase-secreting bacteria and thus provides a new, safe, effective, and universal approach for the treatment of extracellular and intracellular bacterial infections.
我们报告了一种新的策略，即用脂肪酶敏感的聚合物三层纳米凝胶（TLN）作为药物载体，将抗生素递送到细菌感染部位。TLN 通过方便的臂首程序合成，使用两亲性嵌段共聚物，即单甲氧基聚（乙二醇）-b-聚（ε-己内酯），引发双官能单体 3-氧杂戊烷-1,5-二基双（乙烯磷酸酯）的开环聚合。疏水性聚（ε-己内酯）（PCL）段塌陷并包围聚磷酸酯核，在水溶液中形成疏水且紧凑的分子围栏，防止抗生素从聚磷酸酯核中释放出来，直到到达细菌感染部位。然而，一旦 TLN 感应到分泌脂肪酶的细菌，TLN 的 PCL 围栏就会降解，释放出抗生素。我们使用金黄色葡萄球菌（S. aureus）作为模型细菌和万古霉素作为模型抗生素，证明只有在存在 S. aureus 的情况下，TLN 在 24 小时内几乎释放了所有包裹的万古霉素，显著抑制了 S. aureus 的生长。TLN 进一步将药物递送到感染细菌的细胞中，并有效地释放药物杀死细胞内细菌。这项技术可以推广到选择性地递送各种抗生素，用于治疗由分泌脂肪酶的细菌引起的各种感染，从而为治疗细胞外和细胞内细菌感染提供了一种新的、安全、有效和通用的方法。
