Tanihara M, Suzuki Y, Nishimura Y, Suzuki K, Kakimaru Y, Fukunishi Y
Graduate School of Materials Science, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan.
J Pharm Sci. 1999 May;88(5):510-4. doi: 10.1021/js980418j.
The aim of this study was to construct a novel drug delivery system suitable for controlled release of antibiotics. There is a need for devices that release antibiotics only during microbial infection, because prophylactic or prolonged use of antibiotics leads to serious problems, such as renal and liver toxicity and the emergence of drug-resistant bacteria (e.g., meticillin-resistant Staphylococcusaureus). We found previously that Staphylococcus aureus-infected wound fluid showed high thrombin-like activity; therefore, in this study we designed an antibiotic release system triggered by thrombin activity. We synthesized an insoluble polymer-drug conjugate in which gentamicin was bound to poly(vinyl alcohol) hydrogel through a newly developed thrombin-sensitive peptide linker. The conjugate released gentamicin when it was incubated with Staphylococcus aureus-infected wound fluid, with thrombin and leucine aminopeptidase, or with human plasma and Ca2+, whereas no biologically active gentamicin was released when the conjugate was incubated with noninfected wound fluid, with leucine aminopeptidase alone, with thrombin alone, or with plasma. Furthermore, the conjugate reduced the bacterial number in an animal model of Staphylococcus aureus infection. These results demonstrated that the conjugate has sufficient specificity and excellent potential as a stimulus-responsive, controlled drug release system.
本研究的目的是构建一种适用于抗生素控释的新型药物递送系统。需要仅在微生物感染期间释放抗生素的装置，因为预防性或长期使用抗生素会导致严重问题，如肾毒性和肝毒性以及耐药菌的出现（例如，耐甲氧西林金黄色葡萄球菌）。我们之前发现金黄色葡萄球菌感染的伤口液具有高凝血酶样活性；因此，在本研究中，我们设计了一种由凝血酶活性触发的抗生素释放系统。我们合成了一种不溶性聚合物 - 药物偶联物，其中庆大霉素通过新开发的凝血酶敏感肽接头与聚乙烯醇水凝胶结合。当该偶联物与金黄色葡萄球菌感染的伤口液、凝血酶和亮氨酸氨肽酶一起孵育，或与人血浆和Ca2 +一起孵育时，会释放庆大霉素，而当该偶联物与未感染的伤口液、单独的亮氨酸氨肽酶、单独的凝血酶或血浆一起孵育时，不会释放具有生物活性的庆大霉素。此外，该偶联物在金黄色葡萄球菌感染的动物模型中减少了细菌数量。这些结果表明，该偶联物具有足够的特异性，作为刺激响应性控释药物系统具有优异的潜力。
