Koch Institute for Integrative Cancer Research and Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, 92093, USA.
Adv Mater. 2017 Sep;29(35). doi: 10.1002/adma.201701527. Epub 2017 Jul 12.
There is an urgent need for new materials to treat bacterial infections. In order to improve antibacterial delivery, an anti-infective nanomaterial is developed that utilizes two strategies for localization: i) a biodegradable nanoparticle carrier to localize therapeutics within the tissue, and ii) a novel tandem peptide cargo to localize payload to bacterial membranes. First, a library of antibacterial peptides is screened that combines a membrane-localizing peptide with a toxic peptide cargo and discovers a tandem peptide that displays synergy between the two domains and is able to kill Pseudomonas aeruginosa at sub-micromolar concentrations. To apply this material to the lung, the tandem peptide is loaded into porous silicon nanoparticles (pSiNPs). Charged peptide payloads are loaded into the pores of the pSiNP at ≈30% mass loading and ≈90% loading efficiency using phosphonate surface chemistry. When delivered to the lungs of mice, this anti-infective nanomaterial exhibits improved safety profiles over free peptides. Moreover, treatment of a lung infection of P. aeruginosa results in a large reduction in bacterial numbers and markedly improves survival compared to untreated mice. Collectively, this study presents the selection of a bifunctional peptide-based anti-infective agent and its delivery via biodegradable nanoparticles for application to an animal model of lung infection.
目前急需新的材料来治疗细菌感染。为了提高抗菌药物的递送效果，开发了一种抗感染纳米材料，该材料利用了两种定位策略：i）可生物降解的纳米颗粒载体将治疗剂定位于组织内，ii）新型串联肽货物将有效载荷定位于细菌膜上。首先，筛选了一个抗菌肽文库，该文库将一个膜定位肽与毒性肽货物结合在一起，并发现了一种串联肽，该肽在两个结构域之间显示出协同作用，并且能够以亚微摩尔浓度杀死铜绿假单胞菌。为了将该材料应用于肺部，将串联肽载入多孔硅纳米颗粒（pSiNPs）中。使用膦酸酯表面化学，将带电荷的肽有效载荷以约 30%的质量负载和约 90%的负载效率载入 pSiNP 的孔中。当将这种抗感染纳米材料递送至小鼠肺部时，与游离肽相比，其安全性显著提高。此外，与未治疗的小鼠相比，铜绿假单胞菌肺部感染的治疗可显著降低细菌数量并明显提高存活率。总之，本研究提出了一种基于双功能肽的抗感染剂的选择及其通过可生物降解的纳米颗粒进行递送至动物肺部感染模型的应用。
