Bioinformatics Institute (A*STAR), 30 Biopolis Str., #07-01 Matrix, 38671 Singapore, Singapore.
Silesian University of Technology, Faculty of Chemistry, Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Krzywoustego 4, 44-100 Gliwice, Poland.
J Colloid Interface Sci. 2021 Dec 15;604:670-679. doi: 10.1016/j.jcis.2021.07.023. Epub 2021 Jul 8.
Carbon nanotubes (CNTs) represent a novel platform for cellular delivery of therapeutic peptides. Chemically-functionalized CNTs may enhance peptide uptake by improving their membrane targeting properties.
Using coarse-grained (CG) molecular dynamics (MD) simulations, we investigate membrane interactions of a peptide conjugated to pristine and chemically-modified CNTs. As proof of principle, we focus on their interactions with PM2, an amphipathic stapled peptide that inhibits the E3 ubiquitin ligase HDM2 from negatively regulating the p53 tumor suppressor. CNT interaction with both simple planar lipid bilayers as well as spherical lipid vesicles was studied, the latter as a surrogate for curved cellular membranes.
Membrane permeation was rapid and spontaneous for both pristine and oxidized CNTs when unconjugated. This was slowed upon addition of a noncovalently attached peptide surface "sheath", which may be an effective way to slow CNT entry and avert membrane rupture. The CNT conjugates were observed to "desheath" their peptide layer at the bilayer interface upon insertion, leaving their cargo behind in the outer leaflet. This suggests that a synergy may exist to optimize CNT safety whilst enhancing the delivery efficiency of "hitchhiking" therapeutic molecules.
碳纳米管（CNTs）代表了一种新型的治疗性肽细胞内传递平台。化学功能化的 CNT 可以通过改善其膜靶向特性来增强肽的摄取。
我们使用粗粒（CG）分子动力学（MD）模拟，研究了与原始和化学修饰的 CNT 偶联的肽的膜相互作用。作为原理的证明，我们专注于它们与 PM2 的相互作用，PM2 是一种具有两亲性的订书肽，可抑制 E3 泛素连接酶 HDM2 对 p53 肿瘤抑制因子的负调节。研究了 CNT 与简单的平面脂质双层以及球形脂质囊泡的相互作用，后者是弯曲的细胞膜的替代物。
当未偶联时，原始和氧化的 CNT 都可以快速自发地穿过细胞膜。当添加非共价连接的肽表面“护套”时，这种速度会减慢，这可能是一种有效减缓 CNT 进入和避免膜破裂的方法。观察到 CNT 缀合物在插入时在双层界面处“脱壳”其肽层，将其货物留在外层中。这表明可能存在协同作用，以优化 CNT 的安全性，同时提高“搭便车”治疗分子的递送效率。
