Structural plasticity of a transmembrane peptide allows self-assembly into biologically active nanoparticles
Structural plasticity of a transmembrane peptide allows self-assembly into biologically active nanoparticles
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DOI：
10.1073/pnas.1014598108
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发表时间：
2011-06-14
影响因子：
11.1
通讯作者：
Tarasova, Nadya I.
中科院分区：
文献类型：
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作者：
Tarasov, Sergey G.;Gaponenko, Vadim;Tarasova, Nadya I.
针对肿瘤的纳米颗粒递送系统的开发已经投入了大量的努力。然而，纳米粒子的临床应用受到以下因素的阻碍：尺寸不够均匀，难以重复性合成和制造，肝脏经常高摄取，载体(特别是无机纳米粒子)的全身毒性，以及对肿瘤细胞的选择性不足。我们发现，经过适当修饰的膜蛋白跨膜结构域的合成类似物可以自组装成具有天然生物活性的非常均匀的球形纳米颗粒。自组装是由多肽的结构转变驱动的，在水溶液中主要采用β-发夹构象，但在纳米粒子与细胞膜自发融合时折叠成α-螺旋。与CXCR4的第二跨膜螺旋相对应的24个氨基酸的多肽形成自组装颗粒，在体外抑制CXCR4的功能，在体内阻止CXCR4依赖的肿瘤转移。此外，这种纳米颗粒可以包裹疏水药物，从而提供了一种具有双重生物活性的递送系统。
Significant efforts have been devoted to the development of nanoparticular delivering systems targeting tumors. However, clinical application of nanoparticles is hampered by insufficient size homogeneity, difficulties in reproducible synthesis and manufacturing, frequent high uptake in the liver, systemic toxicity of the carriers (particularly for inorganic nanoparticles), and insufficient selectivity for tumor cells. We have found that properly modified synthetic analogs of transmembrane domains of membrane proteins can self-assemble into remarkably uniform spherical nanoparticles with innate biological activity. Self-assembly is driven by a structural transition of the peptide that adopts predominantly a beta-hairpin conformation in aqueous solutions, but folds into an alpha-helix upon spontaneous fusion of the nanoparticles with cell membrane. A 24-amino acid peptide corresponding to the second transmembrane helix of the CXCR4 forms self-assembled particles that inhibit CXCR4 function in vitro and hamper CXCR4-dependent tumor metastasis in vivo. Furthermore, such nanoparticles can encapsulate hydrophobic drugs, thus providing a delivery system with the potential for dual biological activity.