Structural Biophysics Laboratory, National Cancer Institute, PO Box B, Frederick, MD 21702-1201, USA.
Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9798-803. doi: 10.1073/pnas.1014598108. Epub 2011 May 31.
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.
人们投入了大量精力来开发针对肿瘤的纳米颗粒靶向递药系统。然而，由于纳米颗粒的尺寸均一性不足、重现性合成和制造困难、在肝脏中经常被高摄取、载体的全身毒性（特别是对于无机纳米颗粒）以及对肿瘤细胞的选择性不足，纳米颗粒的临床应用受到了阻碍。我们发现，经过适当修饰的跨膜蛋白跨膜结构域的合成类似物可以自组装成具有固有生物活性的非常均匀的球形纳米颗粒。自组装是由肽的结构转变驱动的，该肽在水溶液中主要采用β发夹构象，但在纳米颗粒与细胞膜自发融合时折叠成α螺旋。对应于 CXCR4 的第二个跨膜螺旋的 24 个氨基酸肽形成自组装颗粒，体外抑制 CXCR4 功能，并阻碍 CXCR4 依赖性肿瘤转移。此外，此类纳米颗粒可以包封疏水性药物，从而提供了一种具有双重生物活性的递药系统。
