title: Structural plasticity of a transmembrane peptide allows self-assembly into biologically active nanoparticles.
abstract: 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.
authors.affiliation: Structural Biophysics Laboratory, National Cancer Institute, PO Box B, Frederick, MD 21702-1201, USA. Nadya.Tarasova@nih.gov
authors.forename: Sergey G
authors.initials: SG
authors.lastname: Tarasov
authors.forename: Vadim
authors.initials: V
authors.lastname: Gaponenko
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Chen
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: Marzena A
authors.initials: MA
authors.lastname: Dyba
authors.forename: Sriram
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Youngshim
authors.initials: Y
authors.lastname: Lee
authors.forename: Christopher
authors.initials: C
authors.lastname: Michejda
authors.forename: Nadya I
authors.initials: NI
authors.lastname: Tarasova
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: C527276:CXCR4 protein, human; D008565:Membrane Proteins; D010455:Peptides; D019718:Receptors, CXCR4