title: Gd(III)-labeled peptide nanofibers for reporting on biomaterial localization in vivo.
abstract: Bioactive supramolecular nanostructures are of great importance in regenerative medicine and the development of novel targeted therapies. In order to use supramolecular chemistry to design such nanostructures, it is extremely important to track their fate in vivo through the use of molecular imaging strategies. Peptide amphiphiles (PAs) are known to generate a wide array of supramolecular nanostructures, and there is extensive literature on their use in areas such as tissue regeneration and therapies for disease. We report here on a series of PA molecules based on the well-established β-sheet amino acid sequence V3A3 conjugated to macrocyclic Gd(III) labels for magnetic resonance imaging (MRI). These conjugates were shown to form cylindrical supramolecular assemblies using cryogenic transmission electron microscopy and small-angle X-ray scattering. Using nuclear magnetic relaxation dispersion analysis, we observed that thermal annealing of the nanostructures led to a decrease in water exchange lifetime (τm) of hundreds of nanoseconds only for molecules that self-assemble into nanofibers of high aspect ratio. We interpret this decrease to indicate more solvent exposure to the paramagnetic moiety on annealing, resulting in faster water exchange within angstroms of the macrocycle. We hypothesize that faster water exchange in the nanofiber-forming PAs arises from the dehydration and increase in packing density on annealing. Two of the self-assembling conjugates were selected for imaging PAs after intramuscular injections of the PA C16V3A3E3-NH2 in the tibialis anterior muscle of a murine model. Needle tracts were clearly discernible with MRI at 4 days postinjection. This work establishes Gd(III) macrocycle-conjugated peptide amphiphiles as effective tracking agents for peptide amphiphile materials in vivo over the timescale of days.
authors.affiliation: Departments of Chemistry, Materials Science and Engineering, and Institute for BioNanotechnology in Medicine, ‡Chemical and Biological Engineering, §Departments of Chemistry, Molecular Biosciences, Neurobiology and Radiology, and ⊥Center for Advanced Molecular Imaging, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Preslar
authors.forename: Giacomo
authors.initials: G
authors.lastname: Parigi
authors.forename: Mark T
authors.initials: MT
authors.lastname: McClendon
authors.forename: Samantha S
authors.initials: SS
authors.lastname: Sefick
authors.forename: Tyson J
authors.initials: TJ
authors.lastname: Moyer
authors.forename: Chad R
authors.initials: CR
authors.lastname: Haney
authors.forename: Emily A
authors.initials: EA
authors.lastname: Waters
authors.forename: Keith W
authors.initials: KW
authors.lastname: MacRenaris
authors.forename: Claudio
authors.initials: C
authors.lastname: Luchinat
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Stupp
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Meade
mesh_terms: D000818:Animals; D002122:Calcium Chloride / Q000737:chemistry; D003287:Contrast Media / Q000737:chemistry; D005682:Gadolinium / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008279:Magnetic Resonance Imaging; D051379:Mice; D008958:Models, Molecular; D009132:Muscles / Q000378:metabolism; D057139:Nanofibers / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D021381:Protein Transport
chemical_list: D003287:Contrast Media; D010455:Peptides; D005682:Gadolinium; D002122:Calcium Chloride