title: Gadolinium-Functionalized Peptide Amphiphile Micelles for Multimodal Imaging of Atherosclerotic Lesions.
abstract: The leading causes of morbidity and mortality globally are cardiovascular diseases, and nanomedicine can provide many improvements including disease-specific targeting, early detection, and local delivery of diagnostic agents. To this end, we designed fibrin-binding, peptide amphiphile micelles (PAMs), achieved by incorporating the targeting peptide cysteine-arginine-glutamic acid-lysine-alanine (CREKA), with two types of amphiphilic molecules containing the gadoliniuim (Gd) chelator diethylenetriaminepentaacetic acid (DTPA), DTPA-bis(stearylamide)(Gd), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[(poly(ethylene glycol) (PEG))-2000]-DTPA(Gd) (DSPE-PEG2000-DTPA(Gd)). The material characteristics of the resulting nanoparticle diagnostic probes, clot-binding properties in vitro, and contrast enhancement and safety for dual, optical imaging-magnetic resonance imaging (MRI) were evaluated in the atherosclerotic mouse model. Transmission electron micrographs showed a homogenous population of spherical micelles for formulations containing DSPE-PEG2000-DTPA(Gd), whereas both spherical and cylindrical micelles were formed upon mixing DTPA-BSA(Gd) and CREKA amphiphiles. Clot-binding assays confirmed DSPE-PEG2000-DTPA(Gd)-based CREKA micelles targeted clots over 8-fold higher than nontargeting (NT) counterpart micelles, whereas no difference was found between CREKA and NT, DTPA-BSA(Gd) micelles. However, in vivo MRI and optical imaging studies of the aortas and hearts showed fibrin specificity was conferred by the peptide ligand without much difference between the nanoparticle formulations or shapes. Biodistribution studies confirmed that all micelles were cleared through both the reticuloendothelial system and renal clearance, and histology showed no signs of necrosis. In summary, these studies demonstrate the successful synthesis, and the molecular imaging capabilities of two types of CREKA-Gd PAMs for atherosclerosis. Moreover, we demonstrate the differences in micelle formulations and shapes and their outcomes in vitro versus in vivo for site-specific, diagnostic strategies, and provide the groundwork for the detection of thrombosis via contrast-enhancing agents and concurrent therapeutic delivery for theranostic applications.
authors.affiliation: Institute for Molecular Engineering, University of Chicago , 5747 South Ellis Avenue, Chicago, Illinois, 60637, United States.
authors.forename: Sang Pil
authors.initials: SP
authors.lastname: Yoo
authors.affiliation: Department of Radiology, University of Chicago , 5841 South Maryland Avenue, MC2026, Chicago, Illinois 60637, United States.
authors.forename: Federico
authors.initials: F
authors.lastname: Pineda
authors.affiliation: Institute for Molecular Engineering, University of Chicago , 5747 South Ellis Avenue, Chicago, Illinois, 60637, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Department of Chemistry, University of Chicago , 929 E. 57th Street, Chicago, Illinois 60637, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Poon
authors.affiliation: Institute for Molecular Engineering, University of Chicago , 5747 South Ellis Avenue, Chicago, Illinois, 60637, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tirrell
authors.affiliation: Institute for Molecular Engineering, University of Chicago , 5747 South Ellis Avenue, Chicago, Illinois, 60637, United States.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Chung