title: Biocompatible nanotemplate-engineered nanoparticles containing gadolinium: stability and relaxivity of a potential MRI contrast agent.
abstract: In this article, we use a nanotemplate engineering approach to prepare biodegradable nanoparticles composed of FDA-approved materials and possessing accessible gadolinium (Gd) atoms and demonstrate their potential as a Magnetic Resonance Imaging (MRI) contrast agent. Nanoparticles containing dimyristoyl phosphoethanolamine diethylene triamine penta acetate (PE-DTPA) were prepared using 3.5 mg of Brij 78, 2.0 mg of emulsifying wax and 0.5 mg of PE-DTPA/ml from a microemulsion precursor. After the addition of GdCl3, the presence of Gd on the surface of nanoparticles was characterized using inductively coupled plasma atomic emission spectroscopy and Scanning Transmission Electron Microscopy (STEM). The in vitro relaxivities of the PE-DTPA-Gd nanoparticles in different media were assessed at different field strengths. The conditional stability constant of Gd binding to the nanoparticles was determined using competitive spectrophotometric titration. Transmetallation kinetics of the gadolinium ion from PE-DTPA-Gd nanoparticles with zinc as the competing ionic was measured using the relaxivity evolution method. Nanoparticles with a diameter of approximately 130 nm possessing surface chelating functions were made from GRAS (Generally Regarded As Safe) materials. STEM demonstrated the uniform distribution of Gd3+ on the surface of the nanoparticles. The thermodynamic binding constant for Gd3+ to the nanoparticles was approximately 10(18) M(-1) and transmetallation studies with Zn2+ yielded kinetic constants K1 and K(-1) of 0.033 and 0.022 1/h, respectively, with an equilibrium constant of 1.5. A payload of approximately 10(5) Gd/nanoparticle was achieved; enhanced relaxivities were observed, including a pH dependence of the transverse relaxivity (r2). Nanoparticles composed of materials that have been demonstrated to be hemocompatible and enzymatically metabolized and possessing accessible Gd ions on their surface induce relaxivities in the bulk water signal that make them potentially useful as next-generation MRI tumor contrast enhancement agents.
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington 40536-0082, USA.
authors.forename: Donghua
authors.initials: D
authors.lastname: Zhu
authors.forename: R D
authors.initials: RD
authors.lastname: White
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hardy
authors.forename: Natthida
authors.initials: N
authors.lastname: Weerapreeyakul
authors.forename: Khaetthareeya
authors.initials: K
authors.lastname: Sutthanut
authors.forename: Michael
authors.initials: M
authors.lastname: Jay
mesh_terms: D001665:Binding Sites; D001672:Biocompatible Materials / Q000737:chemistry*; D003287:Contrast Media / Q000737:chemistry*; D004355:Drug Stability; D005682:Gadolinium / Q000737:chemistry*; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods; D008280:Magnetics; D008422:Materials Testing; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure*; D019047:Phantoms, Imaging; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013499:Surface Properties
chemical_list: D001672:Biocompatible Materials; D003287:Contrast Media; D005682:Gadolinium