title: Synergy between surface and core entrapped metals in a mixed manganese-gadolinium nanocolloid affords safer MR imaging of sparse biomarkers.
abstract: High-relaxivity T1-weighted (T1w) MR molecular imaging nanoparticles typically present high surface gadolinium payloads that can elicit significant acute complement activation (CA). The objective of this research was to develop a high T1w contrast nanoparticle with improved safety. We report the development, optimization, and characterization of a gadolinium-manganese hybrid nanocolloid (MnOL-Gd NC; 138±10 (Dav)/nm; PDI: 0.06; zeta: -27±2 mV). High r1 particulate relaxivity with minute additions of Gd-DOTA-lipid conjugate to the MnOL nanocolloid surface achieved an unexpected paramagnetic synergism. This hybrid MnOL-Gd NC provided optimal MR TSE signal intensity at 5 nM/voxel and lower levels consistent with the level expression anticipated for sparse biomarkers, such as neovascular integrins. MnOL NC produced optimal MR TSE signal intensity at 10 nM/voxel concentrations and above. Importantly, MnOL-Gd NC avoided acute CA in vitro and in vivo while retaining minimal transmetallation risk. From the clinical editor: The authors developed a gadolinium-manganese hybrid nanocolloid (MnOL-Gd NC) in this study. These were used as a high-relaxivity paramagnetic MR molecular imaging agent in experimental models. It was shown that MnOL-Gd NC could provide high T1w MR contrast for targeted imaging. As the level of gadolinium used was reduced, there was also reduced risk of systemic side effects from complement activation.
authors: Department of Radiology, the Fourth Hospital of Harbin Medical University Molecular Imaging Center of Harbin Medical University, Harbin, China; Division of Cardiology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Kezheng
authors: K
authors: Wang
authors: Division of Cardiology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Dipanjan
authors: D
authors: Pan
authors: Division of Cardiology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Anne H
authors: AH
authors: Schmieder
authors: Division of Cardiology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Angana
authors: A
authors: Senpan
authors: Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Dennis E
authors: DE
authors: Hourcade
authors: Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Christine T N
authors: CT
authors: Pham
authors: Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Lynne M
authors: LM
authors: Mitchell
authors: Division of Cardiology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Shelton D
authors: SD
authors: Caruthers
authors: Division of Cardiology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Grace
authors: G
authors: Cui
authors: Division of Cardiology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Samuel A
authors: SA
authors: Wickline
authors: Department of Radiology, the Fourth Hospital of Harbin Medical University Molecular Imaging Center of Harbin Medical University, Harbin, China. Electronic address: shenbzh@vip.sina.com.
authors: Baozhong
authors: B
authors: Shen
authors: Division of Cardiology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: greg.lanza@me.com.
authors: Gregory M
authors: GM
authors: Lanza
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D003102:Colloids; D003167:Complement Activation / Q000187:drug effects*; D003287:Contrast Media / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005682:Gadolinium / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008345:Manganese / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry
chemical_list: D015415:Biomarkers; D003102:Colloids; D003287:Contrast Media; D008345:Manganese; D005682:Gadolinium
keywords: Complement activation; Contrast media; Gadolinium; MRI; Manganese; Nanoparticle
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