Tailored biological retention and efficient clearance of pegylated ultra-small MnO nanoparticles as positive MRI contrast agents for molecular imaging

Abstract

A majority of MRI procedures requiring intravascular injections of contrast agents are performed with paramagnetic chelates. Such products induce vascular signal enhancement and they are rapidly excreted by the kidneys. Unfortunately, each chelate is made of only one paramagnetic ion, which, taken individually, has a limited impact on the MRI signal. In fact, the detection of molecular events in the nanomolar range using T 1 -weighted MRI sequences requires the design of ultra-small particles containing hundreds of paramagnetic ions per contrast agent unit. Ultra-small nanoparticles of manganese oxide (MnO, 6-8 nm diameter) have been developed and proposed as an efficient and at least 1000Â more sensitive "positive" MRI contrast agent. However no evidence has been found until now that an adequate surface treatment of these particles could maintain their strong blood signal enhancement, while allowing their rapid and efficient excretion by the kidneys or by the hepatobiliairy pathway. Indeed, the sequestration of MnO particles by the reticuloendothelial system followed by strong uptake in the liver and in the spleen could potentially lead to Mn 2+ -induced toxicity effects. For ultra-small MnO particles to be applied in the clinics, it is necessary to develop coatings that also enable their efficient excretion within hours. This study demonstrates for the first time the possibility to use MnO particles as T 1 vascular contrast agents, while enabling the excretion of >70% of all the Mn injected doses after 48 h. For this, small, biocompatible and highly hydrophilic pegylated bis-phosphonate dendrons (PDns) were grafted on MnO particles to confer colloidal stability, relaxometric performance, and fast excretion capacity. The chemical and colloidal stability of MnO@PDn particles were confirmed by XPS, FTIR and DLS. The relaxometric performance of MnO@PDns as "positive" MRI contrast agents was assessed (r 1 ¼ 4.4 mM À1 s À1 , r 2 /r 1 ¼ 8.6; 1.41 T and 37 C). Mice were injected with 1.21 mg Mn per kg (22 mmol Mn per kg), and scanned in MRI up to 48 h.The concentration of Mn in key organs was precisely measured by neutron activation analysis and confirmed, with MRI, the possibility to avoid RES nanoparticle sequestration through the use of phosphonate dendrons. Due to the fast kidney and hepatobiliairy clearance of MnO particles conferred by PDns, MnO nanoparticles can now be considered for promising applications in T 1 -weighted MRI applications requiring less toxic although highly sensitive "positive" molecular contrast agents.

Simultaneously electrochemical exfoliation and functionalization of graphene nanosheets: Multifunctional reinforcements in thermal, flame‐retardant, and mechanical properties of polyacrylonitrile composite fibers

“…In the P 2p spectrum of FGNS, one symmetrical peak was observed at 132.2 eV, corresponding to the P 5+ in organophosphonate groups . Meanwhile, the P 2p band shifted from 134.0 eV for DGNS to 132.2 eV for FGNS, confirming the complexation between DTPMP and Fe 3+ . As shown in Figure C, the O 1s spectrum could be deconvoluted into three peaks at 530.4, 531.4, and 532.5 eV, corresponding to the PO, P─O─Fe, and C─OH, respectively .…”

Effect of the Functionalization Process on the Colloidal, Magnetic Resonance Imaging, and Bioelimination Properties of Mono‐ or Bisphosphonate‐Anchored Dendronized Iron Oxide Nanoparticles

“…We already reported the synthesis of the two dendron molecules. [13,42,43] The structures of the dendrons D2 and D2-2P are presented in Figure 1.…”

Modulation of Relaxivity, Suspension Stability, and Biodistribution of Dendronized Iron Oxide Nanoparticles as a Function of the Organic Shell Design

“…These results confirm a rapid elimination of dendronized NPs, as already noticed in earlier studies. [10a,b], No fluorescence is recorded in the subcutaneous tumor too.…”