T1-positive Contrast Agent Research Articles

Chitosan‐Based Nanogels Containing Ln3+ Chelates (Ln=Gd, Dy) as T1 and T2 MRI Probes

AbstractNovel nanogels, characterized by high stability and incorporating macrocyclic chelates of Gd(III) and Dy(III), were synthesized and assessed for their effectiveness as T1 and T2 relaxation agents, respectively. In this specific design, we employed octacoordinated bifunctional Gd‐1,7‐DOTAGA2 chelate to cross‐link chitosan chains. The results revealed that the sample exhibited a relaxivity value at clinical magnetic field strengths (1.5 T), approximately seven times higher than that of currently available clinical contrast agents and good MRI contrast efficacy at both 7.1 and 1 T. Furthermore, the nanogel displayed excellent stability in biological fluids, with no discernible interactions with serum biomolecules and no release of metal. In addition to Gd(III)‐based probes commonly used as T1 positive contrast agents, the nanogel with the corresponding Dy‐1,7‐DOTAGA2 chelate was prepared to explore its potential as a T2 MRI probe. Dy‐based nanogel demonstrated notably elevated transverse relaxivity values compared to the free chelate at high magnetic fields (>3 T) and significant T2 MRI contrast at 7.1 T, a capability often lacking when employing an equivalent concentration of a low‐molecular‐weight Dy(III) complex. The characterization of paramagnetic complexes was completed through the measurement of 1H NMRD profiles and 17O NMR data.

In vivo MRI evaluation of anterograde manganese transport along the visual pathway following whole eye transplantation

Background: Since adult mammalian retinal ganglion cells cannot regenerate after injury, we have recently established a whole-eye transplantation (WET) rat model that provides an intact optical system to investigate potential surgical restoration of irreversible vision loss. However, it remains to be elucidated whether physiological axoplasmic transport exists in the transplanted visual pathway.New Method: We developed an in vivo imaging model system to assess WET integration using manganese-enhanced magnetic resonance imaging (MEMRI) in rats.Since Mn2+ is a calcium analogue and an active T1-positive contrast agent, the levels of anterograde manganese transport can be evaluated in the visual pathways upon intravitreal Mn2+ administration into both native and transplanted eyes.Results: No significant intraocular pressure difference was found between native and transplanted eyes, whereas comparable manganese enhancement was observed between native and transplanted intraorbital optic nerves, suggesting the presence of anterograde manganese transport after WET. No enhancement was detected across the coaptation site in the higher visual areas of the recipient brain.Comparison with Existing Methods: Existing imaging methods to assess WET focus on either the eye or local optic nerve segments without direct visualization and longitudinal quantification of physiological transport along the transplanted visual pathway, hence the development of in vivo MEMRI.Conclusion: Our established imaging platform indicated that essential physiological transport exists in the transplanted optic nerve after WET. As neuroregenerative approaches are being developed to connect the transplanted eye to the recipient’s brain, in vivo MEMRI is well-suited to guide strategies for successful WET integration for vision restoration.

Iron (III)-Quercetin Complex: Synthesis, Physicochemical Characterization, and MRI Cell Tracking toward Potential Applications in Regenerative Medicine.

In cell therapy, contrast agents T1 and T2 are both needed for the labeling and tracking of transplanted stem cells over extended periods of time through magnetic resonance imaging (MRI). Importantly, the metal-quercetin complex via coordination chemistry has been studied extensively for biomedical applications, such as anticancer therapies and imaging probes. Herein, we report on the synthesis, characterization, and labeling of the iron (III)-quercetin complex, “IronQ,” in circulating proangiogenic cells (CACs) and also explore tracking via the use of a clinical 1.5 Tesla (T) MRI scanner. Moreover, IronQ had a paramagnetic T1 positive contrast agent property with a saturation magnetization of 0.155 emu/g at 1.0 T and longitudinal relaxivity (r1) values of 2.29 and 3.70 mM−1s−1 at 1.5 T for water and human plasma, respectively. Surprisingly, IronQ was able to promote CAC growth in conventional cell culture systems without the addition of specific growth factors. Increasing dosages of IronQ from 0 to 200 μg/mL led to higher CAC uptake, and maximum labeling time was achieved in 10 days. The accumulated IronQ in CACs was measured by two methodologies, an inductively coupled plasma optical emission spectrometry (ICP-EOS) and T1-weighted MRI. In our research, we confirmed that IronQ has excellent dual functions with the use of an imaging probe for MRI. IronQ can also act as a stimulating agent by favoring circulating proangiogenic cell differentiation. Optimistically, IronQ is considered beneficial for alternative labeling and in the tracking of circulation proangiogenic cells and/or other stem cells in applications of cell therapy through noninvasive magnetic resonance imaging in both preclinical and clinical settings.

Targeted MR Imaging Adopting T1-Weighted Ultra-Small Iron Oxide Nanoparticles for Early Hepatocellular Carcinoma: An in vitro and in vivo Study.

Objective The purpose of this study was to produce an arginylglycylaspartic acid (RGD) peptide-modified ultra-small superparamagnetic iron oxide (Fe3O4) nanoparticles (NPs) for targeted magnetic resonance (MR) imaging of hepatocellular carcinoma (HCC) cells and verify its utility as a T1 positive MRI imaging contrast agent in vitroand in vivo.Methods The carboxylated Fe3O4 NPs stabilized with sodium citrate were conjugated with polyethylene glycol (PEG)-linked RGD nanoparticles to form a novel target contrast agent Fe3O4-PEG-RGD NPs. The specificity of Fe3O4-PEG-RGD to bind RGD receptor was investigated in vitro by HepG2 cellular uptake and cell MR imaging, and in vivo by MR imaging of subcutaneous HepG2 tumors of nude mice.Results The formed Fe3O4-PEG-RGD NPs displayed good biocompatibility, and the ultrahigh r1 relaxivity was 1.37 mM -1S -1. The synthesized Fe3O4-PEG-RGD NPs were demonstrated spherical-like with an approximate diameter of 2.7 nm in similar size. The targeting effect to HepG2 cells was confirmed by in vitro cellular uptake and cell MR imaging. The in vivo MR imaging of nude mice demonstrated that the MR signal intensity enhancement of HepG2 tumor in Fe3O4-PEG-RGD NPs treated mice was significantly higher than in mice treated with non-targeted Fe3O4-mPEG NPs at the same post-administration time point. Conclusion The results indicate that the Fe3O4-PEG-RGD particles have potential utility as T1 positive contrast agent in targeted MR imaging.

Folic acid-conjugated GdPO4:Tb3+@SiO2 Nanoprobe for folate receptor-targeted optical and magnetic resonance bi-modal imaging

Both fluorescent and magnetic nanoprobes have great potential applications for diagnostics and therapy. In the present work, a folic acid-conjugated and silica-modified GdPO4:Tb3+ (GdPO4:Tb3+@SiO2-FA) dual nanoprobe was strategically designed and synthesized for the targeted dual-modality optical and magnetic resonance (MR) imaging via a facile aqueous method. Their structural, optical, and magnetic properties were determined using transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR), ultraviolet-visible spectra (UV-Vis), photoluminescence (PL), and superconducting quantum interference device (SQUID). These results indicated that GdPO4:Tb3+@SiO2-FA were uniform monodisperse core-shell structured nanorods (NRs) with an average length of ~200 nm and an average width of ~25 nm. The paramagnetic property of the synthesized GdPO4:Tb3+@SiO2-FA NRs was confirmed with its linear hysteresis plot (M-H). In addition, the NRs displayed an obvious T1-weighted effect and thus it could potentially serve as a T1-positive contrast agent. The NRs emitted green lights due to the 5D4 → 7F5 transition of the Tb3+. The in vitro assays with NCI-H460 lung cancer cells and human embryonic kidney cell line 293T cells indicated that the GdPO4:Tb3+@SiO2-FA nanoprobe could specifically bind the cells bearing folate receptors (FR). The MTT assay of the NRs revealed that its cytotoxicity was very low. Further in vivo MRI experiments distinctively depict enhanced anatomical features in a xenograft tumor. These results suggest that the GdPO4:Tb3+@SiO2-FA NPs have excellent imaging and cell-targeting abilities for the folate receptor-targeted dual-modality optical and MR imaging and can be potentially used as the nanoprobe for bioimaging.

In depth analysis of apoptosis induced by silica coated manganese oxide nanoparticles in vitro

Manganese oxide nanoparticles (MnO NPs) have been regarded as a new class of T1-positive contrast agents. The cytotoxicity of silica coated MnO NPs (MnO@SiO2 NPs) was investigated in human cervical carcinoma cells (HeLa) and mouse fibroblast cells (L929). The changes of cell viability, cell morphology, cellular oxidative stress, mitochondrial membrane potential and cell cycle induced by MnO@SiO2 NPs were evaluated. Compared to HeLa cells, L929 cells showed lower cell viability, more strongly response to oxidative stress and higher percentage in the G2/M phase of cell cycle. The appearance of sub-G1 peak, double staining with Annexin V-FITC/PI and the increase of Caspase-3 activity further confirmed apoptosis should be the major form of cell death. Moreover, the apoptotic pathway was clarified as follows. Firstly, reactive oxygen species (ROS) is generated induced by MnO@SiO2 NPs, then p53 is activated followed by an increase in the bax and a decrease in the bcl-2, ultimately leading to G2/M phase arrest, increasing the activity of caspase-3 and inducing apoptosis.

Chain Length Effect of the Multidentate Block Copolymer Strategy to Stabilize Ultrasmall Fe3O4Nanoparticles

A multidentate block copolymer (MDBC) strategy to stabilize ultrasmall superparamagnetic iron oxide nanoparticles (USNPs) as biocompatible T1-positive contrast agents for magnetic resonance imaging (MRI) is explored. The MDBC is designed with a poly(methacrylic acid) (PMAA) block having pendant carboxylates as multidentate anchoring groups and a hydrophilic polymethacrylate block having pendant oligo(ethylene oxide) chains (POEOMA). A series of multifunctional MDBCs with different chain lengths of POEOMA and PMAA blocks were synthesized by atom transfer radical polymerization and subsequent hydrolytic cleavage. The resultant aqueous MDBC/USNP colloids fabricated through a ligand-exchange process were characterized to investigate the effect of chain lengths of POEOMA-b-PMAA copolymers on size, morphology, and colloidal stability as well as relaxometric properties and in vitro MRI performance. The results suggest that the optimal design of chain lengths of both anchoring and hydrophilic blocks is required for enhanced colloidal stability under biologically relevant conditions as well as effective T1-weighted contrast enhancement.

Multidentate block-copolymer-stabilized ultrasmall superparamagnetic iron oxide nanoparticles with enhanced colloidal stability for magnetic resonance imaging.

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) with diameters <5 nm hold great promise as T1-positive contrast agents for in vivo magnetic resonance imaging. However, control of the surface chemistry of USPIOs to ensure individual colloidal USPIOs with a ligand monolayer and to impart biocompatibility and enhanced colloidal stability is essential for successful clinical applications. Herein, an effective and versatile strategy enabling the development of aqueous colloidal USPIOs stabilized with well-defined multidentate block copolymers (MDBCs) is reported. The multifunctional MDBCs are designed to consist of an anchoring block possessing pendant carboxylates as multidentate anchoring groups strongly bound to USPIO surfaces and a hydrophilic block having pendant hydrophilic oligo(ethylene oxide) chains to confer water dispersibility and biocompatibility. The surface of USPIOs is saturated with multiple anchoring groups of MDBCs, thus exhibiting excellent long-term colloidal stability as well as enhanced colloidal stability at biologically relevant electrolyte, pH, and temperature conditions. Furthermore, relaxometric properties as well as in vitro and in vivo MR imaging results demonstrate that the MDBC-stabilized USPIO colloids hold great potential as an effective T1 contrast agent.

Ultrasmall Manganese Ferrite Nanoparticles as Positive Contrast Agent for Magnetic Resonance Imaging

Reducing ferromagnetic particle size is an important strategy to improve their positive effect on imaging through the suppression of their negative effect, demonstrated by ultrasmall manganese ferrite nanoparticles prepared from an environmentally-friendly aqueous route. These ultrasmall particles exhibit pronounced paramagnetic characteristics and nontoxicity, making them efficient T1-positive contrast agent and manganese contrast agents for manganese enhanced MRI.

Multifunctional NaYF4:Yb/Er/Gd nanocrystal decorated SiO2 nanotubes for anti-cancer drug delivery and dual modal imaging

Silica nanotubes (SNTs) functionalized with magnetic and up-conversion luminescent (UCL) NaYF4:Yb/Er/Gd nanocrystals (NCs) (denoted as MUCNCs@SNTs) have been prepared by single-nozzle electrospinning based on a phase separation effect without any templates. Monodisperse and hydrophilic cubic α-NaYF4:Yb/Er/Gd NCs decorated with polyethyleneimine (PEI) were fabricated in a facile hydrothermal route. Then, the Gd3+-doped α-NaYF4:Yb/Er NCs were dispersed into the electrospinning precursor solution containing polyvinylpyrrolidone (PVP) and tetraethylorthosilicate (TEOS), followed by the preparation of precursor nanotubes via electrospinning process. Finally, after annealing at 600 °C, pure MUCNCs@SNTs were obtained. The biocompatibility test on L929 fibroblast cells using MTT assay reveals low cytotoxicity of the composites. Doxorubicin hydrochloride (DOX), a typical anti-cancer drug, was introduced into MUCNCs@SNTs to evaluate the loading and sustained release behaviours. The composite carriers provide pH-dependent drug release behaviour owing to abundant Si–OH active bonds of silica and its interactions with DOX. The in vitro cytotoxicity and cell uptake behaviour of the MUCNCs@SNTs for HeLa cells were evaluated. For in vitro magnetic resonance imaging (MRI), the composites show the promising spin lattice relaxation time (T1) weighted effect and could potentially apply as a T1-positive contrast agent. In addition, the composites show near-infrared UC luminescence and were successfully applied in the bioimaging of HeLa cells. Considering the good biocompatibility, high drug releasing content and pH-dependent drug release of the materials, these magnetic and luminescent composite nanotubes have potential applications in drug sustained release and magnetic resonance/UC luminescence modality imaging.

A new type of silica-coated Gd2(CO3)3:Tb nanoparticle as a bifunctional agent for magnetic resonance imaging and fluorescent imaging

We report a new type of dual modal nanoprobe to combine optical and magnetic resonance bioimaging. A simple reverse microemulsion method and coating process was introduced to synthesize silica-coated Gd2(CO3)3:Tb nanoparticles, and the particles, with an average diameter of 16 nm, can be dispersed in water. As in vitro cell imaging of the nanoprobe shows, the nanoprobe accomplishes delivery to gastric SGC7901 cancer cells successfully in a short time, as well as NCI-H460 lung cancer cells. Furthermore, it presents no evidence of cell toxicity or adverse affect on kidney cell growth under high dose, which makes the nanoprobe’s optical bioimaging modality available. The possibility of using the nanoprobe for magnetic resonance imaging is also demonstrated, and the nanoprobe displays a clear T1-weighted effect and could potentially serve as a bimodal T1-positive contrast agent. Therefore, the new nanoprobe formed from carbonate nanoprobe doped with rare earth ions provides the dual modality of optical and magnetic resonance imaging.