Search

T1/T2 dual-mode magnetic resonance (MR) contrast agents (DMCAs) have gained much attention because of their ability to improve accuracy by providing two pieces of complementary information with one instrument. However, most of these agents are "always ON" systems that emit MR contrast regardless of their interaction with target cells or biomarkers, which may result in poor target-to-background ratios. Herein, we introduce a rationally designed magnetic relaxation switch (MGRS) for an activatable T1/T2 dual MR imaging system. Redox-responsive heteronanocrystals, consisting of a superparamagnetic Fe3O4 core and a paramagnetic Mn3O4 shell, are synthesized through seed-mediated growth and subsequently surface-modified with polysorbate 80. The Mn3O4 shell acts as both a protector of Fe3O4 in aqueous environments to attenuate T2 relaxation and as a redoxable switch that can be activated in intracellular reducing environments by glutathione. This simultaneously generates large amounts of magnetically decoupled Mn(2+) ions and allows Fe3O4 to interact with the water protons. This smart nanoplatform shows an appropriate hydrodynamic size for the EPR effect (10-100 nm) and demonstrates biocompatibility. Efficient transitions of OFF/ON dual contrast effects are observed by in vitro imaging and MR relaxivity measurements. The ability to use these materials as DMCAs is demonstrated via effective passive tumor targeting for T1- and T2-weighted MR imaging in tumor-bearing mice., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The specific delivery of ribonucleic acid (RNA) interfering molecules to disease-related cells is still a critical blockade for in vivo systemic treatment. Here, this study suggests a robust delivery carrier for targeted delivery of RNA-interfering molecules using galactosylated magnetic nanovectors (gMNVs). gMNVs are an organic-inorganic polymeric nanomaterial composed of polycationics and magnetic nanocrystal for delivery of RNA-interfering molecules and tracking via magnetic resonance (MR) imaging. In particular, the surface of gMNVs was modified by galactosylgluconic groups for targeted delivering to asialoglycoprotein receptor (ASGPR) of hepatocytes. Moreover, the small interfering RNAs were used to regulate target proteins related with low-density lipoprotein level and in vivo MR imaging was conducted for tracking of nanovectors. The obtained results show that the prepared gMNVs demonstrate potential as a systemic theragnostic nanoplatform for RNA interference and MR imaging.

Objectives: To obtain compensatory ultra-short echo time (UTE) imaging and T2-weighted (T2W) imaging of Watanabe heritable hyperlipidemic (WHHL) rabbits following dextran-coated magnetic nanocluster (DMNC) injection for the effective in vivo detection of inflammatory vascular wall., Methods: Magnetic nanoparticle was synthesized by thermal decomposition and encapsulated with dextran to prepare DMNC. The contrast enhancement efficiency of DMNC was investigated using UTE (repetition time [TR] = 5.58 and TE = 0.07 ms) and T2W (TR = 4000 and TE = 60 ms) imaging sequences. To confirm the internalization of DMNC into macrophages, DMNC-treated macrophages were visualized by cellular transmission electron microscope (TEM) and magnetic resonance (MR) imaging. WHHL rabbits expressing macrophage-rich plaques were subjected to UTE and T2W imaging before and after intravenous DMNC (120 μmol Fe/kg) treatment. Ex vivo MR imaging of plaques and immunostaining studies were also performed., Results: Positive and negative contrast enhancement of DMNC solutions with increasing Fe concentrations were observed in UTE and T2W imaging, respectively. The relative signal intensities of the DMNC solution containing 2.9 mM Fe were calculated as 3.53 and 0.99 in UTE and T2W imaging, respectively. DMNC uptake into the macrophage cytoplasm was visualized by electron microscopy. Cellular MR imaging of DMNC-treated macrophages revealed relative signals of 3.00 in UTE imaging and 0.98 in T2W imaging. In vivo MR images revealed significant brightening and darkening of plaque areas in the WHHL rabbit 24 h after DMNC injection in UTE and T2W imaging, respectively. Ex vivo MR imaging results agreed with these in vivo MR imaging results. Histological analysis showed that DMNCs were localized to areas of inflammatory vascular wall., Conclusions: Using compensatory UTE and T2W imaging in conjunction with DMNC is an effective approach for the noninvasive in vivo imaging of atherosclerotic plaque.

In this study, we developed the maleimidyl magnetic nanoplatform, which enables functional targeting of a biomarker-specific moiety for molecular imaging via MRI. The maleimide group of the maleimidyl magnetic nanoplatform is conjugated with a thiol group without additional crosslinkers and side products. A physicochemical analysis was conducted to verify the effectiveness of the maleimidyl magnetic nanoplatform, and the existence of the maleimidyl group was investigated using the platform. To prepare biomarker-specific MRI probes, a thiolated aptamer and peptide were immobilized onto the maleimidyl group of the maleimidyl magnetic nanoplatform. The fabricated MRI probes were applied to four cancer cell lines: HT1080, MCF7, MKN45, and HEK293T. To investigate the potential of the molecular MRI probe, the target-biomarker specificity was confirmed without serious cytotoxicity, and in vivo MRI analysis using a xenograft mouse model was demonstrated. We believe these results will be useful for fabricating molecular MRI probes for the diagnosis of cancer.

Oleyl dextran-coated magnetic nanoclusters (ODMCs) are fabricated for the accurate detection of macrophage-rich atherosclerotic plaques using magnetic resonance (MR) imaging. Dextran is introduced to the cluster surface of magnetic nanocrystals (MNCs) through self-assembly using amphiphilic oleic acid-conjugated dextran (ODex) to provide not only hydrophilicity but also a high affinity to macrophages. Enhanced magnetism of the ODMCs is engineered by optimizing the degree of substitution (DS) of the oleyl group in ODex and the concentration of ODex used for the synthesis of ODMC. Consequently, ODMCs exhibit significantly increased T2 relaxivity and excellent macrophage-targeting ability without cytotoxicity, in vitro. Moreover, in vivo T2-weighted MR imaging after intravenous injection of ODMCs into a rat artery balloon injury model demonstrates considerable MR contrast strength efficacy in the plaques of the injured carotid artery. These novel ODMCs may offer a highly efficient MR imaging nanoprobes for the selective diagnosis of atherosclerosis., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We developed Pyrene-Gadolinium (Py-Gd) nanoparticles as pH-sensitive magnetic resonance imaging (MRI) contrast agents capable of showing a high-Mr signal in cancer-specific environments, such as acidic conditions. Py-Gd nanoparticles were prepared by coating Py-Gd, which is a complex of gadolinium with pyrenyl molecules, with pyrenyl polyethyleneglycol PEG using a nano-emulsion method. These particles show better longitudinal relaxation time (T1) MR signals in acidic conditions than they do in neutral conditions. Furthermore, the particles exhibit biocompatibility and MR contrast effects in both in vitro and in vivo studies. From these results, we confirm that Py-Gd nanoparticles have the potential to be applied for accurate cancer diagnosis and therapy.

In this study, dextran-encrusted magnetic nanoclusters (DMNCs) were synthesized using a one-pot solution phase method for detection of atherosclerosis by magnetic resonance imaging. Pyrenyl dextran was used as a surfactant because of its electron-stabilizing effect and its amphiphilic nature, rendering the DMNCs stable and water-dispersible. The DMNCs were 65.6±4.3 nm, had a narrow size distribution, and were superparamagnetic with a high magnetization value of 60.1 emu/g. Further, they showed biocompatibility and high cellular uptake efficiency, as indicated by a strong interaction between dextran and macrophages. In vivo magnetic resonance imaging demonstrated the ability of DMNCs to act as an efficient magnetic resonance imaging contrast agent capable of targeted detection of atherosclerosis. In view of these findings, it is concluded that DMNCs can be used as magnetic resonance imaging contrast agents to detect inflammatory disease.

Cancer cells can express specific biomarkers, such as cell membrane proteins and signaling factors. Thus, finding biomarkers and delivering diagnostic agents are important in the diagnosis of cancer. In this study, we investigated a biomarker imaging agent for the diagnosis of hepatic cancers. The asialoglycoprotein receptor (ASGPr) was selected as a biomarker for hepatoma cells and the ASGPr-targetable imaging agent bearing a galactosyl group was prepared using manganese ferrite nanoparticles (MFNP) and galactosylgluconic acid. The utility of the ASGPr-targetable imaging agent, galactosylated MFNP (G-MFNP) was assessed by several methods in ASGPr-expressing HepG2 cells as target cells and ASGPr-deficient MCF7 cells. Physical and chemical properties of G-MFNP were examined using Fourier-transform infrared spectroscopy, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. No significant cytotoxicity was observed in either cell line. Targeting ability was assessed using flow cytometry, magnetic resonance imaging, inductively coupled plasma atomic emission spectroscopy, absorbance analysis, dark-field microscopy, Prussian blue staining, and transmission electron microscopy. We demonstrated that G-MFNP target successfully and bind to ASGPr-expressing HepG2 cells specifically. We suggest that these results will be useful in strategies for cancer diagnoses based on magnetic resonance imaging.

Multimodal imaging systems may eliminate the disadvantages of individual imaging modality by providing complementary information about cellular and molecular activites. In this sutdy, we developed a reverse complementary multimodal imaging system to image microRNAs (miRNA, miR) during neurognesis using transferrin receptor (TfR) and a magnetic fluorescence (MF) nanoparticle-conjugated peptide targeting TfR (MF targeting TfR). Both in vitro and in vivo imaging demonstrated that, in the absence of miR9 during pre-differentiation of P19 cells, the MF targeting TfR nanoparticles greatly targeted TfR and were successfully internalized into P19 cells, resulting in high fluorescence and low MR signals. When the miR9 was highly expressed during neurogenesis of P19 cells, the MF targeting TfR nanoparticles were hardly targeted due to the miR9 function, which represses the expression and functional activity of TfR from the miRNA TfR reproter gene, resulting in low fluorescence and high MR signals. The reverse complementary multimodal miRNA imaging system may serve as a new imaging probe to montior miRNA-involved cellular developments and diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We fabricated hyaluronan-modified magnetic nanoclusters (HA-MNCs) for detection of CD44-overexpressing breast cancer using magnetic resonance (MR) imaging. CD44 is closely associated with cancer growth, including proliferation, metastasis, invasion, and angiogenesis. Hence, pyrenyl hyaluronan (Py-HA) conjugates were synthesized as CD44-targetable surfactants with hyaluronan (HA) and 1-pyrenylbutyric acid (Py) to modify hyaluronan on hydrophobic magnetic nanocrystals. Subsequently, HA-MNCs were fabricated using the nano-emulsion method; magnetic nanocrystals were simultaneously self-assembled with Py-HA conjugates, and their physical and magnetic properties depended on the degree of substitution (DS) of Py in Py-HA conjugates. HA-MNCs exhibited superior targeting efficiency with MR sensitivity as well as excellent biocompatibility through in vitro/in vivo studies. This suggests that HA-MNCs can be a potent cancer specific molecular imaging agent via targeted detection of CD44 with MR imaging., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

We fabricated multimode nanoprobes for acquisition of biological information at different object levels, i.e., in vivo detection and ex vivo validation for characterizing tumor angiogenesis. Fluorescent magnetic nanoprobes (FMNPs) were synthesized by using amphiphilic pyrenyl polyethylene glycol (Py-PEG) and superparamagnetic MnFe(2)O(4) nanocrystals (MNCs). Py-PEG, which is synthesized by conjugation of hydrophilic PEG with hydrophobic and fluorescent 1-pyrenebutyric acid through an esterification process, is capable of self-assembly and maintaining a high UV fluorescent intensity in aqueous phase. Py-PEG can be used as a fluorescent surfactant that simultaneously and efficiently encapsulates MNCs to exhibit fluorescent and magnetic properties as well as maintaining high water-solubility. Consequently, we proved that our biologically non-toxic FMNPs were prominent multimode imaging probes by showing not only excellent MR sensitivity but also high illumination intensity with strong signal strength under short exposure time of UV light from the extensive imaging studies of in vitro/vivo and ex vivo using orthotopic and xenograft mice models., (Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.)

Precise diagnosis by magnetic resonance imaging (MRI) requires sensitive magnetic resonance probes to detect low concentrations of magnetic substances. Ionic magnetic clusters (IMCs) as versatile magnetic probes were successfully synthesized for enhancing the magnetic resonance (MR) contrast effect as well as ensuring high water solubility. IMCs with various sizes were prepared by assembly of MNCs using cationic cetyltrimethylammonium bromide (CTAB) and anionic sodium dodecyl sulfate (SDS). To synthesize IMCs in the aqueous phase, magnetic nanocrystals in an organic solvent were assembled with CTAB and SDS using the nanoemulsion method, to fabricate cationic magnetic clusters (CMCs) and anionic magnetic clusters (AMCs), respectively. IMCs demonstrated ultrasensitivity by MR imaging and sufficient magnetic mobility under an external magnetic field.

Manganese oxide (MnO) nanocubes were fabricated and their surface were modified by ligand encapsulation or ligand exchange, to render them water-soluble. And then, MnO formed the hollow structure by etching using acidic solution (phthalate buffer, pH 4.0). Depending on the ligand of the MnO surface, it increases the interaction between MnO and water molecules. Also, the hollow structure of MnO, as well as the ligand, can greatly enhance the accessibility of water molecules to metal ions by surface area-to-volume ratio. These factors provide high R1 relaxation, leading to strong T1 MRI signal. We have confirmed T1-weighted MR contrast effect using 4-kinds of MnO nanocubes (MnOEn, MnOEnHo, MnOEx and MnOExHo). They showed enough a MR contrast effect and biocompatibility. Especially, among them, MnOExHo exhibited high T1 relaxivity (r1) (6.02 mM−1 s−1), even about 1.5 times higher sensitivity than commercial T1 MR contrast agents. In vitro/in vivo studies have shown that MnOExHo provides highly sensitive T1-weighted MR imaging, thereby improving diagnostic visibility at the disease site. [ABSTRACT FROM AUTHOR]

An understanding of neovascularization and/or angiogenesis in cancer is acutely required for effective cancer therapy due to concerns about tumor growth and metastasis. In particular, integrin αvβ3 is closely associated with cell migration and invasion during angiogenesis. Hence, we developed aptamerαvβ3-conjugated magnetic nanoparticles (Aptαvβ3-MNPs) to enable precise detection of integrin-expressing cancer cells using magnetic resonance imaging. Aptαvβ3-MNPs exhibited not only cytocompatibility, but also an efficient targeting ability with high magnetic sensitivity through in vitro/ in vivo studies. The results of this study demonstrate that Aptαvβ3-MNPs have the potential to be used for accurate tumor diagnosis and therapy. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 49-59, 2014. [ABSTRACT FROM AUTHOR]

Carboxymethyl-dextran (CM-dextran) replaced the hydrophobic oleylamine ligands on the surfaces of MnO nanoparticles, rendering them highly water-soluble by allowing direct contact with excited water protons. Solution MRI studies of the two types of nanoparticles, exchanged and bilayered, with different core sizes have shown that the exchanged ligand structure exhibits significantly enhanced longitudinal relaxation. The modification with dextran converted the nanoparticles into effective T1 MRI contrast agents, as well as promoting strong interactions with macrophages. Thus, it is a potential MR contrast agent for visualizing inflammatory macrophages. [ABSTRACT FROM AUTHOR]

With an increase in the older individuals, the global incidence of Alzheimer's disease (AD) is increasing. Early diagnosis of AD necessitates long‐term monitoring; however, conventional diagnostic methods such as positron emission tomography (PET) and magnetic resonance imaging (MRI) are unsuitable for frequent use because of infrastructure limitations. The eye, connected to the brain via the optic nerve, offers a potential window for monitoring neurodegenerative diseases. This study presents a novel system for continuous intraocular monitoring using a fluorescent aptamer‐conjugated intraocular lens (FAIOL). FAIOL emits fluorescent signals in the presence of beta‐secretase‐1 (BACE1), an enzyme associated with amyloid beta 1–42 production. These signals can be analyzed using mobile phone applications. In vitro, experiments demonstrates that FAIOL responded to BACE1 by detecting low concentrations of the target molecule over extended periods. Ex vivo tests using porcine eyeballs shows an increase in the fluorescence signal intensity by more than 8% within 5 h in the presence of BACE1. The integrated image analysis program reduces sensor noise and provides numerical signal values, facilitating a straightforward interpretation. FAIOL holds significant potential as an innovative platform for the early diagnosis and long‐term monitoring of AD and promises improved patient outcomes through timely intervention and ongoing surveillance. [ABSTRACT FROM AUTHOR]

We designed a high-sensitivity magnetic resonance imaging contrast agent that could be used to diagnose diseases. First, magnetic nanocrystals were synthesized by a thermal decomposition method on an organic solvent to obtain a high magnetism and methoxy poly(ethylene glycol)-poly(lactic acid) as an amphiphilic polymer using the ring-opening polymerization method to stably disperse the magnetic nanocrystals in an aqueous phase. Subsequently, the magnetic nanoclusters simultaneously self-assembled with methoxy poly(ethylene glycol)-poly(lactic acid) using the nano-emulsion method to form magnetic nanoclusters. Because their shape was similar to a raspberry, they were named PEGylated magnetic nano-assemblies. The PEGylated magnetic nano-assemblies were dispersed stably in the aqueous phase with a uniform size of approximately 65–70 nm for an extended period (0 days: 68.8 ± 5.1 nm, 33 days: 69.2 ± 2.0 nm, and 44 days: 63.2 ± 5.6). They exhibited both enough of a magnetic resonance (MR) contrast effect and biocompatibility. In an in vivo study, the PEGylated magnetic nano-assemblies provided a high contrast effect for magnetic resonance images for a long time after one treatment, thereby improving the diagnostic visibility of the disease site. [ABSTRACT FROM AUTHOR]

Abstract: Novel bifunctional fluorescent magneto polymeric nanoprobes (FMPNs) were synthesized to provide simultaneous diagnostic information via magnetic resonance imaging (MRI) and optical imaging. FMPNs consist of ultra-sensitive magnetic nanocrystals that function as MR probes combined with Nile Red, which functions as a fluorescent probe. FMPNs were encapsulated by a nano-emulsion method in polyvinyl alcohol (PVA, 87–89% hydrolyzed) through a matrix of polymethyl methacrylate (PMMA). FMPNs exhibited excellent colloidal stability and monodispersity. The production of MR and optical images demonstrated that FMPNs have potential as dual-mode imaging agents. [Copyright &y& Elsevier]

As stem cells show great promise in regenerative therapy, stem cell-mediated therapeutic efficacy must be demonstrated through the migration and transplantation of stem cells into target disease areas at the pre-clinical level. In this study, we developed manganese-based magnetic nanoparticles with hollow structures (MnOHo) and modified them with the anti-human integrin β1 antibody (MnOHo-Ab) to enable the minimal-invasive monitoring of transplanted human stem cells at the pre-clinical level. Compared to common magnetic resonance imaging (MRI)-based stem cell monitoring systems that use pre-labeled stem cells with magnetic particles before stem cell injection, the MnOHo-Ab is a new technology that does not require stem cell modification to monitor the therapeutic capability of stem cells. Additionally, MnOHo-Ab provides improved T1 MRI owing to the hollow structure of the MnOHo. Particularly, the anti-integrin β1 antibody (Ab) introduced in the MnOHo targets integrin β1 expressed in the entire stem cell lineage, enabling targeted monitoring regardless of the differentiation stage of the stem cells. Furthermore, we verified that intravenously injected MnOHo-Ab specifically targeted human induced pluripotent stem cells (hiPSCs) that were transferred to mice testes and differentiated into various lineages. The new stem cell monitoring method using MnOHo-Ab demonstrates whether the injected human stem cells have migrated and transplanted themselves in the target area during long-term stem cell regenerative therapy. • New strategy to monitor human stem cell transplantation at the pre-clinical level. • MnOHo-Ab enables minimal-invasive monitoring of in vivo transplanted human cells. • Human integrin β1 antibody of MnOHo-Ab targets transplanted human stem cells. • MnOHo-Ab targets human stem cells regardless of differentiation state. • This system can be applied in various fields of stem cell-based therapy. [ABSTRACT FROM AUTHOR]