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Abstract Background Macromoleculization of nitroxides has been an effective strategy to improve low relaxivities and poor in vivo stability, however, nitroxides-based metal-free magnetic resonance imaging (MRI) macromolecular contrast agents (mCAs) are still under-performed. These mCAs do not possess a high nitroxides content sufficient for a cumulative effect. Amphiphilic nanostructures in these mCAs are not stable enough for highly efficient protection of nitroxides and do not have adequate molecular flexibility for full contact of the paramagnetic center with the peripheral water molecules. In addition, these mCAs still raise the concerns over biocompatibility and biodegradability due to the presence of macromolecules in these mCAs. Results Herein, a water-soluble biodegradable nitroxides-based mCA (Linear pDHPMA-mPEG-Ppa-PROXYL) was prepared via covalent conjugation of a nitroxides (2,2,5,5-tetramethyl-1-pyrrolidinyl-N-oxyl, PROXYL) onto an enzyme-sensitive linear di-block poly[N-(1, 3-dihydroxypropyl) methacrylamide] (pDHPMA). A high content of PROXYL up to 0.111 mmol/g in Linear pDHPMA-mPEG-Ppa-PROXYL was achieved and a stable nano-sized self-assembled aggregate in an aqueous environment (ca. 23 nm) was formed. Its longitudinal relaxivity (r 1 = 0.93 mM− 1 s− 1) was the highest compared to reported nitroxides-based mCAs. The blood retention time of PROXYL from the prepared mCA in vivo was up to ca. 8 h and great accumulation of the mCA was realized in the tumor site due to its passive targeting ability to tumors. Thus, Linear pDHPMA-mPEG-Ppa-PROXYL could provide a clearly detectable MRI enhancement at the tumor site of mice via the T1WI SE sequence conventionally used in clinical Gd3+-based contrast agents, although it cannot be compared with DTPA-Gd in the longitudinal relaxivity and the continuous enhancement time at the tumor site of mice. Additionally, it was demonstrated to have great biosafety, hemocompatibility and biocompatibility. Conclusions Therefore, Linear pDHPMA-mPEG-Ppa-PROXYL could be a potential candidate as a substitute of metal-based MRI CAs for clinical application. Graphic Abstract

Background: Macromoleculization of nitroxides has been an effective strategy to improve low relaxivities and poor in vivo stability, however, nitroxides-based metal-free magnetic resonance imaging (MRI) macromolecular contrast agents (mCAs) are still under-performed. These mCAs do not possess a high nitroxides content sufficient for a cumulative effect. Amphiphilic nanostructures in these mCAs are not stable enough for highly efficient protection of nitroxides and do not have adequate molecular flexibility for full contact of the paramagnetic center with the peripheral water molecules. In addition, these mCAs still raise the concerns over biocompatibility and biodegradability due to the presence of macromolecules in these mCAs. Results: Herein, a water-soluble biodegradable nitroxides-based mCA (Linear pDHPMA-mPEG-Ppa-PROXYL) was prepared via covalent conjugation of a nitroxides (2,2,5,5-tetramethyl-1-pyrrolidinyl-N-oxyl, PROXYL) onto an enzyme-sensitive linear di-block poly[N-(1, 3-dihydroxypropyl) methacrylamide] (pDHPMA). A high content of PROXYL up to 0.111 mmol/g in Linear pDHPMA-mPEG-Ppa-PROXYL was achieved and a stable nano-sized self-assembled aggregate in an aqueous environment (ca. 23 nm) was formed. Its longitudinal relaxivity (r1 = 0.93 mM− 1 s− 1) was the highest compared to reported nitroxides-based mCAs. The blood retention time of PROXYL from the prepared mCA in vivo was up to ca. 8 h and great accumulation of the mCA was realized in the tumor site due to its passive targeting ability to tumors. Thus, Linear pDHPMA-mPEG-Ppa-PROXYL could provide a clearly detectable MRI enhancement at the tumor site of mice via the T1WI SE sequence conventionally used in clinical Gd3+-based contrast agents, although it cannot be compared with DTPA-Gd in the longitudinal relaxivity and the continuous enhancement time at the tumor site of mice. Additionally, it was demonstrated to have great biosafety, hemocompatibility and biocompatibility. Conclusions: Therefore, Linear pDHPMA-mPEG-Ppa-PROXYL could be a potential candidate as a substitute of metal-based MRI CAs for clinical application. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) is a promising technique widely used in clinical diagnose. Poly(α-amino acid)s are excellent carriers for MRI due to their excellent biocompatibility. PDOPA-b-PSar copolymers (defined as "DoS") are synthesized by sequential polymerizations of 3,4-dihydroxy-L-phenylalanine N-thiocarboxyanhydride (DOPA-NTA) and sarcosine N-thiocarboxyanhydride (Sar-NTA) initiated by neopentylamine in tetramethylene sulfone. Mn2+@DoS micelles have been prepared as T1-weighted MRI contrast agents according to efficient coordination between catechol units and Mn2+ cation. High longitudinal relaxivity (27.7 mM−1·s−1) of Mn2+@PDOPA12-b-PSar72 was observed, and the aqueous micelle exhibits effective MRI contrast enhancement in vivo of nude mice. Mn2+@DoS shows potential clinical application in diagnostic radiology as a novel MRI contrast agent. Gd3+@DoS micelles are also investigated presenting a longitudinal relaxivity of 16.4 mM−1·s−1. Unfortunately, the Gd3+ loading percentage is quite low as 19%. [ABSTRACT FROM AUTHOR]

The present work introduces thiacalix[4]arene adopting 1,3-alternate conformation with alkyl-malonate terminal substituents as ligands for Gd(III) ions. pH-dependent complex formation of Gd(III) ions via alkyl-malonate substituents in aqueous DMSO solutions results in a precipitation. The precipitated complexes were converted into hydrophilic colloids of "plum-pudding" morphology, where the Gd(III) complexes form hard small (1.5–4 nm) cores included into larger (about 180 nm) soft PSS shells. The precipitate-to-colloid transformation is facilitated by polystyrolsulfonate (PSS) for Gd(III) complexes with thiacalix[4]arene bearing propyl-malonate groups, while the presence of PSS triggers a dissolution of the precipitated complexes for thiacalix[4]arenes with pentyl-malonate substituents. To a lesser extent the similar tendency disturbs the formation of PSS-stabilized colloids on the basis of butyl-malonate substituted thiacalix[4]arene. The PSS-stabilized colloids exhibit high longitudinal and transverse relaxivities (r 1 = 23.8 and r 2 = 29.4 mM−1 s−1 at 0.47 T, respectively), while the recoating of the PSS-stabilized colloids with polyethyleneimine is accompanied by the dissolution of the hard cores. High relaxivity along with low cytotoxicity of PSS-stabilized colloids indicates their applicability as contrast agents in MRI. [ABSTRACT FROM AUTHOR]

Objectives: In this study, a novel targeted MRI contrast agent was developed by coating gadolinium oxide nanoparticles (Gd2O3 NPs) with β-cyclodextrin (CD)-based polyester and targeted by folic acid (FA). Materials and methods: The developed Gd2O3@PCD–FA MRI contrast agent was characterized and evaluated in relaxivity, in vitro cell targeting, cell toxicity, blood compatibility and in vivo tumor MR contrast enhancement. Results: In vitro cytotoxicity and hemolysis assays revealed that Gd2O3@PCD–FA NPs have no significant cytotoxicity after 24 and 48 h against normal human breast cell line (MCF-10A) at concentration of up to 50 µg Gd+3/mL and have high blood compatibility at concentration of up to 500 µg Gd+3/mL. In vitro MR imaging experiments showed that Gd2O3@PCD–FA NPs enable targeted contrast T1- and T2-weighted MR imaging of M109 as overexpressing folate receptor cells. Besides, the in vivo analysis indicated that the maximum contrast-to-noise ratio (CNR) of tumor in mice increased after injection of Gd2O3@PCD–FA up to 5.89 ± 1.3 within 1 h under T1-weighted imaging mode and reduced to 1.45 ± 0.44 after 12 h. While CNR increased up to maximum value of 1.98 ± 0.28 after injection of Gd2O3@PCD within 6 h and reduced to 1.12 ± 0.13 within 12 h. Conclusion: The results indicate the potential of Gd2O3@PCD–FA to serve as a novel targeted nano-contrast agent in MRI. [ABSTRACT FROM AUTHOR]

Highlights • Co 0.3 Zn 0.7 Fe 2 O 4 ferrite particle clusters of 210 nm size were fabricated. • Particles show strong temperature variation of magnetization near body temperature. • Nuclear relaxivities R 1 , R 2 , and R 2 ∗ are temperature dependent. • Relative changes of temperature determined with accuracy of ±1.0 K at 310 K. Abstract Recently, we reported the application of magnetic particles as temperature sensors for use in magnetic resonance imaging thermometry (tMRI). In this novel method, the brightness of the magnetic resonance (MR) image changes with temperature due to a temperature-dependent local magnetic field inhomogeneity caused by the dipolar field of the magnetic particles. Ferrites are new and promising compounds for tMRI applications because of their biocompatibility and because their magnetic properties can be varied by changing composition. Earlier studies used micrometer sized ferrite particles in a proof-of-concept demonstration. However, such large particles cannot be administered intravenously for in-vivo use. In this report, we establish the use of nanoscale ferrite particles as temperature sensors for tMRI. Scanning transmission electron microscopy and X-ray diffraction demonstrate the synthesis of 210 nm Co 0.3 Zn 0.7 Fe 2 O 4 clusters comprised of 10–30 nm crystallites. Temperature-dependent magnetization measurements reveal a Curie temperature of around 275 K. We conducted nuclear magnetic resonance (NMR) and MRI studies of samples with different concentrations of ferrite nanoparticles suspended in agar gel. The relative MR image intensity shows a near-linear temperature dependence. At concentrations as low as 0.12 g/L these ferrite nanoparticles provide sufficient image contrast to determine temperature changes with accuracy of ±1.0 K at 310 K, bolstering the potential viability of this material for bio-medical applications. [ABSTRACT FROM AUTHOR]

The present paper introduces specific structure of thiacalix[4]arenes derivatives adopting 1,3-alternate conformation with alkyl-carboxyl substituents as ligands for conversion of their complexes with Gd(III) ions into hydrophilic colloids with longitudinal (r1) and transverse relaxivities (r2) higher than that of Gd(III)-based commercial contrast agents (r1 = 20.53 and r2 = 23.46 mM−1 s−1 at 0.47 T). pH-dependent coordination of Gd(III) ions via carboxyl substituents of the thiacalix[4]arenes is the driving force for the complex formation, while the precipitation of the complexes is the basis for the colloids formation. Tert-butyl and butyl substituents of thiacalix[4]arenes were found to be of crucial impact on the complex precipitation. The specific inner- and outer-sphere ligand environment provided by the thiacalix[4]arene ligands was revealed as the optimal for high r1 and r2 values of the colloids. High relaxivities along with negligible cytotoxicity open up the possibility of their further use as positive contrast agents in magnetic resonance imaging (MRI). [ABSTRACT FROM AUTHOR]

It is highly desired to develop the dual-modality fluorescence and magnetic resonance imaging (MRI) probes in medical imaging because it can provide high-resolution macroscopical anatomical information and high-sensitivity microscopical optical signal simultaneously. In this study, harmless gadolinium-doped carbon dots (Gd-CDs) were prepared via a convenient one-pot hydrothermal approach for fluorescence/MR bimodal imaging. The derived Gd-CDs exhibit enhanced blue photoluminescence with a quantum yield as high as 69.86% and significantly improved longitudinal relaxivity ( r 1 = 14.33 mM −1 s −1 , 0.5 T) in comparison with commercial Magnevist (Gd-DTPA, r 1 = 4.5 mM −1 s −1 , 0.5 T). Here Gd 3+ ions are simply chelated onto CDs by carboxyl groups. Moreover, unlike the previous reports, Gd 3+ chelation does not perturb core optical properties of CDs. Excellent water solubility, good cell-membrane permeability and negligible cytotoxicity make Gd-CDs an ideal dual-modal fluorescence/MR imaging nanoprobe, suggesting its potential and significance in practical biological and clinic applications in the future. [ABSTRACT FROM AUTHOR]

GdIII-based metal-organic frameworks, Gd-pDBI-1 and Gd-pDBI-2, have been synthesized using the linker pDBI (pDBI=1,4-bis(5-carboxy-1H-benzimidazole-2yl)benzene). They exhibited structural diversity due to subtle change in reaction constituents. Owing to the judicious choice of the fluorescent linker, the materials could be used for bimodal imaging (fluorescent and magnetic resonance) and displayed a modest T1 relaxivity value. [ABSTRACT FROM AUTHOR]

Gd(III) chelate is currently used as positive magnetic resonance imaging (MRI) contrast agent in clinical diagnosis, but generally induces the risk of nephrogenic systemic fibrosis (NSF) due to the dissociated Gd 3+ from Gd(III) chelates. To develop a novel positive MRI contrast agent with low toxicity and high sensitivity, ultrasmall MnO nanoparticles were PEGylated via catechol-Mn chelation and conjugated with cRGD as active targeting function to tumor. Particularly, the MnO nanoparticles with a size of ca. 5 nm were modified by α,β-poly(aspartic acid)-based graft polymer containing PEG and DOPA moieties and, meanwhile, conjugated with cRGD to produce the contrast agent with a size of ca. 100 nm and a longitudinal relaxivity ( r 1 ) of 10.2 mM −1 S −1 . Such nanoscaled contrast agent integrated passive- and active-targeting function to tumor, and its efficient accumulation behavior in tumor was verified by in vivo distribution study. At the same time, the PEG moiety played a role of hydrophilic coating to improve the biocompatibility and stability under storing and physiological conditions, and especially might guarantee enough circulation time in blood. Moreover, in vivo MRI revealed a good and long-term effect of enhancing MRI signal for as-fabricated contrast agent while cell viability assay proved its acceptable cytotoxicity for MRI application. On the whole, the as-fabricated PEGylated and cRGD-functionalized contrast agent based on ultrasmall MnO nanoparticles showed a great potential to the T 1 -weighted MRI diagnosis of tumor. [ABSTRACT FROM AUTHOR]

Europium (Eu) is a paramagnetic lanthanide element that possesses an outstanding luminescent property. Eu complexes are ideal fluorescence imaging (FI) agents. Eu2+ has satisfactory relaxivity and optical properties, and can realize magnetic resonance (MRI)-fidual imaging applications when used with appropriate cryptands that render it oxidatively stable. By contrast, based on the chemical exchange saturation transfer (CEST) mechanism, Eu3+ complexes can provide enhanced MRI sensitivity when used with optimal cryptands, incorporated into polymeric CEST agents or blended with Gd3+. Eu complexes are promising in MRI-fidual imaging applications and have a bright future. [ABSTRACT FROM AUTHOR]

Abstract: A novel and facile strategy was firstly developed to synthesize an efficient magnetic resonance imaging contrast agent via linking the Gd-complex (Gd-DTPA) onto the surfaces of ferroferric oxide nanoparticles. The new contrast agent is easily soluble in water media and shows better targeting ability on the liver organ. In addition, the synthesized contrast agent shows excellent magnetic resonance contrast behavior with longitudinal relaxivity value of 62.58mM−1 s−1 and emits strong bright fluorescence in the cellular environment. Furthermore, the new magnetic resonance imaging contrast agent is superparamagnetic at room temperature and has no apparent cytotoxicity on human HeLa cells. [Copyright &y& Elsevier]

Abstract: The field of molecular imaging aims to visualize and quantify (patho)physiological processes at the cellular and molecular level. Sensitive and site-targeted contrast agents are employed to visualize molecular constituents of processes of interest. The principal aim of this study was to develop a magnetic resonance imaging (MRI) detectable liposome with high relaxivity and stability. To this end, Gd(III)DOTA-DSPE was synthesized and incorporated in a liposomal formulation. The resulting liposomes were extensively characterized in vitro in terms of contrast agent efficiency and structural properties. The liposomes were shown to have a high longitudinal relaxivity, which is crucial for the detection of low concentration molecular markers in molecular imaging studies. We also demonstrated that Gd(III)DOTA-DSPE exhibits no detectable transmetallation upon incubation with Zn(II). This is important as it significantly contributes to the biocompatibility of the contrast agent. The present liposome preparation will serve as versatile and well characterized platform for molecular imaging and targeted drug delivery studies. [Copyright &y& Elsevier]

A single-atom metal doped on carbonaceous nanomaterials has attracted increasing attention due to its potential applications as high-performance catalysts. However, few studies focus on the applications of such nanomaterials as nanotheranostics for simultaneous bioimaging and cancer therapy. Herein, it is pioneeringly demonstrated that the single-atom Gd anchored onto graphene quantum dots (SAGd-GQDs), with dendrite-like morphology, was successfully prepared. More importantly, the as-fabricated SAGd-GQDs exhibits a robustly enhanced longitudinal relaxivity ( r 1 = 86.08 mM -1 s -1 ) at a low Gd 3+ concentration of 2 μmol kg -1 , which is 25 times higher than the commercial Gd-DTPA ( r 1 = 3.44 mM -1 s -1 ). In vitro and in vivo studies suggest that the obtained SAGd-GQDs is a highly potent and contrast agent to obtain high-definition MRI, thereby opening up more opportunities for future precise clinical theranostics.

Manganese ferrite nanoparticles are superparamagnetic and have very high saturation magnetization, which makes them candidates for application as MRI contrast agents. Because these nanoparticles are very effective enhancers of transverse relaxation, they are particularly suitable as negative (T 2 -weighted) contrast agents. The magnitude of the relaxivity of nanoparticulate Mn ferrites seems to be determined mainly by the method of preparation, their dimensions, and their saturation magnetization., Competing Interests: Declaration of Competing Interest The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Abstract: The longitudinal relaxivity on the protons of water of a Gd–chelate–albumin compound was measured at 7T as a function of the macromolecular content of a cross-linked matrix. In agreement with previous works, the results demonstrate that the effect of gadolinium on water proton relaxivity is not constant, rising moderately with increase in the concentration of bovine serum albumin (BSA). About 35% variation in relaxivity was observed over a 0%–25% range of BSA concentrations (ℜ=3.893+0.0502×BSA [%], SE=0.0119 and 0.1740, t =4.215 and 22.383, p <0.014 and 0.001). [ABSTRACT FROM AUTHOR]