Longitudinal Relaxivity Research Articles

Renal-clearable zwitterionic conjugated hollow ultrasmall Fe3O4 nanoparticles for T1-weighted MR imaging in vivo.

Monodispersed hollow Fe3O4 nanoparticles with the diameters of 7 and 10 nm were prepared via a high-temperature pyrolysis method and the Kirkendall effect by regulating the ratio of oleylamine to oleic acid. The water solubility was studied by zwitterionic dopamine sulfonate (ZDS) to obtain ZDS-conjugated Fe3O4 nanoparticles (Fe3O4@ZDS NPs). The 7 nm Fe3O4@ZDS NPs exhibited a good T1 positive contrast with a longitudinal relaxivity (r1) of 0.23 mM-1 s-1 and a small ratio of r1 to transversal relaxivity (r2) of 4.00. In the 4T1 xenograft mouse model, the tumor signal from T1-weighted MRI was positively enhanced by ∼23% after the intravenous injection of 7-Fe3O4@ZDS NPs (40 mg kg-1). More importantly, 7-Fe3O4@ZDS NPs can be partially metabolized by the kidney, which is an important step for the use of MRI contrast agents in clinic.

Synthesis of gadolinium/iron-bimetal-phenolic coordination polymer nanoparticles for theranostic applications.

Integration of diagnostic and therapeutic components into a single coordination polymer nanoparticle is desirable for theranostic applications, but still challenging. Herein, we report the synthesis of bimetal-phenolic coordination polymer nanoparticles using gadolinium nitrate and ferrous sulphate as a metal source, and plant polyphenols (i.e., tannic acid) as an organic ligand via a metal-catechol coordination assembly process. Such coordination polymers show a tunable molar ratio of Gd/Fe and high dispersibility and stability in aqueous solution. The coordination polymers reveal composition-dependent performance for longitudinal relaxivity and photothermal conversion. The longitudinal relaxivity is positively related to the molar ratio of Gd/Fe, while the photothermal performance is negatively related to the molar ratio of Gd/Fe in the coordination polymers. The coordination polymers with an optimized molar ratio of Gd/Fe exhibit an ultra-small hydrodynamic diameter (∼23 nm), a high r1 value (9.3 mM-1 s-1) with low r2/r1 (1.26) and high photothermal conversion efficiency (η = 37%). They can be used as a contrast agent for T1-weighted magnetic resonance imaging of EMT-6 tumor bearing mice, which can effectively enhance the signals of tumors. They can also effectively suppress tumor growth via photothermal therapy. This work brings new insights for the synthesis of multifunctional coordination polymer nanoparticles and extending their potential applications in theranostics.

Delivery of polymeric nanostars for molecular imaging and endoradiotherapy through the enhanced permeability and retention (EPR) effect.

Expression levels of biomarkers are generally unknown at initial diagnosis. The development of theranostic probes that do not rely on biomarker availability would expand therapy options for cancer patients, improve patient selection for nanomedicine and facilitate treatment of inoperable patients or patients with acquired therapy resistance. Herein, we report the development of star polymers, also known as nanostars, that allow for molecular imaging and/or endoradiotherapy based on passive targeting via the enhanced permeability and retention (EPR) effect.Methods: We synthesised a star copolymer, consisting of 7-8 centre-cross-linked arms that were modified with Gd3+ for magnetic resonance imaging (MRI), and functionalised either with 89Zr for in vivo quantification and positron emission tomography (PET) imaging, or with 177Lu for endoradiotherapy. 1H longitudinal relaxivities were determined over a continuum of magnetic field strengths ranging from 0.24 mT - 0.94 T at 37 °C (nuclear magnetic relaxation dispersion (NMRD) profile) and T1-weighted MRI contrast enhancement was visualized at 3 T and 7 T. PET imaging and ex vivo biodistribution studies were performed in mice bearing tumours with high EPR (CT26) or low EPR (BxPC3) characteristics. Therapy studies were performed in mice with high EPR tumours and mean absorbed organ doses were estimated for a standard human model.Results: The star copolymer with Gd3+ displayed a significantly superior contrast enhancement ability (T1 = 0.60 s) compared to the standard clinical contrast agent Gadovist (T1 = 1.0 s). Quantification of tumour accumulation using the radiolabelled nanostars in tumour-bearing mice demonstrated an exceptionally high uptake in tumours with high EPR characteristics (14.8 - 21.7 %ID/g). Uptake of the star polymers in tumours with low EPR characteristics was significantly lower (P<0.001), suggesting passive tumour accumulation of the nanostars via the EPR effect. Survival of mice treated with high dose 177Lu-labelled star polymers was significantly higher than survival of mice treated with lower therapy doses or control mice (P=0.001), demonstrating the utility of the 177Lu-labelled star polymers as platforms for endoradiotherapy.Conclusion: Our work highlights the potential of star polymers as probes for the molecular imaging of cancer tissue or for the passive delivery of radionuclides for endoradiotherapy. Their high functionalisability and high tumour accumulation emphasises their versatility as powerful tools for nanomedicine.

Single-step formulation of levodopa-based nanotheranostics - strategy for ultra-sensitive high longitudinal relaxivity MRI guided switchable therapeutics.

Nanotheranostics (combined diagnosis and therapy) is emerging as an integral part of future therapeutic strategies. However, the development and fabrication of a nanotheranostic module involves multistep processes and always faces formulation challenges. The complexity involved in its multi-step formulations hinders its reproducible industrial production and clinical translation. Therefore, a facile synthesis of multifunctional nanotheranostics is critical to its translational success. In this report, we have developed a one-pot facile strategy to prepare a MRI-visible photothermal theranostic switchable module (T-SWITCH). These nanoparticles are synthesized through polymerization of levodopa together with the reduction of KMnO4 in the presence of silk sericin for the formation of manganese dioxide particles within the T-SWITCH. The synthesized T-SWITCH showed a uniform size distribution of around 95.77 nm and high longitudinal relaxivity coefficient (r1) of up to 61.94 mM-1 s-1. The reported r1 of the T-SWITCH is exceedingly higher than that of any other previously reported manganese-based contrast agents with first-rate in vitro and in vivo contrast enhancement capability. The T-SWITCH can be activated to switch its therapeutic mode using near-infrared (NIR) light. It exhibited strong excitable absorption in the safer and biological NIR window between 650 and 900 nm. We have validated the significant anti-cancer therapeutic efficacy of T-SWITCH both in vitro and in vivo through switchable photothermal therapy.

Nanocomposites of ionic copolymer integrating Gd-containing polyoxometalate as a multiple platform for enhanced MRI and pH-response chemotherapy.

This article describes the fabrication of nanosized paramagnetic drug carriers via the assembly of a pH-responsive hydrophilic block copolymer poly(polyethylene glycol methyl ether methacrylate)-b-poly(methacrylic acid-co-trimethyl ammonium bromide propyl methacrylate) (PPMT) and polyoxometalate K13[Gd(β2-SiW11O39)2] (GdSiW11) through electrostatic interaction. Owing to the hydrophilicity, large molecular weight, and high content of the GdSiW11 cluster bearing in the nanocomposites, the organic-inorganic nanocomposite exhibited an impressive longitudinal relaxivity as a contrast agent for magnetic resonance imaging (MRI). The surplus negative charges from the polyoxometalate cluster in the polymer nanocomposites facilitated the capture of the anti-tumor drug doxorubicin (DOX). The DOX-loaded nanocomposites were stable under the physiological environment, whereas a responsive release of DOX was achieved at pH values similar to the tumor microenvironment due to the regulation of the polyoxometalate and carboxyl groups. The DOX-loaded PPMT2-GdSiW11 nanocomposites were observed to enrich effectively at tumor sites through MRI after intravenous injection. Furthermore, the DOX-loaded composites manifested enhanced in vivo anti-tumor therapeutic efficacy and sustainable circulation time of more than 5 h, which were favourable for imaging measurement. With the advantages of the designed composite system, the present experiments propose a strategy for developing a new multiple imaging-drug delivery-local therapy platform for synergistic diagnosis and therapy.

HSA functionalized Gd2O3:Eu3+ nanoparticles as an MRI contrast agent and a potential luminescent probe for Fe3+, Cr3+, and Cu2+ detection in water

PVP capped Gd2O3:Eu3+ (PVP@Gd2O3:Eu3+) and HSA functionalised PVP@Gd2O3:Eu3+ (HSA@PVP@Gd2O3:Eu3+) NPs as fluorescent detection probe for metal ion detection and MRI contrast agent.

Role of Gd2O3-doped carbon-11-choline-lenvatinib nanoparticles contrast agent PET/CT in the diagnosis of patients with lung cancer.

Positron emission tomography-computed tomography (PET/CT) is an efficient method for the diagnosis of various types of human cancer. Studies have demonstrated that Gd2O3-doped carbon-11-choline (GdCho) can be used as a contrast nanoparticle for PET/CT in the diagnosis of patients with lung cancer. The aim of the present study was to evaluate the effect of GdCho-lenvatinib nanoparticles contrast-PET/CT (GdCho-Len-PET) in the diagnosis and treatment planning of a cohort of patients suspected of having lung cancer. The results of the present study demonstrated that GdCho-Len could be used as an efficient PET/CT contrast agent for the diagnosis of patients with lung cancer. GdCho-Len nanoparticles contrast agent exhibited a significantly improved longitudinal relaxivity compared with GdCho. The outcomes of the present study were that GdCho-Len-PET diagnosed 152 patients with lung cancer, whereas GdCho-PET diagnosed 130 patients with lung cancer among the 172 patients. GdCho-Len-PET presented with higher accuracy and sensitivity compared with GdCho-PET in diagnosing patients with lung cancer. All patients were further confirmed via histological analysis. GdCho-Len-PET contributed to the anticancer treatments in 56 out of 62 (90.3%) patients with lung cancer who were candidates for radiation therapy, 52 out of 57 (91.2%) patients with lung cancer undergoing adjuvant radiotherapy, and 13 out of 17 (76.5%) patients with lung cancer undergoing comprehensive therapy. Patients diagnosed using GdCho-Len-PET improved the survival of patients with lung cancer during a 420-day follow up. In conclusion, GdCho-Len-PET increased the diagnostic efficacy and had a significant effect on survival for patients with lung cancer, and may therefore serve as a reliable method for human cancer diagnosis.

Cobalt/Manganese Oxides as Theragnosis Nanoplatforms With Magnetic Resonance/Near-Infrared Imaging for Efficient Photothermal Therapy of Tumors

The combination of near-infrared (NIR) response and imaging response is a hot research area in which the function of nanomaterials are maximized. However, such materials reported so far have problems such as complex synthesis. Herein, hydrophilic porous and hollow cobalt/manganese oxide (CMO) nanocrystals (NCs) were successfully prepared via a facile and green hydrothermal route. The CMO NCs show strong near-infrared (NIR) absorption, resulted from the defect structure due to a coexistence of Co2+ and Co3+ in as-prepared CMO NCs. Thus the CMO NCs exhibit an excellent photothermal performance, showing photothermal efficiency up to 43.2%. In addition, the CMO NCs possess the ability for magnetic resonance (MR) imaging with the longitudinal relaxivity (r1) is up to 3.48 mM−1 s−1. Finally, we, for the first time, proved the CMO nanocrystals as a promising photothermal agent. Our work provides the insight of Mn-based control agents and photothermal agents for photothermal theragnosis therapy.

Activatable Core-Shell Metallofullerene: An Efficient Nanoplatform for Bimodal Sensing of Glutathione.

Metallofullerenes have attracted considerable attention as potential novel noninvasive high-relaxivity magnetic resonance contrast agents. However, the applications of metallofullerenes as stimuli-responsive biosensors to monitor biological processes are still scarce. Herein, manganese-fullerenes core-shell nanocomposites are prepared via a facile one-pot approach to achieve GSH-activatable magnetic resonance/fluorescence bimodal imaging functions. The nanocomposites initially have a FRET-induced quenched fluorescence, and water-resisting stimulated low T1-MRI contrast. Upon exposure to GSH, collapse of the outer MnO2 shell led to reconstruction of the nanoprobes and subsequently resulted in multicolor fluorescence recovery and longitudinal (T1) relaxivity enhancement (r1 value up to 29.8 mM-1 s-1 at 0.5 T based on Mn ion). Our work demonstrates feasibility of using fullerenes to fabricate activatable probes for molecular imaging of GSH, which may promote the development of new fullerene-based stimuli-responsive multimodal probes for the detection and regulation of particular biological processes in vivo.

Biomineralized Gd2 O3 @HSA Nanoparticles as a Versatile Platform for Dual-Modal Imaging and Chemo-Phototherapy-Synergized Tumor Ablation.

A great challenge still remains to explore the facile approaches to construct multifunctional nanoparticles for acquiring precise cancer theranostics. Herein, a biocompatible theranostic nanoplatform capable of simultaneous cancer imaging and therapy is attempted by loading of paclitaxel (PTX) and indocyanine green (ICG) molecules into the matrix of Gd2 O3 @human serum albumin (HSA) nanoparticles (PIGH NPs) via hydrophobic interaction. The subsequent in vitro investigations reveal that the PIGH NPs afford uniform particle size, sustained drug release profile, strong longitudinal relaxivity, potent photothermal effect, effective singlet oxygen generation, and ideal resistance to photobleaching. Moreover, the PIGH NPs achieve high cellular uptake, efficient cytoplasmic drug translocation based on singlet oxygen-triggered endolysosomal disruption and prominent cytotoxicity effect against 4T1 cells under 808 nm near-infrared (NIR) irradiation in contrast to PTX/ICG-loaded HSA nanoparticles (PIH NPs) and free PTX/ICG. After intravenous injection, the PIGH NPs exhibit preferable tumor accumulation and achieve effective tumor ablation in 4T1 tumor bearing mouse model with excellent dual near-infrared fluorescence/magnetic resonance (NIRF/MR) imaging guided synergistic chemo-phototherapy. Hence, the PIGH NPs can be utilized as potential theranostic nanosystem for simultaneous cancer imaging and therapy.

Macrophage-targeted and clearable glutathione-based MRI nanoprobes for atherosclerosis molecular imaging

Foam macrophage infiltration is one of the clinical features of high-risk atherosclerotic plaques. Many imaging modalities such as magnetic resonance imaging (MRI) have been used to detect foam macrophages for evaluating plaque vulnerability. However, targeting efficiency, biocompatibility, and clearance remain pivotal challenges in design of new MRI contrast agents. Herein, we report a sensitive, class AI scavenger receptors (SR-AI)-targeted, glutathione-biomineralized gadolinium-based nanoparticle for noninvasive precise MR imaging of macrophages within carotid atherosclerotic lesions in apoE-deficient (ApoE−/−) mice. The resultant PP1 (16-mer peptide, LSLERFLRCWSDAPAK)-gold-gadolinium nanoparticles (NPs) possessed superior stability, prominent longitudinal relaxivity, and negligible cytotoxicity. In vitro results showed the highest internalization in activated macrophages and in vivo MR images revealed signal augment in carotid atherosclerotic lesions after PP1-gold-gadolinium NP administration at 4 h and 12 h, which were strong testimonial to the formidable macrophage-targeting ability and the subsequent atherosclerosis-retention biofunctions. To summarize, our tactically elaborated biocompatible multifunctional MR NPs integrate T1 signal amplification, precise macrophage targeting, and systematic clearance capabilities, which offer an innovative strategy for noninvasively characterizing vulnerable plaques of early-stage atherosclerosis, or for a wide range of clinical diagnosis and treatment applications.

Mn-Porphyrin-Based Metal-Organic Framework with High Longitudinal Relaxivity for Magnetic Resonance Imaging Guidance and Oxygen Self-Supplementing Photodynamic Therapy.

A nanoplatform for magnetic resonance imaging guidance and oxygen self-supplementing photodynamic therapy (PDT) was constructed on the basis of a porous metal-organic framework (PCN-222(Mn)), which was built by simple Mn-porphyrin ligands and biocompatible Zr4+ ions. Because of the good dispersibility of Mn3+ in the open framework and the high water affinity of the channel, PCN-222(Mn) exhibits a high longitudinal relaxivity of ∼35.3 mM-1 s-1 (1.0 T). In addition, it shows good catalytic activity for the conversion of endogenous hydrogen peroxide into oxygen, thereby improving tumor hypoxia during photodynamic therapy. The intravenous injection of PCN-222(Mn) into tumor-bearing mice mode provided good T1-weighted contrast of the tumor site and effectively inhibited tumor growth upon a single-laser irradiation. The findings provide insights for the development of multifunctional theranostic nanoplatforms based on simple components.

Synthesis Of PEG-Coated, Ultrasmall, Manganese-Doped Iron Oxide Nanoparticles With High Relaxivity For T1/T2 Dual-Contrast Magnetic Resonance Imaging.

BackgroundBeyond magnetic resonance imaging (MRI), which has been widely used clinically, molecular MRI (mMRI) can further provide qualitative and quantitative information at the cellular and molecular levels. However, the diagnostic accuracy may not be satisfactory via single-contrast mMRI due to some interferences in vivo. T1/T2 dual-contrast MRI using the same contrast agent (CA) could significantly improve the detection accuracy. Therefore, in this study, we fabricated poly(ethylene glycol) (PEG)-coated, manganese-doped iron oxide nanocomposites (Mn-IONPs@PEG) as T1/T2 dual-contrast CA, and evaluated its feasibility of T1/T2 dual-contrast MRI in vitro and in vivo.MethodsMn-IONPs were prepared by the thermal decomposition of iron-eruciate and manganese-oleate complexes and were coated with 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy[polyethylene glycol]-2000) (DSPE-PEG 2000). The physicochemical properties and cytotoxicity of the Mn-IONPs were fully characterized, followed by MRI in vitro and in vivo.ResultsUltrasmall 3 nm-sized nanoparticles were successfully prepared and were identified using transmission electron microscopy (TEM), high-resolution TEM, and X-ray diffraction. After coating with DSPE-PEG, the Mn-IONPs@PEG displayed excellent hydrophilicity and good biocompatibility. Due to the manganese-doping and PEG coating, the Mn-IONPs@PEG showed good relaxivity in vitro. Especially, the Mn-IONPs@PEG coated with DSPE-PEG following a mass ratio to Mn-IONPs of 1:20 showed harmonious longitudinal relaxivity (r1 = 7.1 mM−1s−1) and transversal relaxivity (r2 = 120.9 mM−1s−1), making it a better candidate for T1/T2 dual-contrast mMRI. After administrated via a caudal vein, the Mn-IONPs@PEG can induce significant enhancement in both T1-weighted and T2-weighted MR images and the time at 10 mins after injection was regarded as a suitable time for imaging because both the T1 and T2 enhancement were optimum at that time.ConclusionThe obtained Mn-IONPs@PEG exhibited good r1 and r2 and was a reasonable candidate for T1/T2 dual-contrast mMRI.

Comparison of MRI Properties between Multimeric DOTAGA and DO3A Gadolinium-Dendron Conjugates.

The inherent lack of sensitivity of MRI needs the development of new Gd contrast agents in order to extend the application of this technique to cellular imaging. For this purpose, two multimeric MR contrast agents obtained by peptidic coupling between an amido amine dendron and GdDOTAGA chelates (premetalation strategy, G1-4GdDOTAGA) or DO3A derivatives which then were postmetalated (G1-4GdDO3A) have been prepared. By comparison to the monomers, an increase of longitudinal relaxivity has been observed for both structures. Especially for G1-4GdDO3A, a marked increase is observed between 20 and 60 MHz. This structure differs from G1-4GdDOTAGA by an increased rigidity due to the aromatic linker between each chelate and the organic framework. This has the effect of limiting local rotational movements, which has a positive impact on relaxivity.

Understanding the High Longitudinal Relaxivity of Gd(DTPA)-Intercalated (Zn,Al)-Layered Double Hydroxide Nanoparticles.

In this study, biocompatible gadolinium diethylenetriaminepentaacetate (Gd(DTPA))-intercalated (Zn,Al)-layered double hydroxide (LDH) nanoparticles were synthesized, characterized for Gd(DTPA) loading percentage and nanostructure, and the spin-lattice relaxation times (T1) measured to determine their suitability as a potential T1-weighted contrast agent for magnetic resonance imaging (MRI). Compared to the most commonly used contrast agent in clinical MRI (i.e., molecular Gd(DTPA)), significant increases in longitudinal relaxivity (r1) were measured for all Gd(DTPA)-intercalated nanoparticles. For a specific Zn2Al(OH)6(Cl,0.5CO3)0.56Gd(DTPA)0.086·xH2O composition, r1 was found to be 28.38 s-1 mM-1, which is over 6 times the r1 of molecular Gd(DTPA). This dramatic increase in r1 is attributed to (a) the much longer rotational correlation time (τR) of nanoparticles and (b) the inherent water of LDH that forms the second-/outer-sphere in the vicinity of intercalated Gd(DTPA)2-. The latter, with an extensive hydrogen bonding network and insignificant translational motion, results in a longer mean residence lifetime (τM), which makes the contribution of second-/outer-sphere significant. Therefore, when the Gd(DTPA)2- loading percentage increases from 8.6 to 55%, the diminution of the ratio of inherent water to Gd(DTPA)2- concomitantly diminishes the contributions by second-/outer-sphere water to r1. Additionally, the modest increase in r1 with decreasing particle size (∼315-540 nm) is perhaps due to the shortening of τM. Finally, the spin-spin relaxation times (T2) of 17O, determined at various temperatures, show a negligible exchange of water molecules at room temperature. Therefore, the very high r1 of nanoparticles indicate that protons of the bulk water are still accessible to the Gd3+ centers, possibly dominated by prototropic exchange through the hydrogen bonding network.

D‐Glucuronic Acid‐Coated Ultrasmall Paramagnetic Ln2O3 (Ln = Tb, Dy, and Ho) Nanoparticles: Magnetic Properties, Water Proton Relaxivities, and Fluorescence Properties

Many of the lanthanide‐based nanoparticles are valuable in magnetic resonance imaging (MRI) because they have excellent magnetic properties that make them suitable for MRI contrast agents, while some of them have additional optical properties and thus can serve as fluorescence imaging (FI) agents as well. Herein, we synthesized d‐glucuronic acid‐coated ultrasmall Ln2O3 (Ln = Tb, Dy, and Ho) nanoparticles with average diameters of ∼ 2 nm. All the nanoparticles showed unsaturated but appreciable magnetization of ∼ 4 emu/g at an applied field of 1.8 T at room temperature, and consequently, high transverse water proton relaxivities (r2) of ∼ 7 s–1 mm–1 at 1.5 T, ∼ 35 s–1 mm–1 at 3.0 T, and ∼ 55 s–1 mm–1 at 9.4 T with negligible longitudinal water proton relaxivities (r1), thus being eligible for use as T2 MRI contrast agents at high MR fields. In addition, d‐glucuronic acid‐coated ultrasmall Tb2O3 nanoparticles exhibited fluorescence in the green region, useful for dual‐modal imaging.

Safe and potent MRI contrast agents by complexing gadolinium with enzyme/reduction dual-sensitive branched polymers

To address the issue of inefficient signal enhancement by polymeric magnetic resonance imaging (MRI) contrast agents, herein, we have prepared a high molecular-weight (MW) branched and gadolinium (Gd)-labeled N-(1,3-dihydroxypropyl)methacrylamide (DHPMA) copolymer (branched-pDHPMA-SS-Gd, 192 kDa, about 110 nm) by linking each branched chain by an enzyme-sensitive tetrapeptide (GFLG), and small molecule DOTA-Gd was conjugated to the carrier with a reduction-sensitive disulfide bond to obtain an enzyme/reduction dual-sensitive contrast agent. For control studies, DOTA-Gd was conjugated to an enzyme-sensitive branched carrier without a disulfide bond, resulting in a single sensitive branched copolymer (branched-pDHPMA-Gd, 198 kDa, about 110 nm). The longitudinal relaxivities of branched-pDHPMA-SS-Gd (r1 = 12.48 mM−1 s−1) and branched-pDHPMA-Gd (r1 = 14.37 mM−1 s−1) were 3–4 folds of clinical DTPA-Gd (r1 = 3.53 mM−1 s−1). The in vivo imaging signal enhancement by branched-pDHPMA-SS-Gd (about 130%) was similar to that of branched-pDHPMA-Gd (120%), which was 2.4 to 2.6-fold higher than that of clinical DTPA-Gd (about 50%). Although branched copolymers had the similar capability in enhancing MRI signals, enzyme/reduction dual-sensitive branched-pDHPMA-SS-Gd released low MW Gd-chelates at a more rapid rate, rendering it better biosafety and biodegradability. In conclusion, this study provides an important theoretical and experimental foundation for construction of Gd-based multi-sensitive polymeric MRI contrast agents with great biosafety and high efficiency.

The Transition from Metal-Based to Metal-Free Contrast Agents for T1 Magnetic Resonance Imaging Enhancement.

Magnetic resonance imaging (MRI) has received significant attention as the noninvasive diagnostic technique for complex diseases. Image-guided therapeutic strategy for diseases such as cancer has also been at the front line of biomedical research, thanks to the innovative MRI, enhanced by the prior delivery of contrast agents (CAs) into patients' bodies through injection. These CAs have contributed a great deal to the clinical utility of MRI but have been based on metal-containing compounds such as gadolinium, manganese, and iron oxide. Some of these CAs have led to cytotoxicities such as the incurable Nephrogenic Systemic Fibrosis (NSF), resulting in their removal from the market. On the other hand, CAs based on organic nitroxide radicals, by virtue of their structural composition, are metal free and without the aforementioned drawbacks. They also have improved biocompatibility, ease of functionalization, and long blood circulation times, and have been proven to offer tissue contrast enhancement with longitudinal relaxivities comparable with those for the metal-containing CAs. Thus, this Review highlights the recent progress in metal-based CAs and their shortcomings. In addition, the remarkable goals achieved by the organic nitroxide radical CAs in the enhancement of MR images have also been discussed extensively. The focal point of this Review is to emphasize or demonstrate the crucial need for transition into the use of organic nitroxide radicals-metal-free CAs-as against the metal-containing CAs, with the aim of achieving safer application of MRI for early disease diagnosis and image-guided therapy.

Linear and Core-Crosslinked Glycopolymer-Gadolinium Conjugates: Preparation and Their Behaviors as Nanoscale Magnetic Resonance Imaging Contrast Agents.

In this study, a linear glycopolymer-gadolinium conjugate (pGAEMA-DOTA-Gd) was prepared via the reversible addition fragmentation chain transfer (RAFT) polymerization. In addition, a crosslinked polymer-gadolinium conjugate (Crosslinked pGAEMA-DOTA-Gd) was prepared via a two-step RAFT polymerization approach, and its core was composed of the biodegradable oligopeptide GFLG. The features of the two glycopolymer-gadolinium conjugates as highly efficient and safe nanoscale contrast agents were discussed. These two glycopolymer-DOTA-Gd conjugates have aqueous dynamic particle sizes of 4.8 nm and 21.3 nm with neutral charges. Longitudinal relaxivity (r1) of these two glycopolymer-gadolinium conjugates were three to four times higher than that of clinical agent DTPA-Gd. Animal studies showed that pGAEMA-DOTA-Gd and Crosslinked pGAEMA-DOTA-Gd demonstrated higher signal intensity and the relative change in T1 value (ΔT1) in mouse liver and kidney, and prolonged blood circulation time compared to DTPA-Gd. Notably, the performance of the core-crosslinked glycopolymer conjugate was better than that of the linear polymer. Inductively coupled plasma mass spectrometry (ICP-MS) results showed that polymeric contrast agents, especially the crosslinked one, showed higher aggregation in mouse liver and kidney, and were mainly excreted through renal routes eventually. In vitro and in vivo toxicity studies in healthy mice including cytotoxicity, blood compatibility and systemic toxicity indicated the absence of significant toxicity. Therefore, the prepared glycopolymer-DOTA-Gd conjugates may have significant potential as highly efficient and safe nanoscale MRI contrast agents.

Wüstite-type Fe0.78Mn0.22O nanocubes: A new class for high-sensitive T2-weighted magnetic resonance imaging agent

Wüstite-type Fe0.78Mn0.22O nanocubes, with a uniform size of ∼10 nm in edge length, have been synthesized by thermal-decomposition approach. The nanocubes exhibited superparamagnetic properties at room temperature, associated with a magnetization of 12.6 emu/g. These Fe0.78Mn0.22O nanocubes present transversal (r2) and longitudinal (r1) relaxivities of 325.9 and 0.518 mM−1 s−1 at 7 T for water protons. The ratio of the r2/r1 (629.2) ranks them being the highest sensitivity (r2/r1) comparable to currently reported T2-weighted magnetic resonance imaging (MRI) agents. Meanwhile, the Fe0.78Mn0.22O nanocubes were functionalized and demonstrated to be biocompatible when attached to the surface of mesenchymal stem cells, therefore showing the promise as a new class of MRI agents in clinic applications.