T1 Contrast Agents Research Articles

Gd2O3-mesoporous silica/gold nanoshells: A potential dual T1/T2 contrast agent for MRI-guided localized near-IR photothermal therapy

A promising clinical trial utilizing gold-silica core-shell nanostructures coated with polyethylene glycol (PEG) has been reported for near-infrared (NIR) photothermal therapy (PTT) of prostate cancer. The next critical step for PTT is the visualization of therapeutically relevant nanoshell (NS) concentrations at the tumor site. Here we report the synthesis of PEGylated Gd2O3-mesoporous silica/gold core/shell NSs (Gd2O3-MS NSs) with NIR photothermal properties that also supply sufficient MRI contrast to be visualized at therapeutic doses (≥108 NSs per milliliter). The nanoparticles have r1 relaxivities more than three times larger than those of conventional T1 contrast agents, requiring less concentration of Gd3+ to observe an equivalent signal enhancement in T1-weighted MR images. Furthermore, Gd2O3-MS NS nanoparticles have r2 relaxivities comparable to those of existing T2 contrast agents, observed in agarose phantoms. This highly unusual combination of simultaneous T1 and T2 contrast allows for MRI enhancement through different approaches. As a rudimentary example, we demonstrate T1/T2 ratio MR images with sixfold contrast signal enhancement relative to its T1 MRI and induced temperature increases of 20 to 55 °C under clinical illumination conditions. These nanoparticles facilitate MRI-guided PTT while providing real-time temperature feedback through thermal MRI mapping.

Engineering manganese ferrite shell on iron oxide nanoparticles for enhanced T1 magnetic resonance imaging

Doping Mn (II) ions into iron oxide (IO) as manganese ferrite (MnIO) has been proved to be an effective strategy to improve T1 relaxivity of IO nanoparticle in recent years; however, the high T2 relaxivity of MnIO nanoparticle hampers its T1 contrast efficiency and remains a hurdle when developing contrast agent for early and accurate diagnosis. Herein, we engineered the interfacial structure of IO nanoparticle coated with manganese ferrite shell (IO@MnIO) with tunable thicknesses. The Mn-doped shell significantly improve the T1 contrast of IO nanoparticle, especially with the thickness of ∼0.8 nm. Compared to pristine IO nanoparticle, IO@MnIO nanoparticle with thickness of ∼0.8 nm exhibits nearly 2 times higher T1 relaxivity of 9.1 mM−1s−1 at 3 T magnetic field. Moreover, exclusive engineering the interfacial structure significantly lower the T2 enhancing effect caused by doped Mn (II) ions, which further limits the impairing of increased T2 relaxivity to T1 contrast imaging. IO@MnIO nanoparticles with different shell thicknesses reveal comparable T1 relaxation rates but obvious lower T2 relaxivities and r2/r1 ratios to MnIO nanoparticles with similar sizes. The desirable T1 contrast endows IO@MnIO nanoparticle to provide sufficient signal difference between normal and tumor tissue in vivo. This work provides a detailed instance of interfacial engineering to improve IO-based T1 contrast and a new guidance for designing effective high-performance T1 contrast agent for early cancer diagnosis.

Metal-Free Radical Dendrimers as MRI Contrast Agents for Glioblastoma Diagnosis: Ex Vivo and In Vivo Approaches

Simultaneously being a nonradiative and noninvasive technique makes magnetic resonance imaging (MRI) one of the highly required imaging approaches for the early diagnosis and follow-up of tumors, specifically for brain cancer. Paramagnetic gadolinium (Gd)-based contrast agents (CAs) are the most widely used ones in brain MRI acquisitions with special interest when assessing blood–brain barrier (BBB) integrity, a characteristic of high-grade tumors. However, alternatives to Gd-based contrast agents (CAs) are highly required to overcome their established toxicity. Organic radicals anchored on a dendrimer macromolecule surface (radical dendrimers) are promising alternatives since they also exhibit paramagnetic properties and can act as T1 CAs like Gd-based CAs while being organic species (mitigating concerns about toxic metal accumulation). Here, we studied the third generation of a water-soluble family of poly(phosphorhydrazone) radical dendrimers, with 48 PROXYL radical units anchored on their branches, exploring their potential of ex vivo and in vivo contrast enhancement in brain tumors (in particular, of immunocompetent, orthotopic GL261 murine glioblastoma (GB)). Remarkably, this radical species provides suitable contrast enhancement on murine GL261 GB tumors, which was comparable to that of commercial Gd-based CAs (at standard dose 0.1 mmol/kg), even at its 4 times lower administered dose (0.025 mmol/kg). Importantly, no signs of toxicity were detected in vivo. In addition, it showed a selective accumulation in brain tumor tissues, exhibiting longer retention within the tumor, which allows performing imaging acquisition over longer time frames (≥2.5 h) as opposed to Gd chelates. Finally, we observed high stability of the radicals in biological media, on the order of hours instead of minutes, characteristic of the isolated radicals. All of these features allow us to suggest that the G3-Tyr-PROXYL-ONa radical dendrimer could be a viable alternative to metal-based MRI contrast agents, particularly on MRI analysis of GB, representing, to the best of our knowledge, the first case of organic radical species used for this purpose and one of the very few examples of these types of radical species working as MRI CAs in vivo.

A novel MMP-responsive nanoplatform with transformable magnetic resonance property for quantitative tumor bioimaging and synergetic chemo-photothermal therapy

Quantifying bio-targeted markers in the tumor microenvironment through non-invasive approaches remains challenging. In this study, a novel matrix metalloproteinase-9 (MMP9) responsive nanoplatform (PMP@USPIO/DOX, PMPSD) with transformable magnetic resonance property is designed for quantitative tumor bioimaging and synergetic chemo-photothermal therapy. The nanoplatform acts as a T2 contrast agent in physiological conditions due to the ultrasmall superparamagnetic iron oxide (USPIO) aggregation state, whereas in the tumor microenvironment, the nanoclusters are dissociated by MMP9, thus transforming the nanoplatform into a T1 contrast agent. T1&T2 weighted image and T1&T2 maps are utilized to quantitatively study the correlation between MRI signal changes and MMP9 concentrations and to evaluate MMP9 activity. In addition, the PMP@USPIO/DOX nanoplatform possesses excellent photothermal properties. PMPSD combined with laser irradiation is more effective than single chemo-/photothermal therapy, and up-regulation of the MMP9 level in the tumor can further improve the therapeutic effect. The nanoplatform is of great significance in evaluating disease prognosis and non-invasive monitoring of drug release. The concept reported here provides a creative idea for the non-invasive quantitative study of the tumor microenvironment.

Fe/Mn‐Porphyrin Coordination Polymer Nanoparticles for Magnetic Resonance Imaging (MRI) Guided‐Combination Therapy between Photodynamic Therapy and Chemodynamic Therapy

AbstractCombination therapy is considered to be an effective strategy for enhanced tumor treatment. Here we fabricated amorphous dual metal (FeMn)‐porphyrin based coordination polymer nanoparticles FeMn‐TCPP NPs via a facile and mild protocol. The formed FeMn‐TCPP NPs possessed the combination therapy between photodynamic therapy attributed to TCPP ligand and chemodynamic therapy mainly ascribed to chemodynamic therapy agent Fe (II). Moreover, Mn (II) as a T1 contrast agent endowed the FeMn‐TCPP NPs with significant r1 relaxivity for MRI imaging. Notably, FeMn‐TCPP NPs not only integrated the functional agents into one nanoplatform but also exhibited synergetic effects for enhanced combination therapy. All the features allowed the FeMn‐TCPP NPs as an all‐in‐one nanoplatform toward precision cancer therapy.

Unimolecular Nano-contrast Agent with Ultrahigh Relaxivity and Very Long Retention for Magnetic Resonance Lymphography.

Magnetic resonance (MR) imaging is very important for noninvasive lymphography. However, the present MR contrast agents still cannot supply strong enough tissue contrast and long observation window. To improve the performance of contrast agents, we introduce one-dimensional unimolecular nanoparticles with a confined and compact poly(acrylic acid) core as nanoparticulate chelates of gadolinium ions. Thus, obtained nanoparticulate T1 contrast agents give r1 relaxivity as high as 136.3 mM-1·s-1 under 3.0 T. By injection at the footpad of mice, the contrast agents provide excellent contrast enhancement of lymphatic drainage and they may arrive at popliteal lymph nodes within 30 min and reside for more than 80 h. High performance of the present contrast agent is attributed to the confined and compact core of materials that increase hydration number, intershell water diffusion, and decrease rotational motion.

High content and dispersion of Gd in bimodal porous silica: T2 contrast agents under ultra-high magnetic fields

Silica-based UVM-7-type bimodal mesoporous materials with high gadolinium content (∞ ≥ Si/Gd ≥ 13) have been synthesized through a one-pot surfactant-assisted procedure from hydroalcoholic solution using a cationic surfactant as template, and starting from atrane complexes of Gd and Si as inorganic precursors. The novel synthetic pathway developed in the study preserves the UVM-7-type architecture while optimizing the dispersion of the Gd-guest species at the nanoscale and even at atomic level. It has been determined that the number of Gd atoms forming clusters is always less than 10. The behaviour under exposure to ultra-high magnetic fields reveals a significant increase in the transversal relaxivity value when compared with related materials in the bibliography. Their activity as T2 instead of T1 contrast agents is discussed and explained considering the high Gd-dispersion and concentration, nature of the materials as well as due to the high magnetic fields used, typical of MRM studies. The absence of toxicity has been confirmed in preliminary cell cultures “in vitro” and the degradation of the solids studied under biological conditions. Results suggest that the atrane route could be a suitable synthesis approach for the preparation of Gd containing contrast agents. • Very high Gd-containing (Si/Gd = 11–13) hierarchical bimodal porous silicas have been synthesized. • The materials are monophasic samples without segregation of Gd 2 O 3 nanodomains. • The Gd centres result highly dispersed in the form of Gd n clusters (n < 10). • The high Gd concentration and dispersion confers these materials interest as contrast agents. • A remarkable increase of the T2 relaxivity when working under ultra-high magnetic fields is observed.

Photoinduced Superhydrophilicity of Gd-Doped TiO2 Ellipsoidal Nanoparticles Boosts T1 Contrast Enhancement for Magnetic Resonance Imaging.

The unsatisfactory performance of current gadolinium chelate based T1 contrast agents (CAs) for magnetic resonance imaging (MRI) stimulates the search for better alternatives. Herein, we report a new strategy to substantially improve the capacity of nanoparticle-based T1 CAs by exploiting the photoinduced superhydrophilic assistance (PISA) effect. As a proof of concept, we synthesized citrate-coated Gd-doped TiO2 ellipsoidal nanoparticles (GdTi-SC NPs), whose r1 increases significantly upon UV irradiation. The reduced water contact angle and the increased number of surface hydroxyl groups substantiate the existence of the PISA effect, which considerably promotes the efficiency of paramagnetic relaxation enhancement (PRE) and thus the imaging performance of GdTi-SC NPs. In vivo MRI of SD rats with GdTi-SC NPs further demonstrates that GdTi-SC NPs could serve as a high-performance CA for sensitive imaging of blood vessels and accurate diagnosis of vascular lesions, indicating the success of our strategy.

Heterogeneous Iron Oxide/Dysprosium Oxide Nanoparticles Target Liver for Precise Magnetic Resonance Imaging of Liver Fibrosis.

Challenges remain in precisely diagnosing the progress of liver fibrosis in a noninvasive way. We here synthesized small (4 nm) heterogeneous iron oxide/dysprosium oxide nanoparticles (IO-DyO NPs) as a contrast agent (CA) for magnetic resonance imaging (MRI) to precisely diagnose liver fibrosis in vivo at both 7.0 and 9.4 T field strength. Our IO-DyO NPs can target the liver and show an increased T2 relaxivity along with an increase of magnetic field strength. At a ultrahigh magnetic field, IO-DyO NPs can significantly improve spatial/temporal image resolution and signal-to-noise ratio of the liver and precisely distinguish the early and moderate liver fibrosis stages. Our IO-DyO NP-based MRI diagnosis can exactly match biopsy (a gold standard for liver fibrosis diagnosis in the clinic) but avoid the invasiveness of biopsy. Moreover, our IO-DyO NPs show satisfactory biosafety in vitro and in vivo. This work illustrates an advanced T2 CA used in ultrahigh-field MRI (UHFMRI) for the precise diagnosis of liver fibrosis via a noninvasive means.

Relaxivity properties of magnetoferritin: The iron loading effect

Self-assembling ferritin protein cages have been used as a template for magnetic iron oxide nanoparticle synthesis within its 8nm cavity to be explored as a potential magnetic resonance imaging contrast agent. Here in, magnetic nanocores with various iron content were successfully synthesized using recombinant human H-chain ferritin (HFn) by a controlled mineralization reaction. r1 and r2 relaxivities of the synthesized magnetoferritin nanoparticles were measured and the effect of iron loading factor on the r1 and r2 relaxivity was investigated by using a quite large range of 10 different iron loadings per protein cage (500-5000) at 90MHz and 300MHz. The sample with the highest iron loading of 5329 Fe/cage has r2 value of 165.2mM-1s-1 and r1 value of 1.98mM-1s-1 at 300MHz. This high r2 value together with a very low protein and iron concentrations (0.03-0.2mg/mL and 0.15mM, respectively) renders magnetoferritin very effective T2 contrast agents. However, r1 values were found to be smaller than literature values suggesting that magnetoferritin may not serve as T1 contrast agent in MRI. Moreover, magnetoferritin showed an increase in r2 relaxivity with the iron loadings while r1 values have not been affected by the number of Fe atoms loaded as much as r2 values. This result also sheds light on understanding the formation mechanism of iron oxide core and its contribution on relaxation in MRI.

Gadolinium-Coated Mesoporous Silica Nanoparticle for Magnetic Resonance Imaging.

Magnetic resonance molecular imaging can provide anatomic, functional and molecular information. However, because of the intrinsically low sensitivity of magnetic resonance imaging (MRI), high-performance MRI contrast agents are required to generate powerful image information for image diagnosis. Herein, we describe a novel T 1 contrast agent with magnetic-imaging properties facilitated by the gadolinium oxide (Gd2O3) doping of mesoporous silica nanoparticles (MSN). The size, morphology, composition, MRI relaxivity (r 1 ), surface area and pore size of these nanoparticles were evaluated following their conjugation with Gd2O3 to produce Gd2O3@MSN. This unique structure led to a significant enhancement in T 1 contrast with longitudinal relaxivity (r 1 ) as high as 51.85 ± 1.38 mM−1s−1. Gd2O3@MSN has a larger T 1 relaxivity than commercial gadolinium diethylene triamine pentaacetate (Gd-DTPA), likely due to the geometrical confinement effect of silica nanoparticles. These results suggest that we could successfully prepare a novel high-performance T 1 contrast agent, which may be a potential candidate for in-vivo MRI.

Continuous synthesis of extremely small-sized iron oxide nanoparticles used for T1-weighted magnetic resonance imaging via a fluidic reactor

Extremely small-sized iron oxide nanoparticles (ESIONPs) with sizes less than 5 nm have shown great promise as T1 contrast agents for magnetic resonance imaging (MRI). However, their facile and scalable production with simultaneously endowed biocompatible surface chemistry remains difficult to be realized. In this study, by using the coprecipitation method implemented in a specially designed gas/liquid mixed phase fluidic reactor, polyglucose sorbitol carboxymethyether (PSC) coated ESIONPs were continuously synthesized with controllable particle sizes ranging from 1.8 to 4 nm. Among the differently sized ESIONPs, the 3.7-nm ESIONPs exhibit the best performance as T1 MRI contrast agent, featuring a high r1 value of 4.11 (mmol L−1)−1 s−1 and low r2/r1 ratio of 7.90 under a clinical 3 T MR scanning, as well as the excellent T1 MRI contrast effect in not only water but also the cellular environment and blood vessel. Furthermore, the ESIONPs possess long-term stability and good dispersity in aqueous dispersions, making them ideal candidates as safe and effective T1-weighted MRI contrast agent for real clinical use.

Transition-metal-doped hydrophilic ultrasmall iron oxide modulates MRI contrast performance for accurate diagnosis of orthotopic prostate cancer.

The FDA-approved iron oxide nanocrystals (IONs), as negative magnetic resonance imaging contrast agents (MRICAs), face challenges because of their low relaxation rate and coherent ferromagnetism. Although research has found that metal doping is an efficient approach to improve the magnetic property and MRI contrast performance of IONs, their systemic mechanism has not been fully explained. Herein, we fabricated a series of transition-metal-doped IONs and systemically explored their sizes, structures, and variation in magnetic properties, revealing the oxygen vacancy-mediated MRI contrast enhancement mechanism of transition-metal-doped IONs. Based on these, we found that Zn-doped IONs possess optimal T2 MRI contrast performance and further investigated their potential to diagnose in vivo orthotopic tumor as a T2 contrast agent. The results indicate that the use of Zn-doped IONs significantly enhances T2-weighted MRI signal intensity of orthotopic prostate tumor with low toxicity, which is beneficial for the accurate diagnosis of orthotopic tumor. Collectively, this work clearly illustrates the mechanism of contrast enhancement of transition-metal-doped IONs and provides a novel paradigm for developing a highly efficient T2 contrast agent.

Ultrasound-assisted co-precipitation synthesis of GdFeO3 nanoparticles: structure, magnetic and MRI contrast properties.

Superparamagnetic nanocrystals of gadolinium orthoferrite (GdFeO3) with close to isometric morphology were successfully synthesized by heat treatment of gadolinium and iron(III) hydroxides obtained by direct co-precipitation with and without ultrasonic irradiation. The obtained samples were investigated by PXRD, low-temperature nitrogen adsorption-desorption isotherm measurements, HRTEM and VSM. It was established that ultrasonication during co-precipitation led to a decrease in the average size of GdFeO3 crystallites obtained after heat treatment by approximately 19%, an increase in their BET specific surface area by more than two times, a decrease in the degree of their aggregation by about five times and an improvement in their magnetic properties due to the increase in phase homogeneity. The colloidal solutions of the GdFeO3 nanoparticles synthesized using ultrasound were investigated by 1H NMR to measure the T1 and T2 relaxation times of water protons at 0.47 T. The resulting relaxivities r1 and r2 were approximately recalculated at 1.5, 3 and 4.7 T on the basis of a semi-statistical ad hoc method by analyzing the literature data for a number of structurally similar compounds with reported relaxivity values at different NMR frequencies. According to the experimental and predicted values of the r2/r1 ratio, the investigated GdFeO3 sample may be classified as a T1-contrast agent for MRI at 0.47 and 1.5 T, as a T1-T2 dual-modal contrast agent at 3 T and as a T2-contrast agent at 4.7 T.

Synthesis and structural characterization of silica particles doped with Dy and Gd paramagnetic ions as MRI contrast agents

Silica submicronic particles doped with Dy and Gd paramagnetic ions were successfully synthesized by using chemical synthesis based on the modified Stöber method, having potential applications as contrast agents for magnetic resonance imaging (MRI).Structural characterization analyses show an amorphous character of the particles (XRD), good thermal stability (DTA), and spheroid shape (SEM). The integration of paramagnetic ions into the silica network was demonstrated by the TEM, EPR and FTIR spectroscopies.The magnetic resonance (MR) relaxivity examinations of the samples show a high rate of relaxivity for the particles doped with Dy, making them suitable as T2 contrast agent for magnetic resonance imaging. This is in contrast to the results obtained on the particles doped with Gd, which are an effective T1-weighted MRI contrast agent. Notably, if the silica structure incorporates both Gd and Dy the particles are suitable for contrast enhancement in both T1 and T2 weighted images. These characteristics of the samples are also supported by the value of the relaxivity ratio (r2/r1) for the three samples doped with paramagnetic ions. The results confirm the sustainability of MRI contrast agent applications for all three synthesized samples.

Facile synthesis of superparamagnetic nickel-doped iron oxide nanoparticles as high-performance T1 contrast agents for magnetic resonance imaging.

Small-sized iron oxide nanoparticles (IONPs) are an excellent alternative to clinical gadolinium-based contrast agents (GBCAs) in T1-weighted magnetic resonance imaging (MRI) due to their biosafety. However, their relaxation efficiency and contrast enhancement are not significant compared with those of GBCAs, and the nanomaterials face stability problems in vivo and difficulties in large-scale synthesis. Here, we designed and synthesized a series of 7 nm monodispersed biocompatible and superparamagnetic nickel-doped iron oxide nanoparticles (NiIO NPs) as safe contrast agents (CAs) for ultra-sensitive T1-weighted MR imaging. The nickel doping strategy transforms the iron oxide nanoparticles from traditional T2 CAs to T1 CAs. The Ni0.31Fe2.69O4 NPs exhibited a high longitudinal relaxivity (r1) of 9.1 mM-1 s-1, which is much higher than that of IONPs and 2.4 times that of clinical T1 CAs (Magnevist, 3.8 mM-1 s-1). NiIO NPs enable high-resolution T1-weighted and T2-weighted dual-mode MR imaging in vivo with long circulation time. These results, in hand with the excellent colloidal stability and superior biosafety, demonstrate the potential use of NiIO NPs for accurate diagnosis in deep-tissue T1-T2 dual-mode MR imaging.

A Tumor-Associated Bacteria-Responsive Magnetic Exosome as a Clearable T1 Contrast Agent for Targeted Imaging of Tumors

A Tumor-Associated Bacteria-Responsive Magnetic Exosome as a Clearable T1 Contrast Agent for Targeted Imaging of Tumors

Sub-100 nm and ultra-thin hollow Gd2O3 nanospheres for effective magnetic resonance imaging T1 contrast agent

Gd2O3 nanomaterials with the highly exposed surface are proved to be effective magnetic resonance imaging (MRI) T 1 contrast agents. Most research efforts are focusing on ultra-small Gd2O3 nanoparticles, while sub-100 nm hollow Gd2O3 nanospheres with the ultra-thin shell are another strategy that can be more advantageous to prevent fast renal clearance and enhance cancer-targeted accumulation. Although there have been many reported methods for the synthesis of hollow nanospheres of various materials, the synthesis of Gd2O3 with an ultra-thin shell has not been achieved previously. In this article, we demonstrate a successful strategy for the synthesis of ultra-thin Gd2O33 hollow nanospheres (HNS) with adjustable size and shell thickness through a SiO 2 nanoparticle templating method. The 30 nm Gd2O3 hollow nanospheres with a shell thickness of 2.9 nm showed high MRI T 1 relaxivity with an r 1 value of 3.77 mM − 1 s − 1 at 7 T.

Synthesis and Characterization of Dextran coated Iron Oxide Nanoparticles as a T1 Contrast Agent

This is a second part of iron oxide nanoparticles synthesis by co-precipitation method with various PH values. This study includes stabilizing iron oxide nanoparticles with dextran of molecular weight 10000 Da by aqueous route, then study its characteristics with AFM, FTIR and VSM also using the stabilized material as a contrast agent in T1-weighted image then compare the contrast enhancement with gadolinium based commercially available contrast agent (MagnevistTM). Ph values were (7,11,14), all samples were injected to mice bodies then imaged with MRI best result of T1 contrast enhancement was obtained from sample with Ph 14 compared with gadolinium-based T1 contrast agent with no toxic effects.

Development of Nickel Selenide@polydopamine Nanocomposites for Magnetic Resonance Imaging Guided NIR-II Photothermal Therapy.

The penetration depth of near-infrared laser has greatly restricted the development of most photothermal agents. Recently, photothermal agents in the second near-infrared (NIR-II) window have drawn great attention as they can overcome above barrier. Herein, a novel "all in one" NIR-II responsive nanoplatform (nickel selenide @polydopamine nanocomposites, NiSe@PDA NCs) based on in situ coating the polydopamine (PDA) on the surface of biomineralized nickel selenide nanoparticles (NiSe NPs) for dual-model imaging-guided photothermal therapy is reported. Under the illumination of NIR-II laser (1064nm), the photothermal conversion efficiency of NiSe@PDA NCs can reach 48.4%, which is higher than that of single NiSe NPs due to the enhanced molar extinction coefficient. In addition, because of the paramagnetic effect of NiSe NPs, the constructed NiSe@PDA NCs can be acted as T1 contrast agent for magnetic resonance imaging (MRI). Most importantly, the MRI contrast effect is enhanced with the coating of PDA layer due to the loose structure of PDA. Ultimately, both in vitro and in vivo experiments demonstrate that the developed NCs can achieve efficient MRI-guided photothermal therapy for treating malignant tumor. Therefore, the designed NiSe@PDA NCs with excellent features show great potential for clinical MRI-guided cancer therapy.