Dual-mode Magnetic Resonance Imaging Contrast Research Articles

Clustered ultra-small iron oxide nanoparticles as potential T1/T2 dual–modal magnetic resonance imaging contrast agents and application to tumor model

Many studies have been conducted on the use of ultra-small iron oxide nanoparticles (USIONs) (d < 3 nm) as potential positive magnetic resonance imaging (MRI)-contrast agents (CAs); however, there is dearth of research on clustered USIONs. In this study, nearly monodispersed clustered USIONs were synthesized using a simple two-step one-pot polyol method. First, USIONs (d = 2.7 nm) were synthesized, and clustered USIONs (d = 27.9 nm) were subsequently synthesized through multiple cross-linking of USIONs with poly(acrylic acid-co-maleic acid) (PAAMA) polymers with many -COOH groups. The clustered PAAMA-USIONs exhibited very weak ferromagnetism owing to the magnetic interaction between superparamagnetic USIONs; this was evidenced by their appreciable r1= 3.9 s‒1mM‒1and high r2/r1ratio of 14.6. Their ability to function as a dual-modal T1/T2MRI-CA in T1-weighted MRI was demonstrated when they simultaneously exhibited positive and negative contrasts in T1-weighted MRI of tumor model mice after intravenous injection. They displayed positive contrasts at the kidneys, bladder, heart, and aorta and negative contrasts at the liver and tumor.&#xD.

Rational Design of Magnetic Nanoparticles as T1-T2 Dual-Mode MRI Contrast Agents.

Magnetic nanoparticles (MNPs), either paramagnetic or superparamagnetic depending on their composition and size, have been thoroughly studied as magnetic resonance imaging (MRI) contrast agents using in vitro and in vivo biomedical preclinical studies, while some are clinically used. Their magnetic properties responsible in some cases for high magnetization values, together with large surface area-to-volume ratios and the possibility of surface functionalization, have been used in MRI-based diagnostic and theranostics applications. MNPs are usually used as positive (T1) or negative (T2) MRI contrast agents, causing brightening or darkening of selected regions in MRI images, respectively. This review focusses on recent developments and optimization of MNPs containing Gd, Mn, Fe and other lanthanide ions which may function as dual-mode T1-T2 MRI contrast agents (DMCAs). They induce positive or negative contrast in the same MRI scanner upon changing its operational mode between T1-weighted and T2-weighted pulse sequences. The type of contrast they induce depends critically on their r2/r1 relaxivity ratio, which for DMCAs should be in the 2-10 range of values. After briefly discussing the basic principles of paramagnetic relaxation in MNPs, in this review, the basic strategies for the rational design of DMCAs are presented and typical examples are discussed, including in vivo preclinical applications: (1) the use of NPs with a single type of contrast material, Gd- or Mn-based NPs or superparamagnetic NPs with appropriate size and magnetization to provide T2 and T1 contrast; and (2) inclusion of both types of T1 and T2 contrast materials in the same nanoplatform by changing their relative positions.

A polymeric 1H/19F dual-modal MRI contrast agent with a snowman-like Janus nanostructure.

Magnetic resonance imaging (MRI) has emerged as a pivotal tool in contemporary medical diagnostics, offering non-invasive and high-resolution visualization of internal structures. Contrast agents are essential for enhancing MRI resolution, accurate lesion detection, and early pathology identification. While gadolinium-based contrast agents are widely used in clinics, safety concerns have prompted exploration of metal-free alternatives, including fluorine and nitroxide radical-based MRI contrast agents. Fluorine-containing compounds exhibit excellent MRI capabilities, with 19F MRI providing enhanced resolution and quantitative assessment. Nitroxide radicals, such as PROXYL and TEMPO, offer paramagnetic properties for MRI contrast. Despite their versatility, nitroxide radicals suffer from lower relaxivity values (r1) compared to gadolinium. Dual-modal imaging, combining 1H and 19F MRI, has gained prominence for its comprehensive insights into biological processes and disease states. However, existing dual-modal agents predominantly utilize gadolinium-organic ligands without incorporating nitroxide radicals. Here, we introduce a novel dual-modal MRI contrast agent (J-CA) featuring a Janus asymmetric nanostructure synthesized via seeded emulsion polymerization and post-modification. J-CA demonstrates excellent in vitro and in vivo performance in both 19F and 1H MRI, with a T2 relaxation time of 5 ms and an r1 value of 0.31 mM-1 s-1, ensuring dual-modal imaging capability. Moreover, J-CA exhibits superior biocompatibility and organ targeting, making it a promising candidate for precise lesion imaging and disease diagnosis. This work introduces a new avenue for metal-free dual-modal MRI, addressing safety concerns associated with traditional contrast agents.

Chelating ligand-bridged IO-Gd nanoparticles with enhanced contrast performance for dual-mode MRI

Magnetic resonance imaging (MRI) is a non-invasive medical imaging technique that has been widely applied in the clinical diagnosis of diseases across various fields. Currently, there is a dearth of high-performance dual-mode contrast agents that provide precise diagnostic information for complex diseases. In this study, iron oxide-gadolinium nanoparticles (IO-Gd NPs) bridged by hydrophilic ligand ethylenediamine tetramethylenephosphonic acid (EDTMP) are designed inspired by Solomon-Bloembergen–Morgan (SBM) theory, where T1 and T2 relaxivity increase with a reduction in Gd content. In particular, the NPs with minimum Gd content exhibit excellent dual-mode contrast performance (r1 = 94.42 mM−1 s−1, r2 = 343.62 mM−1 s−1). The underlying mechanism is that the bridged EDTMP coordinate limits Gd tumbling and forces Gd3+ to expose itself to the surface of the NPs. This provides more opportunities for water molecules to coordinate with Gd3+ and significantly enhances proton relaxivity. Moreover, the hydrophilicity of the ligand enhances the water dispersion stability of the NPs and increases the exchange rate of water protons near the NPs, further enhancing the dual-mode contrast effect. Finally, the biocompatibility and in vitro/vivo imaging performances of the IO@EDTMP-Gd NPs are systematically evaluated, and the results demonstrate their potential as dual-mode contrast agents. This study provides a new strategy for developing dual-mode MRI contrast agents that can further improve the accuracy of MRI in the diagnosis of complex diseases.

Tannic acid-mediated synthesis of flower-like mesoporous MnO2 nanostructures as T1–T2 dual-modal MRI contrast agents and dual-enzyme mimetic agents

This study introduces a simple method for preparing a new generation of MnO2 nanomaterials (MNMs) using tannic acid as a template. Two shapes of MnO2 NMs, flower-like M1-MnO2 and near-spherical M2-MnO2, were prepared and compared as dual-active nanozymes and contrast agents in magnetic resonance imaging (MRI). Various parameters, including the crystallinity, morphology, magnetic saturation (Ms), surface functionality, surface area, and porosity of the MNMs were investigated. Flower-like M1-MnO2 NMs were biocompatible and exhibited pH-sensitive oxidase and peroxidase mimetic activity, more potent than near-spherical M2-MnO2. Furthermore, the signal intensity and r1 relaxivity strongly depended on the crystallinity, morphology, pore size, and specific surface area of the synthesized MNMs. Our findings suggest that flower-like M1-MnO2 NM with acceptable dual-enzyme mimetic (oxidase-like and peroxidase-like) and T1 MRI contrast activities could be employed as a promising theranostic system for future purposes.

Magnetic Nanoparticle-Based High-Performance Positive and Negative Magnetic Resonance Imaging Contrast Agents.

In recent decades, magnetic nanoparticles (MNPs) have attracted considerable research interest as versatile substances for various biomedical applications, particularly as contrast agents in magnetic resonance imaging (MRI). Depending on their composition and particle size, most MNPs are either paramagnetic or superparamagnetic. The unique, advanced magnetic properties of MNPs, such as appreciable paramagnetic or strong superparamagnetic moments at room temperature, along with their large surface area, easy surface functionalization, and the ability to offer stronger contrast enhancements in MRI, make them superior to molecular MRI contrast agents. As a result, MNPs are promising candidates for various diagnostic and therapeutic applications. They can function as either positive (T1) or negative (T2) MRI contrast agents, producing brighter or darker MR images, respectively. In addition, they can function as dual-modal T1 and T2 MRI contrast agents, producing either brighter or darker MR images, depending on the operational mode. It is essential that the MNPs are grafted with hydrophilic and biocompatible ligands to maintain their nontoxicity and colloidal stability in aqueous media. The colloidal stability of MNPs is critical in order to achieve a high-performance MRI function. Most of the MNP-based MRI contrast agents reported in the literature are still in the developmental stage. With continuous progress being made in the detailed scientific research on them, their use in clinical settings may be realized in the future. In this study, we present an overview of the recent developments in the various types of MNP-based MRI contrast agents and their in vivo applications.

High-Performance T1-T2 Dual-Modal MRI Contrast Agents through Interface Engineering.

Iron oxide nanoparticles (IONPs) have been developed as contrast agents for T1- or T2-weighted magnetic resonance imaging (MRI) on account of their excellent physicochemical and biological properties. However, general strategies to improve longitudinal relaxivity (r1) often decrease transverse relaxivity (r2), thus synchronously strengthening the T1 and T2 enhancement effect of IONPs remains a challenge. Here, we report interface regulation and size tailoring of a group of FePt@Fe3O4 core-shell nanoparticles (NPs), which possess high r1 and r2 relaxivities. The increase of r1 and r2 is due to the enhancement of the saturation magnetization (Ms), which is a result of the strengthened exchange coupling across the core-shell interface. In vivo subcutaneous tumor study and brain glioma imaging revealed that FePt@Fe3O4 NPs can serve as a favorable T1-T2 dual-modal contrast agent. We envision that the core-shell NPs, through interface engineering, have great potential in preclinical and clinical MRI applications.

Effect of Europium Substitution on the Structural, Magnetic and Relaxivity Properties of Mn-Zn Ferrite Nanoparticles: A Dual-Mode MRI Contrast-Agent Candidate

Magnetic nanoparticles (MNPs) have been widely applied as magnetic resonance imaging (MRI) contrast agents. MNPs offer significant contrast improvements in MRI through their tunable relaxivities, but to apply them as clinical contrast agents effectively, they should exhibit a high saturation magnetization, good colloidal stability and sufficient biocompatibility. In this work, we present a detailed description of the synthesis and the characterizations of europium-substituted Mn-Zn ferrite (Mn0.6Zn0.4EuxFe2-xO4, x = 0.00, 0.02, 0.04, 0.06, 0.08, 0.10, and 0.15, herein named MZF for x = 0.00 and EuMZF for others). MNPs were synthesized by the coprecipitation method and subsequent hydrothermal treatment, coated with citric acid (CA) or pluronic F127 (PF-127) and finally characterized by X-ray Diffraction (XRD), Inductively Coupled Plasma (ICP), Vibrating Sample Magnetometry (VSM), Fourier-Transform Infrared (FTIR), Dynamic Light Scattering (DLS) and MRI Relaxometry at 3T methods. The XRD studies revealed that all main diffraction peaks are matched with the spinel structure very well, so they are nearly single phase. Furthermore, XRD study showed that, although there are no significant changes in lattice constants, crystallite sizes are affected by europium substitution significantly. Room-temperature magnetometry showed that, in addition to coercivity, both saturation and remnant magnetizations decrease with increasing europium substitution and coating with pluronic F127. FTIR study confirmed the presence of citric acid and poloxamer (pluronic F127) coatings on the surface of the nanoparticles. Relaxometry measurements illustrated that, although the europium-free sample is an excellent negative contrast agent with a high r2 relaxivity, it does not show a positive contrast enhancement as the concentration of nanoparticles increases. By increasing the europium to x = 0.15, r1 relaxivity increased significantly. On the contrary, europium substitution decreased r2 relaxivity due to a reduction in saturation magnetization. The ratio of r2/r1 decreased from 152 for the europium-free sample to 11.2 for x = 0.15, which indicates that Mn0.6Zn0.4Eu0.15Fe1.85O4 is a suitable candidate for dual-mode MRI contrast agent potentially. The samples with citric acid coating had higher r1 and lower r2 relaxivities than those of pluronic F127-coated samples.

Tumor microenvironment responsive T1-T2 dual-mode contrast agent Fe3O4@ZIF-8-Zn-Mn NPs for in vivo magnetic resonance imaging.

Activated T1-T2 contrast agents can effectively improve the sensitivity and diagnosis accuracy of magnetic resonance imaging (MRI), but the construction of such contrast agents still remains a great challenge. In this work, a pH- and glutathione (GSH)-responsive T1-T2 dual-mode contrast agent, Fe3O4@ZIF-8-Zn-Mn nanoparticles (NPs), with simple components was constructed via simply assembly of paramagnetic Mn2+ ions (as T1 contrast agent) and Fe3O4 NPs (as T2 contrast agent) into a pH- and GSH-sensitive Zn-zeolitic imidazole framework (ZIF-8) matrix. Under neutral conditions, Fe3O4@ZIF-8-Zn-Mn NPs show good stability and weak T1-T2 dual-mode MRI contrast effect (r1 = 0.82 mM-1 s-1, r2 = 21.28 mM-1 s-1) due to the magnetic interference between Fe3O4 NPs and paramagnetic Mn2+ ions. In contrast, under acidic environment (pH = 6.5-5.5) and in the present GSH (0-4 mM), Fe3O4@ZIF-8-Zn-Mn NPs can be disassembled and release Fe3O4 NPs and paramagnetic Mn2+ ions, which causes simultaneous recovery of T1 and T2 imaging performances with enhanced r1 and r2 relaxation values up to 6.9 and 9.9 times, respectively. Moreover, in vivo MRI experiments showed that after the intravenous injection of Fe3O4@ZIF-8-Zn-Mn NPs for about one hour, the T1-weighted imaging of the tumor site becomes brighter with T1 signal enhanced by about 31%, while the T2-weighted imaging of the tumor site becomes darker with T2 signal enhanced by nearly 30%, suggesting the great potential of Fe3O4@ZIF-8-Zn-Mn NPs to be used as a tumor microenvironment-responsive T1-T2 dual-mode contrast agent for sensitive tumor imaging.

A pH-responsive T1-T2 dual-modal MRI contrast agent for cancer imaging

Magnetic resonance imaging (MRI) is a non-invasive imaging technology to diagnose health conditions, showing the weakness of low sensitivity. Herein, we synthesize a contrast agent, SPIO@SiO2@MnO2, which shows decreased T1 and T2 contrast intensity in normal physiological conditions. In the acid environment of tumor or inflamed tissue, the manganese dioxide (MnO2) layer decomposes into magnetically active Mn2+ (T1-weighted), and the T1 and T2 signals are sequentially recovered. In addition, both constrast quenching-activation degrees of T1 and T2 images can be accurately regulated by the silicon dioxide (SiO2) intermediate layer between superparamagnetic iron oxide (SPIO) and MnO2. Through the “dual-contrast enhanced subtraction” imaging processing technique, the contrast sensitivity of this MRI contrast agent is enhanced to a 12.3-time difference between diseased and normal tissue. Consequently, SPIO@SiO2@MnO2 is successfully applied to trace the tiny liver metastases of approximately 0.5 mm and monitor tissue inflammation.

Synergistic Effect of Oxygen- and Nitrogen-Containing Groups in Graphene Quantum Dots: Red Emitted Dual-Mode Magnetic Resonance Imaging Contrast Agents with High Relaxivity.

Contrast agents (CAs) in magnetic resonance imaging generally involve the dissociative Gd3+. Because of the limited ligancy of Gd3+, the balance between Gd3+ coordination stability (reducing the concentration of dissociative Gd3+) and increases in the number of coordination water molecules (enhancing the relaxivity) becomes crucial. Herein, the key factor of the synergistic effect between the O- and N-containing groups of graphene quantum dots for the structural design of CAs with both high relaxivity and low toxicity was obtained. The nitrogen-doped graphene quantum dots (NGQDs) with an O/N ratio of 0.4 were selected to construct high-relaxivity magnetic resonance imaging (MRI)-fluorescence dual-mode CAs. The coordination stability of Gd3+ can be increased through the synergetic coordination of O- and N-containing groups. The synergetic coordination of O- and N-containing groups can result in the short residency time of the water ligand and achieve high relaxivity. The resulting CAs (called NGQDs-Gd) exhibit a high relaxivity of 32.04 mM-1 s-1 at 114 μT. Meanwhile, the NGQDs-Gd also emit red fluorescence (614 nm), which can enable the MRI-fluorescence dual-mode imaging as the CAs. Moreover, the bio-toxicity and tumor-targeting behavior of NGQDs-Gd were also evaluated, and NGQDs-Gd show potential in MRI-fluorescence imaging in vivo.

PDGF-B conjugating mesoporous IO/GdO nanocomposites for accurate diagnosis of orthotopic prostatic cancer through T1-T2 dual-modal MRI contrast enhancement

The development of highly efficient magnetic resonance imaging (MRI) contrast agent contributes to the early and accurate diagnosis of cancer. Herein, we developed a novel iron oxide and gadolinium oxide (IO/GdO) nanocomposite as T1-T2 dual modal MRI contrast agent through hydrothermal synthesis method. Subsequently, tumor-targeting ligand (PDGFB-PEG) was further conjugated to the surface of IO/GdO nanocomposite (PDGFB-pIO/GdO) to fabricate tumor-targeting MRI probe for accurate diagnosis of orthotopic prostatic cancer. IO/GdO nanocomposite exhibited obvious mesoporous structure, which would promote the contact between water molecules and Gd or Fe centers and enhance the T1 relaxation rate (r1) and T2 relaxation rate (r2) of IO/GdO composite. In addition, the r1 and r2 values of IO/GdO composite were up to be 11.6 mM−1s−1 and 102.7 mM−1s−1, respectively, and the r2/r1 ratio of IO/GdO nanocomposite was calculated to be 8.85, demonstrating a great potential as dual-mode MRI contrast agent. Further study indicated that PDGFB-pIO/GdO exhibited an excellent biocompatibility. Besides, PDGFB-pIO/GdO presented a higher accumulation in tumor than untargeted pIO/GdO, confirming its excellent in vivo tumor-targeting ability. Lastly, in orthotopic prostatic cancer model, the systemic delivery of PDGFB-pIO/GdO significantly enhanced T1- and T2-weighted signal of orthotopic prostatic cancer, achieving high quality of MR images and realizing accurate diagnosis of orthotopic prostatic cancer. Collectively, we proposed a rational designed nanoplatform, PDGF-B conjugating mesoporous IO/GdO nanocomposites, suggesting potential for diagnostic identification of prostate cancer via T1-T2 dual-modal MRI contrast enhancement.

Nanomagnetic hydrogel based on chitosan, hyaluronic acid, and glucose oxidase as a nanotheranostic platform for simultaneous therapeutic and imaging applications

Theranostic platform including therapeutic agent and diagnostics factor is of great interest in the current cancer treatment research. In this study, we constructed a pH-responsive nanomagnetic hydrogel based on chitosan, hyaluronic acid, and glucose oxidase (NMH-CsHA-GOx) as a platform, which represents good performance both as a nanomedicine and as a dual-modal magnetic resonance imaging (MRI) contrast agent. The NMH-CsHA-GOx is a hybrid catalyst that catalyzes a cascade reaction that results in the production of hydroxyl radicals. This leads to the apoptosis and death of cancer cells under the mildly acidic TME. Moreover, the ultrasmall superparamagnetic Fe3O4 NPs act as the T1-weighted and T2-weighted (dual-modal) MRI contrast agents that can be used to identify the cancer cells. The r1 = 6.37, r2 = 27.07/mM/s, and r2/r1 ratio were obtained from MRI relaxivity measurements. The NMH-CsHA-GOx was characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and vibrating sample magnetometry (VSM). The morphology of the hydrogel and nanomagnetic hydrogel were characterized by Field emission scanning electron microscopy (FESEM). The size and distribution of Fe3O4NPs were studied by Transmission electron microscopy (TEM) and X-ray elemental mapping, respectively. The analysis confirmed the very small size of the Fe3O4 NPs (5–12 nm), which were dispersed uniformly. The NMH-CsHA-GOx represents high selectivity between normal cells (L929 mouse fibroblast cell line) and tumor cells (MCF-7 breast cancer cell line). The pH-sensitive NMH-CsHA-GOx, can produce a controlled amount of hydroxyl radical under the mildly acidic TME.

Polyaspartic Acid-Coated Paramagnetic Gadolinium Oxide Nanoparticles as a Dual-Modal T1 and T2 Magnetic Resonance Imaging Contrast Agent

Surface-coating polymers contribute to nanoparticle-based magnetic resonance imaging (MRI) contrast agents because they can affect the relaxometric properties of the nanoparticles. In this study, polyaspartic acid (PASA)-coated ultrasmall Gd2O3 nanoparticles with an average particle diameter of 2.0 nm were synthesized using the one-pot polyol method. The synthesized nanoparticles exhibited r1 and r2 of 19.1 and = 53.7 s−1mM−1, respectively, (r1 and r2 are longitudinal and transverse water–proton spin relaxivities, respectively) at 3.0 T MR field, approximately 5 and 10 times higher than those of commercial Gd-chelate contrast agents, respectively. The T1 and T2 MR images could be obtained due to an appreciable r2/r1 ratio of 2.80, indicating their potential as a dual-modal T1 and T2 MRI contrast agent.

Highly sensitive T 1–T 2 dual-mode MRI probe based on ultra-small gadolinium oxide-decorated iron oxide nanocrystals

Single-mode magnetic resonance imaging (MRI) contrast agents (CAs) in clinical settings are easily disturbed by calcification, bleeding, and adipose signals, which result in inaccurate diagnoses. In this study, we developed a highly efficient T 1–T 2 dual-mode MRI CA using an ultra-small gadolinium oxide-decorated magnetic iron oxide nanocrystal (GMIO). The gadolinium element could effectively alter the magnetic properties of the GMIO from soft-ferromagnetism to superparamagnetism. In addition, when the Gd/Fe ratio was 15% (designated as GMIO-2), the GMIO-2 possessed the best superparamagnetism and highest magnetism. Subsequently, T 1 and T 2 values of GMIO-2 were measured through a series of turbo spin-echo images and then multi-spin echo sequence, respectively. Based on this, T 1 and T 2 relaxivities of GMIO-2 were calculated and were the highest (r 1: 1.306 m M−1 s−1 and r 2: 234.5 m M−1 s−1) when compared to other groups. The cytotoxicity of GMIO-2 was negligible under a wide range of dosages, thus exhibiting excellent cell biocompatibility. Moreover, GMIO-2 could quickly diffuse into cells, leading to its effective accumulation. The systemic delivery of GMIO-2 resulted in an excellent T 1–T 2 dual-mode MRI contrast effect in kidneys, which is expected to improve the diagnosis of kidney lesions. Therefore, this work provides a promising candidate for the development of a T 1–T 2 dual-mode MRI CA.

Manganese oxide/Metal-Organic Frameworks-Based Nanocomposites for Tumr Micro-environment Sensitive 1H/19F Dual-mode Magnetic Resonance Imaging in Vivo

A pH- and GSH-responsive 1H/19F dual-mode magnetic resonance imaging contrast agent (MRI CA) was constructed by incorporating MnOx into Zr-based MOF nanoparticles (MnOx/UiO-66-F/PPEG NPs) with an organic ligand of tetrafluoro-terephthalic acid (F4PTA). Under a weak acidic tumor micro-environment, MnOx/UiO-66-F/PPEG NPs would collapse to release MnOx and free F4PTA. Due to the released free F4PTA, 19F MRI signal was enhanced. Meanwhile, GSH, which is overexpressed in a tumor micro-environment, reduced MnOx to divalent manganese ions and improved the T1-weighted MR imaging capability. As a proof of concept, MnOx/UiO-66-F/PPEG NPs was favorable for dual 1H/19F MRI with a high signal-to-noise ratio in vivo.

A Dual-Modality MR/PA Imaging Contrast Agent Based on Ultrasmall Biopolymer Nanoparticles for Orthotopic Hepatocellular Carcinoma Imaging.

BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer death and early stage diagnosis can greatly increase the survival rate of patient. However, the accurate detection of HCC remains an urgent challenge in medical diagnosis. The combination of magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) are conducive for accurate locating of cancerous tissue. Therefore, it is necessary to explore a more facile and biosafe dual-modal contrast agent for orthotopic HCC detection.MethodsIn this study, a promising contrast agent had been identified based on gadolinium chelated melanin nanoparticles and evaluated its usage as a dual-modal T1 MRI and PAI contrast agent for orthotopic HCC detection.ResultsThe gadolinium-based melanin nanoparticles presented ultrasmall size, high chelation stability and negligible cytotoxicity estimated by CCK-8 assay. Moreover, the nanoparticle exhibited higher r1 relaxivity (45.762 mM−1 s−1) than clinically approved Gadodiamide (4.975 mM−1 s−1) at 1.5 T MR scanning. A linear regression analysis confirmed that the nanoparticles were ideal candidates for PAI in vitro. After the nanoparticles were injected into vein in mice with orthotopic HCC, a dramatic increase in signal of the liver was observed at 0.5 hr by MRI and PAI, while the tumor exerted remarkable signal enhancement at 7 hrs, showing excellent detection sensitivity. In addition, the nanoparticles exhibited excellent biocompatibility and they can be excreted through both hepatobiliary and renal pathways after diagnosis.ConclusionThese results indicate that the ultrasmall gadolinium chelated melanin nanoparticles is a promising candidate as a dual-modal MRI/PAI contrast agent for the detection of orthotopic HCC.

An Albumin-Binding T1- T2 Dual-Modal MRI Contrast Agents for Improved Sensitivity and Accuracy in Tumor Imaging.

Magnetic resonance imaging (MRI) diagnosis is better assisted by contrast agents that can augment the signal contrast in the imaging appearance. However, this technique is still limited by the inherently low sensitivity on the recorded signal changes in conventional T1 or T2 MRI in a qualitative manner. Here, we provide a new paradigm of MRI diagnosis using T1- T2 dual-modal MRI contrast agents for contrast-enhanced postimaging computations on T1 and T2 relaxation changes. An albumin-binding molecule (i.e., truncated Evans blue) chelated with paramagnetic manganese ion was developed as a novel T1- T2 dual-modal MRI contrast agent at high magnetic field (7 T). Furthermore, the postimaging computations on T1- T2 dual-modal MRI led to greatly enhanced signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) in both subcutaneous and orthotopic brain tumor models compared with traditional MRI methods. The T1- T2 dual-modal MRI computations have great potential to eliminate suspicious artifacts and false-positive signals in mouse brain imaging. This study may open new avenues for contrast-enhanced MRI diagnosis and holds great promise for precision medicine.

A biodegradable MnSiO3@Fe3O4 nanoplatform for dual-mode magnetic resonance imaging guided combinatorial cancer therapy

In this work, a tumor microenvironment (TME)-responsive biodegradable MnSiO3@Fe3O4 nanoplatform for dual-mode magnetic resonance imaging (MRI)-guided combinatorial cancer therapy was constructed. Fe3O4 nanoparticles decorated on the surface of MnSiO3 could effectively obstruct the pores of MnSiO3 and reduce the leakage of anticancer drugs under physiological conditions. The structure of the nanoplatform was broken under the weakly acidic and high-concentration glutathione conditions in the TME, resulting in the separation of the Fe3O4 nanoparticles from the nanoplatform and rapid drug release. In addition, the exfoliated Fe3O4 and released Mn2+ can help reduce the interference between their T1 and T2 contrast abilities, resulting in dual-mode MRI contrast enhancement. Furthermore, during the exfoliation process of the Fe3O4 nanocrystals, the catalytic activity of the Fe3O4 nanocrystals toward a Fenton-like reaction within cancer cells could be improved because of the increase in specific surface area, which led to the generation of highly toxic hydroxyl radicals and induced HeLa cell apoptosis. The nanoplatform also displayed excellent T1-T2 dual-mode MRI contrast enhancement and anticancer activity in vivo with reduced systemic toxicity. Thus, this multifunctional nanoplatform could be a potential nanotheranostic for dual-mode MRI-guided combinatorial cancer therapy.

Ternary-Responsive Drug Delivery with Activatable Dual Mode Contrast-Enhanced in Vivo Imaging.

Designing a smart nanotheranostic system has recently attracted tremendous attention and is highly desirable for realizing targeted cancer therapy and early diagnosis. Herein we report the fabrication of smart nanotheranostic system using multiresponsive gatekeeping protocol of mesoporous silica nanoparticles (MSN). Acid, oxidative stress and redox sensitive manganese oxide (MnO x) coated superparamagnetic iron oxide nanoparticle (SPION) were employed as nanolids to regulate the camptothecin drug release from the channels of mesoporous silica and achieve responsive dual-mode MRI contrast. The nonvehicle showed high magnetization and T2 contrast in magnetic resonance imaging (MRI) due to the significant density of SPION onto the surface of MSN, and at the same time the MnO x shell degradation release Mn2+ which enhanced the T1MRI visualization. The efficacy of responsive drug delivery system was investigated on pancreatic cancer cells and tumor-bearing mice, and results reinforced that MnO x-SPION@MSN@CPT nonvehicle is efficacious against cancer cells. We envision that our unique and multiresponsive nanoplatform may find applications in effective delivering of imaging and therapeutic agents to wide range of diseases besides cancer.