Magnetic Resonance Imaging Signal Enhancement Research Articles

Noninvasive ROS imaging and drug delivery monitoring in the tumor microenvironment

Reactive oxygen species (ROS) that are overproduced in certain tumors can be considered an indicator of oxidative stress levels in the tissue. Here, we report a magnetic resonance imaging (MRI)-based probe capable of detecting ROS levels in the tumor microenvironment (TME) using ROS-responsive manganese ion (Mn2+)-chelated, biotinylated bilirubin nanoparticles (Mn@bt-BRNPs). These nanoparticles are disrupted in the presence of ROS, resulting in the release of free Mn2+, which induces T1-weighted MRI signal enhancement. Mn@BRNPs show more rapid and greater MRI signal enhancement in high ROS-producing A549 lung carcinoma cells compared with low ROS-producing DU145 prostate cancer cells. A pseudo three-compartment model devised for the ROS-reactive MRI probe enables mapping of the distribution and concentration of ROS within the tumor. Furthermore, doxorubicin-loaded, cancer-targeting ligand biotin-conjugated Dox/Mn@bt-BRNPs show considerable accumulation in A549 tumors and also effectively inhibit tumor growth without causing body weight loss, suggesting their usefulness as a new theranostic agent. Collectively, these findings suggest that Mn@bt-BRNPs could be used as an imaging probe capable of detecting ROS levels and monitoring drug delivery in the TME with potential applicability to other inflammatory diseases.

Preparation of MnO2@poly-(DMAEMA-co-IA)-conjugated methotrexate nano-complex for MRI and radiotherapy of breast cancer application.

A novel efficient pH-sensitive targeted magnetic resonance imaging (MRI) contrast agent and innovative radio-sensitizing system were synthesized based on MnO2 NPs coated with biocompatible poly-dimethyl-amino-ethyl methacrylate-Co-itaconic acid, (DMAEMA-Co-IA) and targeted with methotrexate (MTX). The as-established NPs were fully characterized and evaluated for MRI signal enhancement, relaxivity, in vitro cell targeting, cell toxicity, blood compatibility, and radiotherapy (RT) efficacy. The targeted NPs MnO2@Poly(DMAEMA-Co-IA) and MTX-loaded NPs inhibited MCF-7 cell viability more effectively than free MTX after 24 and 48h, respectively, with no noticeable toxicity. Additionally, the insignificant hemolytic activity demonstrated their proper hemo-compatibility. T1-weighted magnetic resonance imaging was used to distinguish the differential uptake of the produced MnO2@Poly(DMAEMA-Co-IA)-MTX NPs in malignant cells compared to normal ones in the presence of high and low MTX receptor cells (MCF-7 and MCF-10A, respectively). In MRI, the produced theranostic NPs displayed pH-responsive contrast enhancement. As shown by in vitro assays, treatment of cells with MnO2@Poly(DMAEMA-Co-IA)-MTX NPs prior to radiotherapy in hypoxic conditions significantly enhanced therapeutic efficacy. We draw the conclusion that using MnO2@Poly(DMAEMA-Co-IA)-MTX NPs in MR imaging and combination radiotherapy may be a successful method for imaging and radiation therapy of hypoxia cells.

MRI Appearance of Focal Lesions in Liver Iron Overload.

Liver iron overload is defined as an accumulation of the chemical element Fe in the hepatic parenchyma that exceeds the normal storage. When iron accumulates, it can be toxic for the liver by producing inflammation and cell damage. This can potentially lead to cirrhosis and hepatocellular carcinoma, as well as to other liver lesions depending on the underlying condition associated to liver iron overload. The correct assessment of liver iron storage is pivotal to drive the best treatment and prevent complication. Nowadays, magnetic resonance imaging (MRI) is the best non-invasive modality to detect and quantify liver iron overload. However, due to its superparamagnetic properties, iron provides a natural source of contrast enhancement that can make challenging the differential diagnosis between different focal liver lesions (FLLs). To date, a fully comprehensive description of MRI features of liver lesions commonly found in iron-overloaded liver is lacking in the literature. Through an extensive review of the published literature, we aim to summarize the MRI signal intensity and enhancement pattern of the most common FLLs that can occur in liver iron overload.

An NMR relaxometry approach for quantitative investigation of the transchelation of gadolinium ions from GBCAs to a competing macromolecular chelator

Gadolinium-based contrast agents (GBCAs) have been used in clinical Magnetic Resonance Imaging (MRI) for more than 30 years. However, there is increasing evidence that their dissociation in vivo leads to long-term depositions of gadolinium ions in the human body. In vitro experiments provide critical insights into kinetics and thermodynamic equilibria of underlying processes, which give hints towards the in vivo situation. We developed a time-resolved MRI relaxometry-based approach that exploits distinct relaxivities of Gd3+ in different molecular environments. Its applicability to quantify the transmetallation of GBCAs, the binding of Gd3+ to competing chelators, and the combined transchelation process is demonstrated. Exemplarily, the approach is applied to investigate two representative GBCAs in the presence of Zn2+ and heparin, which is used as a model for a macromolecular and physiologically occurring chelator. Opposing indirect impacts of heparin on increasing the kinetic stability but reducing the thermodynamic stability of GBCAs are observed. The relaxivity of resulting Gd-heparin complexes is shown to be essentially increased compared to that of the parent GBCAs so that they might be one explanation for observed long-term MRI signal enhancement in vivo. In forthcoming studies, the presented method could help to identify the most potent Gd-complexing macromolecular species.

Assessment of Albumin ECM Accumulation and Inflammation as Novel In Vivo Diagnostic Targets for Multi-Target MR Imaging.

Simple SummaryAtherosclerosis is an inflammatory disease associated with extracellular matrix remodeling. It is characterized by endothelial dysfunction with albumin influx into the vessel wall and macrophage accumulation in atherosclerotic lesions. Non-invasive magnetic resonance imaging (MRI) allows for the assessment of the molecular components of the plaque and vessel wall by using two different target-specific MRI contrast agents in one imaging session. Therefore, multi-target MRI is a promising method to improve diagnosis and treatment monitoring in patients with atherosclerosis.Atherosclerosis is a progressive inflammatory vascular disease characterized by endothelial dysfunction and plaque burden. Extracellular matrix (ECM)-associated plasma proteins play an important role in disease development. Our magnetic resonance imaging (MRI) study investigates the feasibility of using two different molecular MRI probes for the simultaneous assessment of ECM-associated intraplaque albumin deposits caused by endothelial damage and progressive inflammation in atherosclerosis. Male apolipoprotein E-deficient (ApoE-/-)-mice were fed a high-fat diet (HFD) for 2 or 4 months. Another ApoE-/--group was treated with pravastatin and received a HFD for 4 months. T1- and T2*-weighted MRI was performed before and after albumin-specific MRI probe (gadofosveset) administration and a macrophage-specific contrast agent (ferumoxytol). Thereafter, laser ablation inductively coupled plasma mass spectrometry and histology were performed. With advancing atherosclerosis, albumin-based MRI signal enhancement and ferumoxytol-induced signal loss areas in T2*-weighted MRI increased. Significant correlations between contrast-to-noise-ratio (CNR) post-gadofosveset and albumin stain (R2 = 0.78, p < 0.05), and signal loss areas in T2*-weighted MRI with Perls’ Prussian blue stain (R2 = 0.83, p < 0.05) were observed. No interference of ferumoxytol with gadofosveset enhancement was detectable. Pravastatin led to decreased inflammation and intraplaque albumin. Multi-target MRI combining ferumoxytol and gadofosveset is a promising method to improve diagnosis and treatment monitoring in atherosclerosis.

Regulation of MRI contrast and cellular retention time by cellular interfacial distribution of Gd agents: Implications for stem cell tracking

Human mesenchymal stem cells (hMSCs) were labeled with Dotarem or (Gd-DOTA)2- EM7 (EM7Gd2) via electroporation (EP). Cellular transmission electron microscopy (TEM) reveals free distribution of Gd agents and formation of EM7Gd2 clusters in the cytosol. Cellular magnetic resonance imaging (MRI) reveals that the free Gd agents induce MRI signal enhancement effect due to its fast exocytosis and subsequent interaction with intercellular water molecules. The EM7Gd2 clusters exhibits a longer intracellular retention time and induce a persistent MRI signal reduction effect. The cellular MRI results are interpreted by taking into account both T1 and T2 relaxation rates and their correlation with cellular binding structures of Dotarem and EM7Gd2.

Prognostic Value of Early Magnetic Resonance Imaging Patterns in Sudden Hearing Loss

Introduction: Sudden sensorineural hearing loss (SSHL) is a relatively frequent disease, but a sensitive marker or a reliable test to identify the underlying cause is still unavailable. Neuroradiology appears to offer the most promising tools, especially magnetic resonance imaging (MRI). In a recent study from our group, we explored the ability of MRI to detect subtle changes in the inner ear compartments by means of a 3D-fluid-attenuated inversion recovery sequence, aiming at identifying 3 distinct MRI patterns (haemorrhagic, inflammatory, brain-labyrinth barrier breakdown). In the present study, we contrasted the MRI patterns at onset with relevant prognostic factors, with the audiological features of each patient’s SSHL and with treatment outcomes. Methods: In this retrospective study, we enrolled 50 adult subjects (54.61 ± 18.26 years) with SSHL. They underwent an MRI within 72 h from admission, and 5 audiological evaluations: at admission, on the 5th day after the start of medical therapy, at the end of the first cycle of hyperbaric oxygen therapy, then 1 and 6 months later. Results: Abnormalities of the MRI signal and/or post-contrast enhancement asymmetry of the cochlea (“pattern+ MRI”) correlated with worse audiological outcomes at 1 month, but the different MRI patterns were not correlated with any specific prognostic model, despite rigid protocol settings. However, a significant difference was found for low-tone SSHL, which were always “pattern” negative at MRI (p = 0.01), and for profound SSHL which demonstrated a pattern+ MRI in 80% (p = 0.04). At the onset of SSHL, a pattern+ MRI was found in 29/50 cases (58.0%) and was related with lesser degree of recovery of pure-tone average at 1 month and lesser chance to retain the hearing threshold benefit in the long term. Given the limited numbers of patients enrolled so far, the relative impact of comorbidities on each MRI pattern remains uncertain. At 6 months, we observed a trend of greater and more stable recovery (p = 0.023) and less frequent recurrence of SSHL in patients with a normal MRI. Conclusions: The 3 observed MRI patterns did not correlate consistently with specific audio-vestibular features or any peculiar aspect of the patient’s clinical history. Larger series of patients with SSHL are needed, possibly from multicentric studies.

Amphiphilic block polymer-gadolinium conjugates: Design, synthesis and application as efficient and safe nanoscale magnetic resonance imaging contrast agents

Abstract Although polymer-gadolinium conjugates-based contrast agents (CAs) have shown great promise in safe and efficient magnetic resonance imaging (MRI), very few studies on the use of self-assembled polymers to prepare CAs have been reported. The effect of the self-assembled architectural structures of CAs on their MRI performance remains unclear. Herein, two block amphiphilic polymer-gadolinium conjugates (Linear Agent and Cross-Linked Agent3) were designed and fabricated via an approach of two-step reversible addition-fragmentation chain transfer (RAFT) polymerization and cross-linking. These conjugates self-assembled into nanoscale CAs with a spherical or worm-like morphology. These CAs had low toxicity and great hemocompatibility. Both of them displayed an evident increase in the longitudinal relaxivity and the blood circulation time over small molecular CAs (i.e., Gd-DTPA). Linear Agent exhibited superior MRI signal enhancement to Cross-Linked Agent3 in both subcutaneous and orthotopic breast tumor sites. Cross-Linked Agent3 was easily uptaken by tumor cells, but its tumor-specific responsive degradation contributed to a decrease in its MRI efficiency. In the major organs, two agents were able to generate clear and long-lasting images. Moreover, their long residence time in the blood endowed them as magnetic resonance angiography (MRA) agents. A large number of blood vessels, including liver vessels and kidney vessels, could be clearly observed after injection of both CAs, and the contrast-enhanced MR signals in these vessels lasted for over 4 h. Cross-Linked Agent3 excelled over Linear Agent in displaying the terminal of branch blood vessels in the liver and kidney. Overall, the strategy to prepare self-assembled CAs with tunable morphologies would allow a better understanding of the structure–function relationship of these CAs and provide insights into novel designs of polymer-gadolinium conjugates.

Assessment of Gold-Coated Iron Oxide Nanoparticles as Negative T2 Contrast Agent in Small Animal MRI Studies.

PurposeMagnetic resonance imaging (MRI) contrast agents are pharmaceuticals that enable a better visualization of internal body structures. In this study, we present the synthesis, MRI signal enhancement capabilities, in vitro as well as in vivo cytotoxicity results of gold-coated iron oxide nanoparticles (Fe3O4@AuNPs) as potential contrast agents.MethodsFe3O4@AuNPs were obtained by synthesizing iron oxide nanoparticles and gradually coating them with gold. The obtained Fe3O4@AuNPs were characterized by spectroscopies, transmission electron microscopy (TEM) and energy dispersive X-ray diffraction. The effect of the nanoparticles on the MRI signal was tested using a 7T Bruker PharmaScan system. Cytotoxicity tests were made in vitro on Fe3O4@AuNP-treated retinal pigment epithelium cells by WST-1 tests and in vivo by following histopathological changes in rats after injection of Fe3O4@AuNPs.ResultsStable Fe3O4@AuNPs were successfully prepared following a simple and fast protocol (<1h worktime) and identified using TEM. The cytotoxicity tests on cells have shown biocompatibility of Fe3O4@AuNPs at small concentrations of Fe (<1.95×10−8 mg/cell). Whereas, at higher Fe concentrations (eg 7.5×10−8 mg/cell), cell viability decreased to 80.88±5.03%, showing a mild cytotoxic effect. MRI tests on rats showed an optimal Fe3O4@AuNPs concentration of 6mg/100g body weight to obtain high-quality images. The histopathological studies revealed significant transient inflammatory responses in the time range from 2 hours to 14 days after injection and focal cellular alterations in several organs, with the lung being the most affected organ. These results were confirmed by hyperspectral microscopic imaging of the same, but unstained tissues. In most organs, the inflammatory responses and sublethal cellular damage appeared to be transitory, except for the kidneys, where the glomerular damage indicated progression towards glomerular sclerosis.ConclusionThe obtained stable, gold covered, iron oxide nanoparticles with reduced cytotoxicity, gave a negative T2 signal in the MRI, which makes them suitable for candidates as contrast agent in small animal MRI applications.

The effect of metal ions on endogenous melanin nanoparticles used as magnetic resonance imaging contrast agents.

Melanin nanoparticles are of great importance in biomedicine. They have excellent affinity for metallic cations, especially paramagnetic ions, which has sparked interest in their application in the development of magnetic resonance imaging (MRI) contrast agents. In this work, we prepared ultrasmall water-soluble melanin nanoparticles, and investigated the binding properties of melanin toward different metal cations (Gd3+, Mn2+, Fe3+ and Cu2+), and compared their physicochemical properties and the MRI contrast enhancement ability in various metal chelated forms (MNP-PEG-M) in vitro and in vivo. We show that the saturation binding numbers of Gd3+, Mn2+, Fe3+ and Cu2+ per MNP-PEG were 49, 59, 69 and 62, respectively. MNP-PEG-Gd, MNP-PEG-Mn, MNP-PEG-Fe and MNP-PEG-Cu exhibited the maximum r1 relaxivities at the loading mass ratios of Gd3+ : MNP = 1 : 1, Mn2+ : MNP = 0.5 : 1, Fe3+ : MNP = 0.1 : 1 and Cu2+ : MNP = 0.1 : 1, corresponding to 49, 57, 54 and 51 chelated metals per MNP-PEG, respectively. The maximal per metal ion r1 relaxivity values were 61.9, 48.7, 11.1 and 9.7 mM-1 s-1 for MNP-PEG-Gd, MNP-PEG-Mn, MNP-PEG-Fe and MNP-PEG-Cu at 1.5 T, respectively. MNP-PEG-Gd and MNP-PEG-Fe presented larger sizes (6.9 nm and 5.8 nm) than MNP-PEG-Mn and MNP-PEG-Cu (3.4 nm and 3.7 nm), all featuring excellent solubility, high stability and ultrasmall size. A significant in vivo MRI signal enhancement in tissues was observed for all MNP-PEG-M after intravenous injection in mice, and these nanoparticles were excreted through renal and hepatobiliary pathways. In agreement with their r1 relaxivity values, MNP-PEG-Gd and MNP-PEG-Mn showed a significantly greater in vivo tissue maximum enhancement than MNP-PEG-Fe and MNP-PEG-Cu. This study could yield valuable insight into the development of a new class of MRI contrast agents.

Design of Gadoteridol-Loaded Cationic Liposomal Adjuvant CAF01 for MRI of Lung Deposition of Intrapulmonary Administered Particles.

Designing effective and safe tuberculosis (TB) subunit vaccines for inhalation requires identification of appropriate antigens and adjuvants and definition of the specific areas to target in the lungs. Magnetic resonance imaging (MRI) enables high spatial resolution, but real-time anatomical and functional MRI of lungs is challenging. Here, we describe the design of a novel gadoteridol-loaded cationic adjuvant formulation 01 (CAF01) for MRI-guided vaccine delivery of the clinically tested TB subunit vaccine candidate H56/CAF01. Gadoteridol-loaded CAF01 liposomes were engineered by using a quality-by-design approach to (i) increase the mechanistic understanding of formulation factors governing the loading of gadoteridol and (ii) maximize the loading of gadoteridol in CAF01, which was confirmed by cryotransmission electron microscopy. The encapsulation efficiency and loading of gadoteridol were highly dependent on the buffer pH due to strong attractive electrostatic interactions between gadoteridol and the cationic lipid component. Optimal gadoteridol loading of CAF01 liposomes showed good in vivo stability and safety upon intrapulmonary administration into mice while generating 1.5-fold MRI signal enhancement associated with approximately 30% T1 relaxation change. This formulation principle and imaging approach can potentially be used for other mucosal nanoparticle-based formulations, species, and lung pathologies, which can readily be translated for clinical use.

Seven-year course of asymptomatic acromioclavicular osteoarthritis diagnosed by MRI

Asymptomatic acromioclavicular osteoarthritis (AC-OA) is a frequent finding in shoulder magnetic resonance imaging (MRI). Its natural course is unknown. Therefore, the question arises whether a resection should be performed simultaneously with shoulder surgery for another reason to prevent future pain and reoperation. The purpose of this study was to investigate the mid-term course of asymptomatic AC-OA. Overall, 114 asymptomatic AC-OA diagnosed on MRI were followed for 7 years between 2011 and 2018. At baseline, MRI signal enhancement in the clavicle and acromion, OA grade, physical demand as well as the parameters (1) Constant Score Visual Analogue Scale, (2) pain on AC-joint compression, and (3) cross-body adduction test were measured. All patients were followed up after 7 years by interview, and in case of symptoms by clinical examination. The endpoint "deterioration" was reached if 2 of the 3 parameters turned worse. Asymptomatic AC-OA remained asymptomatic in 83% of cases, 7% turned better, 10% turned worse. Physical demand and osteoarthritis grade increased the risk of deterioration, whereas MRI signal enhancement in the clavicle or acromion had no influence on outcome. During follow-up, the frequency of pain on AC-joint compression increased from 11% to 16% (P = .24), the frequency of a positive cross-body adduction test increased from 6% to 20% (P = .017), and the mean Constant Score Visual Analogue Scale increased from 10 to 13 points (P < .001) indicating less pain. Asymptomatic AC-OA remained asymptomatic in 90% over 7 years. A simultaneous resection of an asymptomatic AC-OA during shoulder surgery for another reason is not indicated in every patient.

Bovine Serum Albumin-Templated Synthesis of Manganese-Doped Copper Selenide Nanoparticles for Boosting Targeted Delivery and Synergistic Photothermal and Photodynamic Therapy.

Multifunctional nanohybrids integrating diagnostic imaging with photodynamic or photothermal therapy in a single agent feature the next generation of on-demand nanomedicine to meet the challenges in cancer therapy. In the present study, bovine serum albumin (BSA) protein through one pot biomimetic mineralization at its metal binding site synthesized and stabilized manganese-doped copper selenide nanoparticles (Mn:CuSe) with excellent biocompatibility, near-infrared absorption, water solubility, and rich functional groups for further bioconjugation. Mn doping not only imparted the magnetic resonance imaging (MRI) function to the Mn:CuSe@BSA but also enhanced its heat generation ability. By taking advantage of BSA's extraordinary ligand binding capacity, folic acid (FA) and chlorin e6 (Ce6) were then conjugated onto the BSA corona to construct the Mn:CuSe@BSA-FA-Ce6 nanohybrid for specific targeting of overexpressed folate receptor cancer cells. The obtained theranostic agent exhibited dual MRI signal enhancement and synergistic photothermal/photodynamic therapy (PTT/PDT) effect, which was demonstrated in vitro on HeLa cells. As a consequence, dual modal therapy with 1 min PDT laser irradiation doubled cell killing efficiency compared to the single PDT treatment. Having better efficacy regarding biocompatibility and synergistic light-activation therapy, the Mn:CuSe@BSA-FA-Ce6 nanohybrid holds the promise for image-guided cancer therapy.

High-Field Detection of Biomarkers with Fast Field-Cycling MRI: The Example of Zinc Sensing.

Many smart magnetic resonance imaging (MRI) probes provide response to a biomarker based on modulation of their rotational correlation time. The magnitude of such MRI signal changes is highly dependent on the magnetic field and the response decreases dramatically at high fields (>2 T). To overcome the loss of efficiency of responsive probes at high field, with fast‐field cycling magnetic resonance imaging (FFC‐MRI) we exploit field‐dependent information rather than the absolute difference in the relaxation rate measured in the absence and in the presence of the biomarker at a given imaging field. We report here the application of fast field‐cycling techniques combined with the use of a molecular probe for the detection of Zn2+ to achieve 166 % MRI signal enhancement at 3 T, whereas the same agent provides no detectable response using conventional MRI. This approach can be generalized to any biomarker provided the detection is based on variation of the rotational motion of the probe.

Highly Sensitive Detection of Caspase-3/7 Activity in Living Mice Using Enzyme-Responsive 19F MRI Nanoprobes.

Highly sensitive imaging of enzymatic activities in the deep tissues of living mammals provides useful information about their biological functions and for developing new drugs; however, such imaging is challenging. 19F magnetic resonance imaging (MRI) is suitable for noninvasive visualization of enzymatic activities without endogenous background signals. Although various enzyme-responsive 19F MRI probes have been developed, most cannot be used for in vivo imaging because of their low sensitivity. Recently, we developed unique nanoparticles, called FLAMEs, that are composed of a liquid perfluorocarbon core and a robust silica shell, and demonstrated their outstanding sensitivity in vivo. Here, we report a highly functionalized nanoprobe, FLAME-DEVD 2, with an OFF/ON 19F MRI switch for detecting caspase-3/7 activity based on the paramagnetic relaxation enhancement effect. To improve the cleavage efficiency of peptides by caspase-3, we designed a novel Gd3+ complex-conjugated peptide, DEVD X ( X = 1, 2), which is a substrate peptide sequence tandemly repeated X times, and demonstrated that DEVD 2 showed faster cleavage kinetics than DEVD 1. By incorporating this novel concept into a signal activation strategy, FLAME-DEVD 2 showed a high 19F MRI signal enhancement rate in response to caspase-3 activity. After intravenous injection of FLAME-DEVD 2 and an apoptosis-inducing reagent, caspase-3/7 activity in the spleen of a living mouse was successfully imaged by 19F MRI. This imaging platform shows great potential for highly sensitive detection of enzymatic activities in vivo.

Early animal model evaluation of an implantable contrast agent to enhance magnetic resonance imaging of arterial bypass vein grafts.

Background Non-invasive monitoring of autologous vein graft (VG) bypass grafts is largely limited to detecting late luminal narrowing. Although magnetic resonance imaging (MRI) delineates vein graft intima, media, and adventitia, which may detect early failure, the scan time required to achieve sufficient resolution is at present impractical. Purpose To study VG visualization enhancement invivo and delineate whether a covalently attached MRI contrast agent would enable quicker longitudinal imaging of the VG wall. Material and Methods Sixteen 12-week-old male C57BL/6J mice underwent carotid interposition vein grafting. The inferior vena cava of nine donor mice was treated with a gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based contrast agent, with control VGs labeled with a vehicle. T1-weighted (T1W) MRI was performed serially at postoperative weeks 1, 4, 12, and 20. A portion of animals was sacrificed for histopathology following each imaging time point. Results MRI signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were significantly higher for treated VGs in the first three time points (1.73 × higher SNR, P = 0.0006, and 5.83 × higher CNR at the first time point, P = 0.0006). However, MRI signal enhancement decreased consistently in the study period, to 1.29 × higher SNR and 2.64 × higher CNR, by the final time point. There were no apparent differences in graft morphometric analyses in Masson's trichrome-stained sections. Conclusion A MRI contrast agent that binds covalently to the VG wall provides significant increase in T1W MRI signal with no observed adverse effects in a mouse model. Further optimization of the contrast agent to enhance its durability is required.

MnO2-gated Nanoplatforms with Targeted Controlled Drug Release and Contrast-Enhanced MRI Properties: from 2D Cell Culture to 3D Biomimetic Hydrogels.

Multifunctional nanomaterials combining diagnosis and therapeutic properties have attracted a considerable attention in cancer research. Yet some important challenges are still to be faced, including an optimal coupling between these two types of properties that would be effective within complex biological tissues. To address these points, we have prepared novel nanoplatforms associating controlled drug delivery of doxorubicin and Magnetic Resonance Imaging (MRI) contrast-enhancement that exhibit high specificity towards cancer cells compared to normal cells and evaluated them both in 2D cultures and within 3D tissue-like biomimetic matrices.Methods: Nanoplatforms were prepared from hollow silica nanoparticles coated with MnO2 nanosheets and conjugated with the AS1411 aptamer as a targeting agent. They were fully characterized from a chemical and structural point of view as well as for drug release and MRI signal enhancement. Standard two-dimensional monolayer cultures were performed using HeLa and Normal Human Dermal Fibroblasts (NHDF) cells to testify targeting and cytotoxicity. Cellularized type I collagen-based hydrogels were also used to study nanoparticles behavior in 3D biomimetic environments.Results: The as-established nanoplatforms can enter HeLa cells, leading to the dissociation of the MnO2 nanosheets into Mn2+ that enhanced T1 magnetic resonance signals and concomitantly release doxorubicin, both effects being markedly more significant than in the presence of NHDFs. Moreover, particles functionality and specificity were preserved when the cells were immobilized within type I collagen-based fibrillar hydrogels.Conclusion: The use of MnO2 nanosheets as glutathione-sensitive coatings of drug loaded nanoparticles together with surface conjugation with a targeting aptamer offers an effective strategy to obtain efficient and specific nanotheranostic systems for cancer research, both in 2D and 3D. The here-described tissue-like models should be easy to implement and could constitute an interesting intermediate validation step for newly-developed theranostic nanoparticles before in vivo evaluation.

Simulated Measurements of the Magnetic Behavior of New Dual-Mode Nanosized Contrast Agents

Aim of this work was to perform simulated measurements of the magnetic behavior of a novel class of bimodal nanosized contrast agents (CAs), made of a silica core covered by smaller superparamagnetic nanoparticles (NPs) and designed to be detected through both ultrasound and magnetic resonance imaging (MRI), in order to compare their performance in terms of MRI signal enhancement with that of the superparamagnetic NPs alone. The considered bimodal nanocomposites consisted of 330-nm silica nanospheres covered by either superparamagnetic iron oxide NPs or dumbbell-like FePt-IO nanocrystals. We simulated the MRI signal generated by each of the considered CAs during a brain venography in standard clinical conditions. Quantitative assessments of signal enhancement were carried out as a function of the main model parameters. The performed numerical simulations showed that the magnetic response of the novel nanocomposites was similar or better compared to that of the superparamagnetic NPs alone for echo times longer than 20 ms, leading to an easier detection of smaller vessels. Obtained results suggest that the bimodal NPs have an exciting potential for the development of innovative clinical protocols for multimodal imaging, combining quantitative measurements of cerebral blood flow and targeted molecular imaging of specific diseases.

Development of Gd3N@C80 encapsulated redox nanoparticles for high-performance magnetic resonance imaging

As novel magnetic resonance imaging (MRI) contrast agent, gadofullerene encapsulated redox nanoparticles (Gd3NPs) were prepared by encapsulation of Gd3N@C80 in the core of core-shell-type polymer micelles composed of original polyamine with a reactive oxygen species (ROS)-scavenging ability. Because Gd3NPs possess biocompatible PEG shell with a smaller size (ca. 50 nm), they had high colloidal stability in a physiological environment, and showed low cytotoxicity. Specific accumulation of Gd3NPs in a tumor was confirmed in tumor-bearing mice after systemic administration. The tumor/muscle (T/M) ratio of the Gd ion reached five at 7.5 h after the administration. T1-weighted MRI signal enhancement of the T/M ratio increased by 8% at 6 h postinjection of Gd3NPs (Gd dose:14.35 μmol/kg). Although Gd3NPs showed a tendency for extended blood circulation, they did not have severe adverse effects, probably due to the confinement of Gd in a hydrophobic fullerene in addition to the ROS-scavenging capacity of these nanoparticles. In sharp contrast, systemic administration of Gd-chelate nanoparticles (GdCNPs) to mice disrupts liver function, increases leukocyte counts, and destroys spleen and skin tissues. Leaking of Gd ions from GdCNPs may cause such adverse effects. Based on these results, we expect that Gd3NPs is high-performance MRI contrast agents for tumor diagnosis.

Bio-inspired synthesis of PEGylated polypyrrole@polydopamine nanocomposites as theranostic agents for T1-weighted MR imaging guided photothermal therapy.

Polypyrrole nanoparticle (PPy) based theranostic agents for magnetic resonance imaging (MRI) guided photothermal therapy (PTT) have received increasing attention in recent years. However, the limitations of cost and biocompability still offer us opportunities to improve these agents. Considering the versatile character of polydopamine (PDA), PEGylated PPy@Fe3+-chelated PDA nanocomposites (PPDEs) were designed and prepared in an easy way. PPDE with a uniform core-shell structure could be obtained by adjusting the ratio of dopamine and PPys. In this nanocomplex, the shells confer the nanoparticles with good biocompability and MRI signal enhancing ability. Moreover, the PPy cores play a role in photothermal ablation of tumors. Compared with pure PDA nanoparticles, the PPDEs have higher NIR absorbance and better photothermal capability benefitting from the high photothermal conversion of the cores. Additionally, the obtained PPDEs provide significant MRI signal enhancement for both in vitro and in vivo imaging with high longitudinal relaxivity (r1 = 5.055 mM-1 s-1). After intravenous injection, the PPDEs exhibited valid tumor accumulation, as revealed by MRI and verified by biodistribution analysis. Under NIR irradiation, the PPDEs showed highly effective photothermal ablation of 4T1 cells. Notably, excellent biocompability of the PPDEs was confirmed by a relevant MTT assay and histologic analysis. This work achieved an example of exploiting the inherent advantages of PPy and PDA within a single unit and exploring its potential for T1 MRI-guided PTT.