A STING pathway-activatable contrast agent for MRI-guided tumor immunoferroptosis synergistic therapy.

The immunotherapy efficiency of stimulator of interferon genes (STING)-activatable drugs (e.g., 7-ethyl-10-hydroxycamptothecin, SN38) is limited by their non-specificity to tumor cells and the slow excretion of the DNA-containing exosomes from the treated cancer cells. The efficacy of tumor ferroptosis therapy is always limited by the elimination of lipid peroxides (LPO) by the pathways of glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH) and ferroptosis suppressor protein 1(FSP1). To solve these problems, in this study, we developed a STING pathway-activatable contrast agent (i.e., FeGd-HN@TA-Fe2+-SN38 nanoparticles) for magnetic resonance imaging (MRI)-guided tumor immunoferroptosis synergistic therapy. The remarkable in vivo MRI performance of FeGd-HN@TA-Fe2+-SN38 is attributed to its high accumulation at tumor location, the high relaxivities of FeGd-HN core, and the pH-sensitive TA-Fe2+-SN38 layer. The effectiveness and biosafety of the immunoferroptosis synergistic therapy induced by FeGd-HN@TA-Fe2+-SN38 are demonstrated by the in vivo investigations on the 4T1 tumor-bearing mice. The mechanisms of in vivo immunoferroptosis synergistic therapy by FeGd-HN@TA-Fe2+-SN38 are demonstrated by measurements of in vivo ROS, LPO, GPX4 and SLC7A11 levels, the intratumor matured DCs and CD8+ T cells, the protein expresion of STING and IRF-3, and the secretion of IFN-ß and IFN-γ.

Tumor-Generated Reactive Oxygen Species Storm for High-Performance Ferroptosis Therapy.

Ferroptosis therapy (FT) efficacy of tumors suffers from a relatively low concentration of Fenton agents, limited hydrogen peroxide (H2O2) content, and insufficient acidity in the tumor environment (TME), which are unfavorable for reactive oxygen species (ROS) generation based on Fenton or Fenton-like reactions. The glutathione (GSH) overexpression in TME can scavenge ROS and abate the FT performance. In this study, a strategy of ROS storm generation specifically initiated by the TME and our developed nanoplatforms (TAF-HMON-CuP@PPDG) is proposed for high-performance FT of tumors. The GSH in the TME initiates HMON degradation, resulting in tamoxifen (TAF) and copper peroxide (CuP) release from TAF3-HMON-CuP3@PPDG. The released TAF leads to enhanced acidification within tumor cells, which reacts with the released CuP producing Cu2+ and H2O2. The Fenton-like reaction between Cu2+ and H2O2 generates ROS and Cu+, and that between Cu+ and H2O2 generates ROS and Cu2+, forming a cyclic catalysis effect. Cu2+ reacts with GSH to generate Cu+ and GSSG. The increased acidification by TAF can accelerate the Fenton-like reaction between Cu+ and H2O2. The GSH consumption decreases the glutathione peroxidase 4 (GPX4) expression. All of the above reactions generate a ROS storm in tumor cells for high-performance FT, which is demonstrated in cancer cells and tumor-bearing mice.

Astrocyte dysfunction drives abnormal resting-state functional connectivity in depression.

Major depressive disorder (MDD) is a devastating mental disorder that affects up to 17% of the population worldwide. Although brain-wide network-level abnormalities in MDD patients via resting-state functional magnetic resonance imaging (rsfMRI) exist, the mechanisms underlying these network changes are unknown, despite their immense potential for depression diagnosis and management. Here, we show that the astrocytic calcium-deficient mice, inositol 1,4,5-trisphosphate-type-2 receptor knockout mice (Itpr2-/- mice), display abnormal rsfMRI functional connectivity (rsFC) in depression-related networks, especially decreased rsFC in medial prefrontal cortex (mPFC)-related pathways. We further uncover rsFC decreases in MDD patients highly consistent with those of Itpr2-/- mice, especially in mPFC-related pathways. Optogenetic activation of mPFC astrocytes partially enhances rsFC in depression-related networks in both Itpr2-/- and wild-type mice. Optogenetic activation of the mPFC neurons or mPFC-striatum pathway rescues disrupted rsFC and depressive-like behaviors in Itpr2-/- mice. Our results identify the previously unknown role of astrocyte dysfunction in driving rsFC abnormalities in depression.

Facile Synthesis of Weakly Ferromagnetic Organogadolinium Macrochelates-Based T1 -Weighted Magnetic Resonance Imaging Contrast Agents.

To surmount the major concerns of commercial small molecule Gd chelates and reported Gd-based contrast agents (GBCAs) for magnetic resonance imaging (MRI), a new concept of organogadolinium macrochelates (OGMCs) constructed from the coordination between Gd3+ and macromolecules is proposed. A library of macromolecules were screened for Gd3+ coordination, and two candidates [i.e., poly(acrylic acid) (PAA), and poly(aspartic acid) (PASP)] succeeded in OGMC formation. Under optimized synthesis conditions, both Gd-PAA12 and Gd-PASP11 OGMCs are outstanding T1 -weighted CAs owing to their super high r1 values (> 50 mm-1  s-1 , 3.0 T) and ultralow r2 /r1 ratios (< 1.6, 3.0 T). The ferromagnetism of OGMCs is completely different from the paramagnetism of commercial and reported GBCAs. The ferromagnetism is very weak (Ms  < 1.0 emu g-1 ) leading to a low r2 , which is preferred for T1 MRI. Gd3+ is not released from the OGMC Gd-PAA12 and Gd-PASP11, ensuring biosafety for in vivo applications. The safety and T1 -weighted MRI efficiencies of the OGMC Gd-PAA12 and Gd-PASP11 are tested in cells and mice. The synthesis method of the OGMCs is facile and easy to be scaled up. Consequently, the OGMC Gd-PAA12 and Gd-PASP11 are superior T1 -weighted CAs with promising translatability to replace the commercial Gd chelates.

Quantitative evaluation of the characteristic of infrapatellar fat pad Fat Content and Unsaturation Index by using hydrogen proton MR spectroscopy.

OBJECTIVE: To investigate the characteristics of fat content and component in IFP using hydrogen proton MR spectroscopy (1H-MRS), and to explore the correlation with the severity of OA, Hoffa-synovitis, and knee pain. MATERIALS AND METHODS: 80 volunteers were enrolled. Subjects were grouped based on Kellgren-Lawrence (K-L) grading. Fat fraction (FF) and unsaturation index (UI) of IFP were measured using 1H-MRS. Hoffa-synovitis was evaluated based on the MRI Osteoarthritis Knee Score system (MOAKS). Knee pain was assessed by a self-administered Western Ontario and McMaster Osteoarthritis Index (WOMAC) questionnaire. One-way ANOVA or Kruskal-Wallis test and Spearman's correlation tests were applied for statistical analysis. RESULTS: After matching BMI, waistline, and K-L grade, a total of 64 knees were included and divided into 23 normal, 25 mild OA, and 16 advanced OA. The mean values were 76.79% ± 7.24%, 70.35% ± 7.42%, and 58.29% ± 10.32% for FF in the healthy controls, mild OA, and advanced OA group, and 6.36 ± 1.19%, 6.08 ± 1.35%, and 5.69 ± 1.78% for UI, respectively, the statistical difference was found for FF (p < 0.01). A good negative correlation was observed between the FF and the severity of OA, Hoffa-synovitis (r = -0.625, -0.758, respectively, p < 0.0001), and a weak inverse correlation with knee pain. CONCLUSION: FF alteration in IFP is associated with the severity of OA, Hoffa synovitis, and knee pain, and has the potential to be a new quantitative imaging biomarker in knee OA.

Ratiometric chemical exchange saturation transfer pH mapping using two iodinated agents with nonequivalent amide protons and a single low saturation power.

Background: As an essential physiological parameter, pH plays a critical role in maintaining cellular and tissue homeostasis. The ratiometric chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) method using clinically approved iodinated agents has emerged as one of the most promising noninvasive techniques for pH assessment. Methods: In this study, we investigated the ability to use the combination of two different nonequivalent amide protons, chosen from five iodinated agents, namely iodixanol, iohexol, iobitridol, iopamidol, and iopromide, for pH measurement. The ratio of two nonequivalent amide CEST signals was calculated and compared for pH measurements in the range of 5.6 to 7.6. To quantify the CEST signals at 4.3 and 5.5 parts per million (ppm), we employed two analytic methods: magnetization transfer ratio asymmetry and Lorentzian fitting analysis. Lastly, the established protocol was used to measure the pH values in healthy rat kidneys (n=5). Results: The combination of iodixanol and iobitridol at a ratio of 1:1 was found to be suitable for pH mapping. The saturation power level (B1) was also investigated, and a low B1 of 1.5 µT was adopted for subsequent pH measurements. Improved precision and an extended pH detection range were achieved using iodixanol and iobitridol (1:1 ratio) and a single low B1 of 1.5 µT in vitro. In vivo renal pH values were measured as 7.23±0.09, 6.55±0.15, and 6.29±0.23 for the cortex, medulla, and calyx, respectively. Conclusions: These results show that the ratiometric CEST method using two iodinated agents with nonequivalent amide protons could be used for in vivo pH mapping of the kidney under a single low B1 saturation power.

Early detection of increased marrow adiposity with age in rats using Z-spectral MRI at ultra-high field (7 T).

BACKGROUND: Nowadays, the drive towards high-field MRI is fueled by the pursuit of higher signal-to-noise ratio, spatial resolution, and imaging speed. However, high field strength is associated with field inhomogeneity, acceleration of T2 * decay, and increased chemical shift, which may pose challenges to conventional MRI for fat quantification in complex tissues such as bone marrow. With proton MRI spectroscopy (1 H-MRS), on the other hand, it is difficult to produce high resolution. As a novel alternative fat quantification method, high-resolution Z-spectral MRI (ZS-MRI) can achieve fat quantification by acquiring direct saturated images of both fat and water under the same TE , which may be less affected by T2 * decay and field inhomogeneity. PURPOSE: To demonstrate ZS-MRI for marrow adipose tissue (MAT) quantification in rat's lumbar spine and the early detection of MAT changes with age. METHODS: The accuracy of ZS-MRI for fat quantification at ultra-high-field MRI (7 T) was verified with MRS and conventional Dixon MRI in water-oil mixed phantoms with varying fat fraction (FF). Dixon MRI data were processed with iterative decomposition of water and fat with echo asymmetry and least-squares estimation. ZS-MRI was then used to longitudinally monitor the adiposity in the lumbar spine of young healthy rats at 13, 17, and 21 weeks to detect the early changes of FF with age in MAT. Hematoxylin-eosin staining of lumbar spines from separated rat groups was performed for verification. RESULTS: In ex vivo phantom experiments, both Dixon MRI and ZS-MRI were well correlated with 1 H-MRS for the quantification of FF at 7 T (R > 0.99). Compared with Dixon MRI, ZS-MRI showed reduced image artifacts due to field inhomogeneity and presented better agreement with 1 H-MRS for the early detection of increased MAT due to age at 7 T (ZS-MRI R = 0.78 versus Dixon MRI R = 0.34). The increased MAT FF due to age was confirmed by histology. CONCLUSION: ZS-MRI proves itself as an alternative fat quantification method for bone marrow in rats at 7 T.

Quantitative evaluation of bone marrow fat content and unsaturated fatty index in young male soccer players using proton magnetic resonance spectroscopy (1H-MRS): a preliminary study.

BACKGROUND: Marrow fat exists as a distinct adipose tissue and plays a critical role in affecting both the quantity and quality of bone. However, the effect of soccer training on marrow fat has been rarely reported. This study aims to evaluate and characterize the marrow fat content and composition in different bone areas of soccer players and age-matched healthy subjects using proton magnetic resonance spectroscopy (1H-MRS). METHODS: Between May 2020 and June 2020, 20 professional soccer players (20.7±0.9 years) and 20 age-matched healthy subjects (21.2±0.8 years) were enrolled in this cross-sectional study. The 1H-MRS were acquired from the 3rd lumbar vertebrae, bilateral femoral necks, and distal tibias of all subjects using a single-voxel point-resolved spatially localized spectroscopy (PRESS) sequence. Four soccer players underwent a second magnetic resonance (MR) examination within a 30-minute interval after the initial scan to evaluate test-retest reproducibility. Inter- and intra-observer measurement reliabilities were assessed using 10 randomly selected spectra from the soccer players group. All spectra were processed using the jMRUI software package (http://www.jmrui.eu/). Quantified water and lipid signals were used to calculate fat content (FC) and the unsaturated fatty index (UI). RESULTS: Compared with healthy subjects, we found that soccer players had a lower FC in L3 and bilateral femoral necks and higher UI in the left femoral neck (P<0.05). All FC and UI values of the bilateral distal tibias showed no significant differences between the two groups (P>0.05). The UI values of the right femoral neck or distal tibia were markedly higher than the left side in both inactive subjects and soccer players (P<0.05, except for the femoral neck in players), and there were notable ΔUI differences in the lower limbs between the soccer players and the healthy subjects (P<0.05). CONCLUSIONS: Soccer practice can be considered a positive sport that contributes to decreasing FC in lumbar vertebrae and femoral necks and increasing the UI in femoral necks. Quantitative MRS provides an ideal modality to predict marrow fat metabolism caused by mechanical stimulation.

Physiological system analysis of the kidney by high-temporal-resolution T2∗ monitoring of an oxygenation step response.

PURPOSE: Examine the feasibility of characterizing the regulation of renal oxygenation using high-temporal-resolution monitoring of the T2∗ response to a step-like oxygenation stimulus. METHODS: For T2∗ mapping, multi-echo gradient-echo imaging was used (temporal resolution = 9 seconds). A step-like renal oxygenation challenge was applied involving sequential exposure to hyperoxia (100% O2 ), hypoxia (10% O2 + 90% N2 ), and hyperoxia (100% O2 ). In vivo experiments were performed in healthy rats (N = 10) and in rats with bilateral ischemia-reperfusion injury (N = 4). To assess the step response of renal oxygenation, a second-order exponential model was used (model parameters: amplitude [A], time delay [Δt], damping constant [D], and period of the oscillation [T]) for renal cortex, outer stripe of the outer medulla, inner stripe of the outer medulla, and inner medulla. RESULTS: The second-order exponential model permitted us to model the exponential T2∗ recovery and the superimposed T2∗ oscillation following renal oxygenation stimulus. The in vivo experiments revealed a difference in Douter medulla between healthy controls (D < 1, indicating oscillatory recovery) and ischemia-reperfusion injury (D > 1, reflecting aperiodic recovery). The increase in Douter medulla by a factor of 3.7 (outer stripe of the outer medulla) and 10.0 (inner stripe of the outer medulla) suggests that this parameter might be rather sensitive to (patho)physiological oxygenation changes. CONCLUSION: This study demonstrates the feasibility of monitoring the dynamic oxygenation response of renal tissues to a step-like oxygenation challenge using high-temporal-resolution T2∗ mapping. Our results suggest that the implemented system analysis approach may help to unlock questions regarding regulation of renal oxygenation, with the ultimate goal of providing imaging means for diagnostics and therapy of renal diseases.

Detection of gadolinium deposition in cortical bone with ultrashort echo time T1 mapping: an ex vivo study in a rabbit model.

OBJECTIVES: To investigate the capacity of ultrashort echo time (UTE) T1 mapping to non-invasively assess gadolinium deposition in cortical bone after gadolinium-based contrast agent (GBCA) administration. METHODS: Twenty-eight New Zealand rabbits (male, 3.0-3.5 kg) were randomly allocated into control, macrocyclic, high-dose macrocyclic, and linear GBCA groups (n = 7 for each group), and respectively given daily doses of 0.9 ml/kg bodyweight saline, 0.3 mmol/kg bodyweight gadobutrol, 0.9 mmol/kg bodyweight gadobutrol, and 0.3 mmol/kg bodyweight gadopentetate dimeglumine for five consecutive days per week over a period of 4 weeks. After a subsequent 4 weeks of recovery, the rabbits were sacrificed and their tibiae harvested. T1 value of cortical bone was measured using a combination of UTE actual flip angle imaging and variable repetition time on a 7T animal scanner. Gadolinium concentration in cortical bone was measured using inductively coupled plasma mass spectrometry (ICP-MS). Pearson's correlation between R1 value (R1 = 1/T1) and gadolinium concentration in cortical bone was assessed. RESULTS: Bone T1 values were significantly lower in the lower-dose macrocyclic (329.2 ± 21.0 ms, p < 0.05), higher-dose macrocyclic (316.8 ± 21.7 ms, p < 0.01), and linear (296.8 ± 24.1 ms, p < 0.001) GBCA groups compared with the control group (356.3 ± 19.4 ms). Gadolinium concentrations measured by ICP-MS in the control, lower-dose macrocyclic, higher-dose macrocyclic, and linear GBCA groups were 0.04 ± 0.02 µg/g, 2.60 ± 0.48 µg/g, 4.95 ± 1.17 µg/g, and 13.62 ± 1.55 µg/g, respectively. There was a strong positive correlation between R1 values and gadolinium concentrations in cortical bone (r = 0.73, p < 0.001). CONCLUSIONS: These results suggest that UTE T1 mapping has the potential to provide a non-invasive assessment of gadolinium deposition in cortical bone following GBCA administration. KEY POINTS: • Changes in T1 value related to gadolinium deposition were found in bone after both linear and macrocyclic GBCA administrations. • R1 relaxometry correlates strongly with gadolinium concentration in cortical bone. • UTE T1 mapping provides a potential tool for non-invasively monitoring gadolinium deposition in cortical bone.

Ultrasmall T1-T2 Magnetic Resonance Multimodal Imaging Nanoprobes for the Detection of ß-amyloid Aggregates in Alzheimer's Disease Mice.

Alzheimer's disease (AD) is an irreversible brain disorder and imposes a severe burden upon patients and the public health system. Most research efforts have focused on the search for effective therapeutic drugs, but it is time to pursue efficient early diagnosis based on the reasonable assumption that AD may be easier to prevent than reverse. Recent studies have shown that there are several probes for detecting amyloid-ß (Aß) plaques, one of the neuropathological hallmarks found in AD brain. However, it is still a great challenge for nonradioactive, sensitive detection and location of Aß plaques by brain imaging with high spatial resolution. Herein, phenothiazine derivative (PZD)-conjugated sub-5 nm ultrasmall ferrite nanoprobes (UFNPs@PEG/PZD) are designed and prepared for efficient T1-T2 magnetic resonance multimodal imaging of Aß plaques. UFNPs@PEG/PZD not only possess high binding affinity to Aß plaques but also exhibit excellent properties of r1 and r2 relaxivities. This study thus provides a promising ultrasmall nanoplatform as an Aß-targeting multimodal imaging probe for the application of early diagnosis of AD.

Effect of green tea consumption on human brain function in resting-state functional MRI.

BACKGROUND AND OBJECTIVES: Green tea is reported to have wide benefits on psychological states and cognitive functions. Studies that focus on the underlying neural mechanisms of green tea are limited to its single composition while people usually benefit from green tea water that contains various composition. In this study, we examined the human brain activity changes after drinking natural green tea by using regional homogeneity and functional connectivity based on the resting-state functional MRI technique. METHODS AND STUDY DESIGN: Fifteen healthy volunteers participated in two imaging sessions: a control (water) session and a green tea session, each session comprised a predrinking, drinking, and postdrinking section, during the drinking section, the subject consumed 200 mL of green tea infusion or water in 3 to 5 minutes. Then the post-tea and post-water imaging data were selected for regional homogeneity and functional connectivity analysis. RESULTS: Our results revealed that, compared with the control group, the green tea group exhibited an increased regional homogeneity in the frontal, parietal, and occipital areas of the brain, decreased regional homogeneity values in the left cuneus and left lingual gyrus, mainly a decreased functional connectivity in the default mode network, somatosensory, visual cortex, and parieto-frontal areas and enhanced functional connectivity in brain regions associated with memory. CONCLUSIONS: This result indicates that green tea consumption impacts the brain activity during resting state.

Quantitative susceptibility mapping of the spine using in-phase echoes to initialize inhomogeneous field and R2* for the nonconvex optimization problem of fat-water separation.

Quantitative susceptibility mapping (QSM) of human spinal vertebrae from a multi-echo gradient-echo (GRE) sequence is challenging, because comparable amounts of fat and water in the vertebrae make it difficult to solve the nonconvex optimization problem of fat-water separation (R2*-IDEAL) for estimating the magnetic field induced by tissue susceptibility. We present an in-phase (IP) echo initialization of R2*-IDEAL for QSM in the spinal vertebrae. Ten healthy human subjects were recruited for spine MRI. A 3D multi-echo GRE sequence was implemented to acquire out-phase and IP echoes. For the IP method, the R2* and field maps estimated by separately fitting the magnitude and phase of IP echoes were used to initialize gradient search R2*-IDEAL to obtain final R2*, field, water, and fat maps, and the final field map was used to generate QSM. The IP method was compared with the existing Zero method (initializing the field to zero), VARPRO-GC (variable projection using graphcuts but still initializing the field to zero), and SPURS (simultaneous phase unwrapping and removal of chemical shift using graphcuts for initialization) on both simulation and in vivo data. The single peak fat model was also compared with the multi-peak fat model. There was no substantial difference on QSM between the single peak and multi-peak fat models, but there were marked differences among different initialization methods. The simulations demonstrated that IP provided the lowest error in the field map. Compared to Zero, VARPRO-GC and SPURS, the proposed IP method provided substantially improved spine QSM in all 10 subjects.

Magnetic Susceptibility and Fat Content in the Lumbar Spine of Postmenopausal Women With Varying Bone Mineral Density.

BACKGROUND: Osteoporosis is a systemic disease characterized by low bone mass with increased fracture risk. Quantitative imaging biomarkers are important for accurately predicting fracture risk in patients with osteoporosis. PURPOSE: To prospectively study the changes of magnetic susceptibility and fat content in the lumbar spine of postmenopausal females with varying bone mineral density (BMD), and investigate their application to osteoporosis assessment. STUDY TYPE: Cohort. POPULATION: In all, 108 postmenopausal females (58.2 ± 6.7 [range 45-79] years old). FIELD STRENGTH/SEQUENCE: Quantitative computed tomography (QCT) performed on a 64-detector CT scanner; quantitative susceptibility mapping (QSM) and mDixon quant MR imaging performed using a 3.0T imaging system with a 16-channel posterior coil. ASSESSMENT: QCT, QSM, and mDixon were performed in 108 postmenopausal females to measure vertebral BMD, susceptibility, and proton-density fat fraction (PDFF). Mean vertebral QSM and PDFF were compared among three BMD cohorts (normal, osteopenic, and osteoporotic). Receiver operating characteristic analyses were performed to evaluate the performance of QSM, PDFF, and QSM+PDFF for assessing osteoporosis. STATISTICAL TESTS: Parameters were compared using Kruskal-Wallis test and Pearson test. RESULTS: Compared with that of the normal BMD group (-17.0 ± 43.6 ppb), vertebral QSM was significantly increased in osteopenia (30.8 ± 47.0 ppb, P < 0.001), and further increased in osteoporosis (82.0 ± 39.9 ppb, P < 0.001). QSM was negatively correlated with BMD (r = -0.70, P < 0.001) and positively correlated with PDFF (r = 0.64, P < 0.001). Compared with the area under the curve (AUC) of PDFF, the AUC of QSM was higher in differentiating between normal and osteoporosis (P = 0.44), and between osteopenia and osteoporosis (P = 0.13), but without statistical significance. The AUC of QSM+PDFF was significantly higher than that of PDFF for differentiating between osteopenia and osteoporosis (0.82 vs. 0.70, P = 0.039). DATA CONCLUSION: The combination of vertebral susceptibility and fat content may be a promising marker for assessing postmenopausal osteoporosis. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1020-1028.

Magnetic Resonance Imaging Revealed Splenic Targeting of Canine Parvovirus Capsid Protein VP2.

Canine parvovirus (CPV) is a highly contagious infectious virus, whose infectious mechanism remains unclear because of acute gastroenteritis and the lack of an efficient tool to visualize the virus in real time during virology research. In this study, we developed an iron oxide nanoparticle supported by graphene quantum dots (GQD), namely, FeGQD. In this composite material, GQD acts as a stabilizer; thus, vacancies are retained on the surface for further physical adsorption of the CPV VP2 protein. The FeGQD@VP2 nanocomposite product showed largely enhanced colloidal stability in comparison with bare FeGQD, as well as negligible toxicity both in vitro and in vivo. The composite displayed high uptake into transferrin receptor (TfR) positive cells, which are distinguishable from FeGQD or TfR negative cells. In addition, the composite developed a significant accumulation in spleen rather than in liver, where bare FeGQD or most iron oxide nanoparticles gather. As these evident targeting abilities of FeGQD@VP2 strongly suggested, the biological activity of CPV VP2 was retained in our study, and its biological functions might correspond to CPV when the rare splenic targeting ability is considered. This approach can be applied to numerous other biomedical studies that require a simple yet efficient approach to track proteins in vivo while retaining biological function and may facilitate virus-related research.

Preoperative Detection and Intraoperative Visualization of Brain Tumors for More Precise Surgery: A New Dual-Modality MRI and NIR Nanoprobe.

In clinical practice, it is difficult to identify tumor margins during brain surgery due to its inherent infiltrative character. Herein, a unique dual-modality nanoprobe (Gd-DOTA-Ag2S QDs, referred as Gd-Ag2S nanoprobe) is reported, which integrates advantages of the deep tissue penetration of enhanced magnetic resonance (MR) imaging of Gd and the high signal-to-noise ratio and high spatiotemporal resolution of fluorescence imaging in the second near-infrared window (NIR-II) of Ag2S quantum dots (QDs). Due to the abundant tumor angiogenesis and the enhanced permeability and retention effect in the tumor, a brain tumor (U87MG) in a mouse model is clearly delineated in situ with the help of the Gd assisted T1 MR imaging and the intraoperative resection of the tumor is precisely accomplished under the guidance of NIR-II fluorescence imaging of Ag2S QDs after intravenous injection of Gd-Ag2S nanoprobe. Additionally, no histologic changes are observed in the main organs of the mouse after administration of Gd-Ag2S nanoprobe for 1 month, indicating the high biocompatibility of the nanoprobe. We expect that such a novel "Detection and Operation" strategy based on Gd-Ag2S nanoprobe is promising in future clinical applications.

Fates of Fe3O4 and Fe3O4@SiO2 nanoparticles in human mesenchymal stem cells assessed by synchrotron radiation-based techniques.

Superparamagnetic iron oxide nanoparticles (SPIOs) have been widely used as the magnetic resonance imaging (MRI) contrast agent in biomedical studies and clinical applications, with special interest recently in in vivo stem cell tracking. However, a full understanding of the fate of SPIOs in cells has not been achieved yet, which is particularly important for stem cells since any change of the microenvironment may disturb their propagation and differentiation behaviors. Herein, synchrotron radiation-based X-ray fluorescence (XRF) in combination with X-ray absorption spectroscopy (XAS) were used to in situ reveal the fate of Fe3O4 and Fe3O4@SiO2 NPs in human mesenchymal stem cells (hMSCs), in which the dynamic changes of their distribution and chemical speciation were precisely determined. The XAS analysis evidences that Fe3O4 NPs cultured with hMSCs are quite stable and almost keep their initial chemical form up to 14 days, which is contradictory to the previous report that Fe3O4 NPs were unstable in cell labeling assessed by using a simplified lysosomal model system. Coating with a SiO2 shell, Fe3O4@SiO2 NPs present higher stability in hMSCs without detectable changes of their chemical form. In addition, XRF analysis demonstrates that Fe3O4@SiO2 NPs can label hMSCs in a high efficiency manner and are solely distributed in cytoplasm during cell proliferation, making it an ideal probe for in vivo stem cell tracking. These findings with the help of synchrotron radiation-based XAS and XRF improve our understanding of the fate of SPIOs administered to hMSCs and will help the future design of SPIOs for safe and efficient stem cells tracking.

The interplay of T1- and T2-relaxation on T1-weighted MRI of hMSCs induced by Gd-DOTA-peptides.

Three Gd-DOTA-peptide complexes with different peptide sequence are synthesized and used as T1 contrast agent to label human mesenchymal stem cells (hMSCs) for magnetic resonance imaging study. The peptides include a universal cell penetrating peptide TAT, a linear MSC-specific peptide EM7, and a cyclic MSC-specific peptide CC9. A significant difference in labeling efficacy is observed between the Gd-DOTA-peptides as well as a control Dotarem. All Gd-DOTA-peptides as well as Dotarem induce significant increase in T1 relaxation rate which is in favor of T1-weighted MR imaging. Gd-DOTA-CC9 yields the maximum labeling efficacy but poor T1 contrast enhancement. Gd-DOTA-EM7 yields the minimum labeling efficacy but better T1 contrast enhancement. Gd-DOTA-TAT yields a similar labeling efficacy as Gd-DOTA-CC9 and similar T1 contrast enhancement as Gd-DOTA-EM7. The underlying mechanism that governs T1 contrast enhancement effect is discussed. Our results suggest that T1 contrast enhancement induced by Gd-DOTA-peptides depends not only on the introduced cellular Gd content, but more importantly on the effect that Gd-DOTA-peptides exert on the T1-relaxation and T2-relaxation processes/rates. Both T1 and particularly T2 relaxation rate have to be taken into account to interpret T1 contrast enhancement. In addition, the interpretation has to be based on cellular instead of aqueous longitudinal and transverse relaxivities of Gd-DOTA-peptides.

Magnetic resonance imaging of Fe3O4@SiO2-labeled human mesenchymal stem cells in mice at 11.7 T.

Fe(3)O(4)@SiO(2) core-shell nanoparticles were synthesized and used to label human mesenchymal stem cells (hMSCs) for in vitro and in vivo magnetic resonance imaging study. The diameter of the nanoparticles is 24-30 nm with a Fe(3)O(4) core of ∼8 nm and a SiO(2) shell of ~8 nm. Transverse relaxivity of the nanoparticles dispersed in water is measured to be ~106 mM(-1) s(-1). After incubation with hMSCs for 12 h at a concentration of 100 µg Fe/mL, cellular uptake of Fe(3)O(4)@SiO(2) is 20-100 pg Fe/cell, which are located predominantly in the cytoplasm of cells. This level of uptake exhibits no significant influence on hMSCs' viability and differentiation. In vitro imaging of Fe(3)O(4)@SiO(2)-labeled hMSCs evenly distributed in agarose gel yields single cell sensitivity at 11.7 T. In vivo imaging of Fe(3)O(4)@SiO(2)-labeled hMSCs injected into the left brain hemisphere of nude mice yields imaging sensitivity of ~130 hMSCs.

Composites of aminodextran-coated Fe3O4 nanoparticles and graphene oxide for cellular magnetic resonance imaging.

Formation of composites of dextran-coated Fe(3)O(4) nanoparticles (NPs) and graphene oxide (Fe(3)O(4)-GO) and their application as T(2)-weighted contrast agent for efficient cellular magnetic resonance imaging (MRI) are reported. Aminodextran (AMD) was first synthesized by coupling reaction of carboxymethyldextran with butanediamine, which was then chemically conjugated to meso-2,3-dimercaptosuccinnic acid-modified Fe(3)O(4) NPs. Next, the AMD-coated Fe(3)O(4) NPs were anchored onto GO sheets via formation of amide bond in the presence of 1-ethyl-3-(3-dimethyaminopropyl) carbodiimide (EDC). It is found that the Fe(3)O(4)-GO composites possess good physiological stability and low cytotoxicity. Prussian Blue staining analysis indicates that the Fe(3)O(4)-GO nanocomposites can be internalized efficiently by HeLa cells, depending on the concentration of the composites incubated with the cells. Furthermore, compared with the isolated Fe(3)O(4) NPs, the Fe(3)O(4)-GO composites show significantly enhanced cellular MRI, being capable of detecting cells at the iron concentration of 5 µg mL(-1) with cell density of 2 × 10(5) cells mL(-1), and at the iron concentration of 20 µg mL(-1) with cell density of 1000 cells mL(-1).