Camouflaged Nanoreactors Mediated Radiotherapy-Adjuvant Chemodynamic Synergistic Therapy.

Chemodynamic therapy based on the Fenton-like catalysis ability of Fe3O4 has the advantages of no involvement of chemical drugs and minimal adverse effects as well as the limitation of depletable efficacy. Radiotherapy based on high-energy radiation offers the convenience of treatment and cost-effectiveness but lacks precision and cellular adaptation of tumor cells. Approaching such dilemmas from a nanoscale materials perspective, we aim to bridge the weaknesses of both treatment methods by combining the principles of two therapeutics reciprocally. We have designed a camouflaged Fe3O4@HfO2 composite nanoreactor (FHCM), which combines a chemodynamic therapeutic agent Fe3O4 and a radiosensitizer HfO2 that both has passed clinical trials and was inspired by a cell membrane biomimetic technique. FHCM is employed as conceived radiotherapy-adjuvant chemodynamic synergistic therapy of malignant tumors, which has undergone dual scrutiny from both the physical and biological aspects. Experimental results obtained at different levels, including theory, material characterizations, and in vitro and in vivo verifications, suggest that FHCM effectively impaired tumor cells through physical and molecular biological mechanisms involving a HfO2-Fe3O4 photoelectron-electron transfer chain and DNA damage-ferroptosis-immunity chain. It is worth noting that compared to single therapies such as only chemodynamic therapy or radiotherapy, FHCM-mediated radiotherapy-adjuvant chemodynamic synergistic therapy exhibits stronger tumor inhibition efficacy. It significantly addresses the inherent limitations of chemodynamic therapy and radiotherapy and underscores the feasibility and importance of using existing clinical weapons, such as radiotherapy, as auxiliary strategies to overcome certain flaws of emerging antitumor therapeutics like chemodynamic therapy.

Resting-State Functional Connectivity Analyses: Brain Functional Reorganization in a Rat Model of Postherpetic Neuralgia.

Postherpetic neuralgia (PHN) is a chronic neuropathic pain syndrome, similar to other chronic pains, the mechanisms of which are not fully understood. To further understand the neural mechanism of this chronic pain and its transition, we performed functional magnetic resonance imaging (fMRI) scans on PHN rat models. Twelve PHN rat models were established by intraperitoneal injection of resiniferatoxin, with an additional 12 rats serving as controls. Nociceptive behavioral tests were performed on these rats and fMRI scans were performed on days 7 and 14 after modeling. Functional connection (FC) analysis was used to investigate the brain FC alterations associated with chronic pain in PHN rats, with the anterior cingulate cortex (ACC) as a seed. Nociceptive behavioral tests showed that PHN rats presented symptoms similar to those of PHN patients. FC analysis showed that compared to the control group, the PHN group showed different FC patterns on days 7 and 14. As can be seen, the brain FC alterations in the rat model of PHN changed dynamically, shifting from brain regions processing sensory information to regions processing emotions and motives.

Alterations to cognitive abilities and functional networks in rats post broad-band intense noise exposure.

This study aimed to investigate the alterations of cognition and functional connectivity post noise, and find the progress and neural substrates of noise induced hearing loss (NIHL)-associated cognitive impairment. We exposed rats to 122 dB broad-band noise for 2 h to induce hearing loss and the auditory function was assessed by measuring auditory brainstem response thresholds. Morris water maze test and resting state MRI were computed at 0 day, 1, 3, 6 months post noise to reveal cognitive ability and neural substrate. The interregional connections in the auditory network and default mode network, as well as the connections using the auditory cortex and cingulate cortex as seeds were also examined addtionally. The deficit in spatial learning/memory was only observed at 6 months after noise exposure. The internal connections in the auditory network and default mode network were enhanced at 0 day and decreased at 6 months post noise. The connectivity using the auditory cortex and cingulate cortex as seeds generally followed the rule of "enhancement-normal-decrease-widely decrease". A new model accounting for arousal, dementia, motor control of NIHL in is proposed. Our study highlights the fundamental flexibility of neural systems, and may also point toward novel therapeutic strategies for treating sensory disorders.

Moderate cooling coprecipitation for extremely small iron oxide as a pH dependent T1-MRI contrast agent.

Iron based nanomedicine (IBNM) has been one powerful diagnostic tool as a magnetic resonance imaging (MRI) contrast agent (CA) in the clinic for years. Conventional IBNMs are generally employed as T2-MRI CAs, but most of them are constrained in clinical indication expansion by magnetic susceptibility artifacts. In comparison, extremely small iron oxide (ESIO) with a core size less than 5 nm has demonstrated the T1-MRI effect, which provides prospects for a Gd-based agent alternative. Nevertheless, currently developed ESIOs for T1-MRI CAs always require harsh conditions such as a high temperature and high boiling point reagent. Moreover, very few of the currently developed ESIOs meet the stringent pharmaceutical standard. Herein, on the basis of a crystal nuclear precipitation-dissolution equilibrium mechanism and outer/inner sphere T1-MRI theory, monodisperse ESIOs with an average size of 3.43 nm (polydispersity index of 0.104) are fabricated using a moderate cooling procedure with mild coprecipitation reaction conditions. The as-synthesized ESIOs display around 3-fold higher T1 MRI signal intensity than that of commercial Ferumoxytol (FMT), comparable to that of Gd-based CAs in vitro. Additionally, the T1-MRI performance of the ESIOs is pH dependent and delivers bright signal augmentation. Eventually, the internalization into mesenchymal stem cells of the ESIO is realized in the absence of a transferring agent. Considering the identical structure and composition of the ESIOs as compared to that of FMT, they could meet the pharmaceutical criteria, thus providing great potential as T1-MRI Cas, for instance as stem cell tracers.

Silencing of circular RNA HIPK2 in neural stem cells enhances functional recovery following ischaemic stroke.

BACKGROUND: Circular RNAs (circRNAs) have been reported to be involved in central nervous system (CNS) diseases and to have a close connection with neuronal development. However, the role of circRNAs in neural stem cell (NSC) differentiation and the treatment of ischaemic stroke remains unknown. METHODS: Ischaemic stroke was induced in mice using transient middle cerebral artery occlusion (tMCAO). NSCs were transducted with circHIPK2 siRNA (si-circHIPK2-NSCs) or vehicle control (si-circCon-NSCs) and microinjected into lateral ventricle of brain at 7 d post-tMCAO. Magnetic resonance imaging (MRI) was used to detect brain damage, and functional deficits were evaluated with sensorimotor behavioural tests. The distribution of the transplanted NSCs was investigated by near-infrared fluorescence imaging (NIF) and immunofluorescence. The neural plasticity of si-circHIPK2-NSCs was verified by western blot and immunofluorescence in vivo and in vitro. FINDINGS: We investigated the role of circHIPK2 in NCS differentiation. In vitro, silencing of circHIPK2 facilitated NSCs directionally differentiated to neurons but had no effect on the differentiation to astrocytes. In vivo, microinjected NSCs could migrate to the ischaemic hemisphere after stroke induction. Si-circHIPK2-NSCs increased neuronal plasticity in the ischaemic brain, conferred long-lasting neuroprotection, and significantly reduced functional deficits. INTERPRETATIONS: Si-circHIPK2 regulates NSC differentiation, and microinjection of si-circHIPK2-NSCs exhibits a promising therapeutic strategy to neuroprotection and functional recovery after stroke. FUNDING: The National Key Research and Development Program of China; the International Cooperation and Exchange of the National Natural Science Foundation of China; the National Natural Science Foundation of China; the Jiangsu Innovation & Entrepreneurship Team Program.

Rituximab conjugated iron oxide nanoparticles for targeted imaging and enhanced treatment against CD20-positive lymphoma.

Since its launch in 1997, rituximab (RTX) has extensively improved the treatment of CD20-positive follicular and diffuse large B cell non-Hodgkin lymphoma (NHL). The application of RTX is limited usually by the failed therapy because of resistance. Iron oxide nanomaterials have been explored for cancer detection and treatment in recent years. In this study, a multivalent nanoprobe comprising one Fe3O4 nanoparticle and several RTX antibodies was constructed for the targeted imaging and enhanced treatment of NHL. Poly(ethylene glycol) (PEG)-coated Fe3O4 nanoparticles were fabricated via a thermal decomposition method and ligand exchange. RTX was conjugated onto the surface of the Fe3O4-PEG nanoparticles to form Fe3O4-PEG-nAb (n = 2, 5 or 8) multivalent nanoprobes. These multivalent nanoprobes, with a core size of approximately 11 nm and a hydrodynamic diameter of about 22 nm, showed colloidal stability in buffer solution. The r2 relaxation rate of Fe3O4-PEG-nAb was similar to that of Fe3O4-PEG (309 ± 3.08 mM-1 s-1). The specificity of nanoprobes for CD20-positive Raji cells was assessed on a clinical magnetic resonance imaging scanner. The receptor binding site of one multivalent nanoprobe was more than that of one RTX, exhibiting valence-dependent induction of Raji cell apoptosis, and this effect could be enhanced by complement activation from blood serum added. A similar activity was observed in vivo in a NHL xenograft model. The multivalent nanoprobe treatment significantly reduced tumor burden and enhanced survival in comparison to the RTX group. Our studies demonstrate that the appropriate design and preparation of anticancer antibody-nanoparticle conjugates enable the generation of improved anticancer nanomedicines and could thus provide an efficient cancer theranostic strategy.

Morphometric development of the human fetal cerebellum during the early second trimester.

The protracted nature of development makes the cerebellum vulnerable to a broad spectrum of pathologic conditions, especially during the early fetal period. This study aims to characterize normal cerebellar growth in human fetuses during the early second trimester. We manually segmented the fetal cerebellum using 7.0-T high-resolution MR images obtained in 35 specimens with gestational ages ranging from 15 to 22 weeks. Volume measurements and shape analysis were performed to quantitatively evaluate global and regional cerebellar growth. The absolute volume of the fetal cerebellum showed a quadratic growth with increasing gestational age, while the pattern of relative volume changes revealed that the cerebellum grew at a greater pace than the cerebrum after 17 gestational weeks. Shape analysis was used to examine the distinctive development of subregions of the cerebellum. The extreme lateral portions of both cerebellar hemispheres showed the lowest rate of growth. The anterior lobe grew faster than most of the posterior lobe. These findings expand our understanding of the early growth pattern of the human cerebellum and could be further used to assess the developmental conditions of the fetal brain.

Systematic Intracellular Biocompatibility Assessments of Superparamagnetic Iron Oxide Nanoparticles in Human Umbilical Cord Mesenchyme Stem Cells in Testifying Its Reusability for Inner Cell Tracking by MRI.

Until now, there is no effective method for tracking transplanted stem cells in human. Ruicun (RC) is a new ultra-small SPIONs agent that has been approved by China Food and Drug Administration for iron supplementation but not as a stem cell tracer in clinic. In this study, we demonstrated magnetic resonance imaging-based tracking of RC-labeled human umbilical cord derived mesenchymal stem cells (MSCs) transplanted to locally injured site of rat spinal cords. We then comprehensively evaluated the safety and quality of the RC-labeled MSCs under good manufacturing practicecompliant conditions, to investigate the feasibility of SPIONs for inner tracking in stem cell-based therapy (SCT). Our results showed that RC labeling at appropriate dose (200 µg/mL) did not have evident impacts on characteristics of MSCs in vitro, demonstrating safety, non-carcinogenesis, and non-tissue inflammation in vivo. The systematic assessments of intracellular biocompatibility indicated that the RC labeled MSCs met with mandatory requirements and standards for law-regulation systems regarding SCT, facilitating translation of cell-tracking technologies to clinical trials.

Magnetic targeting combined with active targeting of dual-ligand iron oxide nanoprobes to promote the penetration depth in tumors for effective magnetic resonance imaging and hyperthermia.

The combination of multi-targeting magnetic nanoprobes and multi-targeting strategies has potential to facilitate magnetic resonance imaging (MRI) and magnetic induction hyperthermia of the tumor. Although the thermo-agents based on magnetic iron oxide nanoparticles (MION) have been successfully used in the form of intratumoral injection in clinical cure of glioblastoma, the tumor-targeted thermotherapy by intravenous administration remains challenging. Herein, we constructed a c(RGDyK)- and d-glucosamine-grafted bispecific molecular nanoprobe (Fe3O4@RGD@GLU) with a magnetic iron oxide core of size 22.17 nm and a biocompatible shell of DSPE-PEG2000, which can specially target the tumor vessel and cancer cells. The selection of c(RGDyK) could make the nanoprobe enter the neovascularization endotheliocyte through αvß3-mediated endocytosis, which drastically reduced the dependence on the enhanced permeability and retention (EPR) effect in tumor. This dual-ligand nanoprobe exhibited strong magnetic properties and favorable biocompatibility. In vitro studies confirmed the anti-phagocytosis ability against macrophages and the specific targeting capability of Fe3O4@RGD@GLU. Then, the imaging effect and anti-tumor efficacy were compared using different targeting strategies with untargeted nanoprobes, dual-targeted nanoprobes, and magnetic targeting combined with dual-targeted nanoprobes. Moreover, the combination strategy of magnetic targeting and active targeting promoted the penetration depth of nanoprobes in addition to the increased accumulation in tumor tissue. Thus, the dual-targeted magnetic nanoprobe together with the combined targeting strategy could be a promising method in tumor imaging and hyperthermia through in vivo delivery of theranostic agents. STATEMENT OF SIGNIFICANCE: Magnetic induction hyperthermia based on iron oxide nanoparticles has been used in clinic for adjuvant treatment of recurrent glioblastoma. Nonetheless, this application is limited to intratumoral injection, and tumor-targeted hyperthermia by intravenous injection remains challenging. In this study, we developed a multi-targeted strategy by combining magnetic targeting with active targeting of dual-ligand magnetic nanoprobes. This combination mode acquired optimum contrast imaging effect through MRI and tumor-suppressive effect through hyperthermia under an alternating current magnetic field. The design of the nanoprobe was suitable for targeting most tumor lesions, which enabled it to be an effective theranostic agent with extensive uses. This study showed significant enhancement of the penetration depth and accumulation of nanoprobes in the tumor tissue for efficient imaging and hyperthermia.

Fetal ocular development in the second trimester of pregnancy documented by 7.0 T postmortem Magnetic Resonance Imaging.

Few investigators have analyzed fetal ocular growth with Magnetic Resonance Imaging (MRI) of high magnetic strength. Our purpose is to obtain normative biometrics for fetal ocular development in the second trimester of pregnancy. Sixty specimens with a gestational age (GA) of 12-23 weeks were scanned using a 7.0 T MRI scanner. The linear interocular and binocular distances (IOD and BOD, respectively), globe diameter (GD) and lens diameter (LD) were measured on the transverse section of the largest diameter of the eyeballs. The three dimensional (3D) visualization model of the eyeball was reconstructed with Amira software. Then, the globe and lens volumes (GV and LV, respectively) were obtained. All the measurements were plotted as a function of GA. The fetal ocular structures in the second trimester of pregnancy could be clearly delineated on 7.0 T postmortem MRI images. All the linear measurements logarithmically increased with GA, while, the volumetric measurements linearly increased with GA. Postmortem MRI of high magnetic strength can clearly document fetal ocular growth in the second trimester of pregnancy. These quantitative data may be a valuable reference for the assessment of normal fetal eyeball development in clinical settings and may be considered a supplement to anatomical investigations.

Injectable magnetic supramolecular hydrogel with magnetocaloric liquid-conformal property prevents post-operative recurrence in a breast cancer model.

Locoregional recurrence of breast cancer after tumor resection represents several clinical challenges. Here, we demonstrate that co-delivery of chemotherapy and thermotherapeutic agents by a magnetic supramolecular hydrogel (MSH) following tumor resection prevents tumor recurrence in a breast cancer mouse model. The self-assembled MSH was designed through the partial inclusion complexation associated with the threading of α-CD on the copolymer moieties on the surface of the PEGylated iron oxide (Fe3O4) nanoparticles, which enables shear-thinning injection and controllable thermoreversible gel-sol transition. MSH was injected to the postoperative wound uniformly, which became mobile and perfect match with irregular cavity without blind angle due to the magnetocaloric gel-sol transition when exposed to alternating current magnetic field (ACMF). The magnetic nanoparticle-mediated induction heat during the gel-sol transition process caused the triggered release of dual-encapsulated chemotherapeutic drugs and provided an effect of thermally induced cell damage. The hierarchical structure of the MSH ensured that both hydrophobic and hydrophilic drugs can be loaded and consecutively delivered with different release curves. The hydrogel nanocomposite might provide a potential locally therapeutic approach for the precise treatment of locoregional recurrence of cancer. STATEMENT OF SIGNIFICANCE: Tumor recurrence after resection represents several clinical challenges. In this study, we prepared shear-thinning injectable magnetic supramolecular hydrogel (MSH) and demonstrated their therapeutic applications in preventing the post-operative recurrence of breast cancer with facile synthesis and minimally invasive implantation in vivo. MSH was injected to the postoperative wound uniformly, which become mobile and perfect match with irregular cavity without blind angle through magnetocaloric gel-sol transition when exposed to ACMF. The magnetic nanoparticles mediated induction heat during the gel-sol transition process caused the triggered release of dual-encapsulated chemotherapeutic drugs as well as thermally induced cell damage. This study demonstrates that MSH with the controlled administration of combined thermo-chemotherapy exhibit great superiority in terms of preventing post-operation cancer relapse.

Using PEGylated magnetic nanoparticles to describe the EPR effect in tumor for predicting therapeutic efficacy of micelle drugs.

Micelle drugs based on a polymeric platform offer great advantages over liposomal drugs for tumor treatment. Although nearly all of the nanomedicines approved in the clinical use can passively target to the tumor tissues on the basis of an enhanced permeability and retention (EPR) effect, the nanodrugs have shown heterogenous responses in the patients. This phenomenon may be traced back to the EPR effect of tumor, which is extremely variable in the individuals from extensive studies. Nevertheless, there is a lack of experimental data describing the EPR effect and predicting its impact on therapeutic efficacy of nanoagents. Herein, we developed 32 nm magnetic iron oxide nanoparticles (MION) as a T2-weighted contrast agent to describe the EPR effect of each tumor by in vivo magnetic resonance imaging (MRI). The MION were synthesized by a thermal decomposition method and modified with DSPE-PEG2000 for biological applications. The PEGylated MION (Fe3O4@PEG) exhibited high r2 of 571 mM-1 s-1 and saturation magnetization (Ms) of 94 emu g-1 Fe as well as long stability and favorable biocompatibility through the in vitro studies. The enhancement intensities of the tumor tissue from the MR images were quantitatively measured as TNR (Tumor/Normal tissue signal Ratio) values, which were correlated with the delay of tumor growth after intravenous administration of the PLA-PEG/PTX micelle drug. The results demonstrated that the group with the smallest TNR values (TNR < 0.5) displayed the best tumor inhibitory effect. In addition, there was a superior correlation between TNR value and relative tumor delay in individual mice. These analysis results indicated that the TNR value of the tumor region enhanced by Fe3O4@PEG (d = 32 nm) could be used to predict the therapeutic efficacy of the micelle drugs (d ≤ 32 nm) in a certain period of time. Fe3O4@PEG has a potential to serve as an ideal MRI contrast agent to visualize the EPR effect in patients for accurate medication guidance of micelle drugs in the future treatment of tumors.

Improving sensitivity of magnetic resonance imaging by using a dual-targeted magnetic iron oxide nanoprobe.

Developing an ultrasensitive and high-efficient molecular imaging probe for detection of malignant tumors is extremely needed in clinical and remains a big challenge. Here, we report a novel bispecific nanoprobe for dual-targeted T2-weighed magnetic resonance imaging (MRI) of COLO-205 colorectal cancer in vivo. First, the magnetic iron oxide nanoparticles (Fe3O4@OA) were synthesized by a thermal decomposition method. Then, PEGylation of the hydrophobic Fe3O4@OA was implemented by amphiphilic DSPE-PEG2000-COOH, producing water-soluble nanoparticles (Fe3O4@PEG). Lastly, arginine-glycine-asparticacid-tumornecrosis factor-related apoptosis-inducing ligand (RGD-TRAIL), a bispecific fusion protein, was conjugated with the nanoparticle to construct molecularly multi-targeted nanoprobe, which was defined as Fe3O4@RGD-TRAIL. This Fe3O4@RGD-TRAIL was proven to exhibit extremely high relaxation property (r2=534mM-1s-1) and saturation magnetization value (Ms=92 emu/g Fe). In vitro studies showed its dual-targeting combination capacity, favorable biocompatibility and strong ability to resist against the non-specific phagocytosis. Owing to these excellent advantages, high sensitive and efficient imaging of tumor was achieved in vivo. Therefore, this RGD-TRAIL conjugated nanoprobe could be developed as a multi-targeted contrast enhancement agent for magnetic resonance molecular imaging in detection of cancer.

Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress.

BACKGROUND: Non-organic erectile dysfunction (noED) at functional imaging has been related to abnormal brain activity and requires animal models for further research on the associated molecular mechanisms. AIM: To develop a noED animal model based on chronic mild stress and investigate brain activity changes. METHODS: We used 6 weeks of chronic mild stress to induce depression. The sucrose consumption test was used to assess the hedonic state. The apomorphine test and sexual behavior test were used to select male rats with ED. Rats with depression and ED were considered to have noED. Blood oxygen level-dependent-based resting-state functional magnetic resonance imaging (fMRI) studies were conducted on these rats, and the amplitude of low-frequency fluctuations and functional connectivity were analyzed to determine brain activity changes. OUTCOMES: The sexual behavior test and resting-state fMRI were used for outcome measures. RESULTS: The induction of depression was confirmed by the sucrose consumption test. A low intromission ratio and increased mount and intromission latencies were observed in male rats with depression. No erection was observed in male rats with depression during the apomorphine test. Male rats with depression and ED were considered to have noED. The possible central pathologic mechanism shown by fMRI involved the amygdaloid body, dorsal thalamus, hypothalamus, caudate-putamen, cingulate gyrus, insular cortex, visual cortex, sensory cortex, motor cortex, and cerebellum. Similar findings have been found in humans. CLINICAL TRANSLATION: The present study provided a novel noED rat model for further research on the central mechanism of noED. STRENGTHS AND LIMITATIONS: The present study developed a novel noED rat model and analyzed brain activity changes based at fMRI. The observed brain activity alterations might not extend to humans. CONCLUSION: The present study developed a novel noED rat model with brain activity alterations related to sexual arousal and erection, which will be helpful for further research involving the central mechanism of noED. Chen G, Yang B, Chen J, et al. Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress. J Sex Med 2018;15:136-147.

Injectable thermosensitive magnetic nanoemulsion hydrogel for multimodal-imaging-guided accurate thermoablative cancer therapy.

Ferrofluid-based magnetic hyperthermia of cancers has gained significant attention in recent years due to its excellent efficacy, few deleterious side effects and unlimited tissue penetration capacity. However, the high tumor osmotic pressure causes injection leakage and thus position imprecision because of the fluidity of the ferrofluid and the absence of multimodal imaging guidance, which create tremendous challenges for clinical application. Here, a body temperature-induced gelation strategy is constructed for accurate localized magnetic tumor regression based on the unique behaviors of a magnetic nanoemulsion hydrogel (MNH) within tumors. The rapid intra-tumor gelation can securely restrict the MNH in tumor tissue without diffusion and leakage. The magnetically induced nanoparticle assembly-enhanced heating in the hydrogel and the heat accumulation caused by crosslinking among the nanoemulsion droplets further increased the heating efficiency. Meanwhile, US/MR/NIR multimodal imaging can guide the whole therapeutic process, achieving excellent magnetic hyperthermia therapeutic efficiency. This work highlights the great promise for improving the magnetic hyperthermia efficiency and the precision of the injection site for localized tumor therapy.

Detection of volume alterations in hippocampal subfields of rats under chronic unpredictable mild stress using 7T MRI: A follow-up study.

PURPOSE: To determine hippocampal subfields volume loss in depression, which was simulated by a rat chronic unpredictable mild stress (CUMS) model. As different cellular and molecular characteristics in hippocampal subfields, these subfields are regarded as differentially vulnerable to processes associated with stress. MATERIALS AND METHODS: Twenty male Wistar rats were exposed to various stressors until the model was successfully established. The effects of physical exercise on recovery of hippocampal volume in depressed rats were simulated using the wheel running test (WRT). These rats hippocampal volumes were dynamically measured using T2 -weighted images (T2 WIs) at 7T structural magnetic resonance imaging (MRI). RESULTS: After 4 weeks of CUMS (CUMS-4W), the behavioral tests showed that the rat model of depression was successfully established (P < 0.001). In this process, the bilateral CA1 volume was significantly atrophic after 2 weeks of CUMS (CUMS-2W) compared with controls (left: 21.09 ± 2.31 vs. 26.16 ± 3.83 mm3 , P < 0.001; right: 21.05 ± 2.36 vs. 26.12 ± 3.78 mm3 , P < 0.001), whereas the other subfields did not show a similar change (all P > 0.05). The volume of CA3, dentate gyrus (DG), and subiculum displayed atrophy after CUMS-4W (CA3: left:12.23 ± 1.10 mm3 , right: 12.20 ± 1.14 mm3 ; DG: left:8.16 ± 0.58 mm3 , right: 8.18 ± 0.92 mm3 ; subiculum: left: 4.30 ± 0.52 mm3 , right: 4.29 ± 0.44 mm3 ; all P < 0.05). The rats' (CUMS-4W) hippocampal DG volume was restored (left: 10.67 ± 1.60 mm3 , right: 10.71 ± 1.58 mm3 ), and the depression-like behaviors of these rats improved after WRT-4W (P < 0.05). CONCLUSION: In general, volume loss was demonstrated in various rat hippocampal subfields during the development and recovery from depression, which were detected by ultrahigh-field MRI. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1456-1463.

Active-target T1-weighted MR Imaging of Tiny Hepatic Tumor via RGD Modified Ultra-small Fe3O4 Nanoprobes.

Developing ultrasensitive contrast agents for the early detection of malignant tumors in liver is highly demanded. Constructing hepatic tumors specific targeting probes could provide more sensitive imaging information but still faces great challenges. Here we report a novel approach for the synthesis of ultra-small Fe3O4 nanoparticles conjugated with c(RGDyK) and their applications as active-target T1-weighted magnetic resonance imaging (MRI) contrast agent (T1-Fe3O4) for imaging tiny hepatic tumors in vivo. RGD-modified T1-Fe3O4 nanoprobes exhibited high r1 of 7.74 mM(-1)s(-1) and ultralow r2/r1 of 2.8 at 3 T, reflecting their excellent T1 contrast effect at clinically relevant magnetic field. High targeting specificity together with favorable biocompatibility and strong ability to resist against non-specific uptake were evaluated through in vitro studies. Owing to the outstanding properties of tumor angiogenesis targeting with little phagocytosis in liver parenchyma, hepatic tumor as small as 2.2 mm was successfully detected via the T1 contrast enhancement of RGD-modified T1-Fe3O4. It is emphasized that this is the first report on active-target T1 imaging of hepatic tumors, which could not only significantly improve diagnostic sensitivity, but also provide post therapeutic assessments for patients with liver cancer.

Multi-modal Mn-Zn ferrite nanocrystals for magnetically-induced cancer targeted hyperthermia: a comparison of passive and active targeting effects.

The high performance and increased tumor-targeting accumulation of magnetic nanocrystals (MNCs) are the most important considerations in cancer targeted magnetic hyperthermia (TMH). To achieve these goals, our study was firstly done using well-established fluorescence/magnetic Mn-Zn ferrite MNCs (core size: 14 nm) as multi-modal imaging contrast agents and highly-efficient "heat generators", which were coated with a biocompatible PEG-phospholipid (DSPE-PEG2000) and further modified by a cyclic tripeptide of arginine-glycine-aspartic acid (RGD). By using a mouse model bearing breast carcinoma (4T1), we then systematically compared PEGylated MNCs (MNCs@PEG)- and RGD-PEGylated MNCs (MNCs@RGD)-mediated tumor targeting abilities by intravenous administration. The MNCs@PEG-based passive targeting could successfully accumulate at the tumor due to the enhanced permeability and retention (EPR) effects, but the non-targeted localization might make the MNCs@PEG "leaking" from larger pores of tumor fenestrated vascular networks. Our designed MNCs@RGD, simultaneously functionalized with PEG and RGD ligands, might promote a synergistic effect including efficient tumor vasculature active targeting and EPR-mediated passive targeting, improving total MNC concentration and retention time in tumor tissues. By combining fluorescence/magnetic resonance (MR)/thermal multi-modal imaging-guided diagnostics and continuous TMH treatment under an alternating current magnetic field (ACMF, 2.58 kA m(-1), 390 kHz), the tumor surface could be heated to approximately 43-44 °C based on the MNC-mediated repeated injections. Sufficient temperature elevation induced the apoptosis of tumor cells, and inhibited the tumor angiogenesis. Compared with MNCs@PEG, the active MNCs@RGD-based tumor targeting MR image was significantly more efficient due to both the higher and long-lasting tumor accumulation, but its antitumor efficacy was not obviously improved in the TMH treatments. To achieve a singularly promising tumor TMH therapy, a greatly increased MNC content in tumor was needed. This insight indicated that not only the tumor vasculature targeting, but also the active tumor cells targeting of MNCs should receive considerable attention in future clinical TMH therapy application.

Surface Modified Iron Oxide Nanoparticles as Fe Source Precursor to Induce the Formation of Prussian Blue Nanocubes.

Nano-sized Prussian blue (PB) cubes were synthesized at room temperature by simply stirring the mixture of surface modified iron oxide nanoparticles (IONPs) and potassium ferrocyanide in an aqueous acid solution. The nanocubes were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM) and X-ray diffraction (XRD). The influence of different molecules modified on the surface of IONPs on the cube formation was discussed. The surface modification with dimercaptosuccinic acid (DMSA), 3-aminopropyltriethoxysilane (APTS) and citric acid (CA) all displayed a key role in the formation precess of PB nanocubes, but which could not be formed as bare IONPs or Fe3+ were used as precursor. Combined with the reaction process tracing with UV-vis absorption spectroscopy and TEM, a possible kinetically controlled growth mechanism was proposed where slower formation rate of amorphous PB due to very low release rate of Fe ions from the surface modified IONPs and subsequent recrystallization are responsible for the obtained PB nanocubes. The peroxidase-like catalytic activity of the synthesized nanocubes was investigated and catalysis was found to follow Michaelis-Menten kinetics. The potential of using such PB nanocubes as an effective MRI contrast agent was also demonstrated.