Relaxivity R1 Research Articles

ROS-responsive chlorin e6 and silk fibroin loaded ultrathin magnetic hydroxyapatite nanorods for T1-magnetic resonance imaging guided photodynamic therapy in vitro

Magnetite hydroxyapatite nanoparticles show notable multifunctional therapeutic features in nanomedicine. However, designing MHAp nanoparticles with optimum dimensions, good stability and biocompatibility for specific biomedical applications is still in its infancy. Herein, a facile approach was employed to prepare ROS-responsive chlorin e6 and silk fibroin-loaded ultrathin magnetic hydroxyapatite nanorods for T1-magnetic resonance imaging and photodynamic therapy. Specifically, the Fe3O4-HAp nanorods were synthesized by the hydrothermal method, and then Pluronic® F-127 was used to improve the aqueous dispersion, biocompatibility, and loading capacity. Moreover, silk fibroin protein was encapsulated by a tri-block copolymer with good loading efficiency. Finally, the theranostic nano-assembly MHNRs-SF-Ce6 was completed by the addition of Ce6. The prepared MHNRs demonstrated excellent biocompatibility, cellular uptake, and ROS generation ability in in vitro after 660 nm laser irradiation, leading to the apoptosis of 4T1 mouse breast cancer cells. Notably, the designed MHNRs exhibited excellent r1 relaxivity value and T1 magnetic resonance imaging in vitro due to their minimal width (2 nm) of nanorods. Therefore, the obtained MHNRs-SF-Ce6 self-assembled nanoparticles provide an effective strategy for cancer diagnosis and photodynamic therapy.

Magnetic properties, phase evolution, hollow structure and biomedical application of hematite (α-Fe2O3) and QUAIPH

We investigate synthesis, phase evolution, hollow and porous structure and magnetic properties of quasi-amorphous intermediate phase (QUAIPH) and hematite (α-Fe2O3) nanostructure synthesized by annealing of akaganeite (β-FeOOH) nanorods. It is found that the annealing temperature determines the phase composition of the products, the crystal structure/size dictates the magnetic properties whereas the final nanorod morphology is determined by the starting material. Annealing of β-FeOOH at ∼300 °C resulted in the formation of hollow QUAIPH nanorods. The synthesized material shows low-cytotoxicity, superparamagnetism and good transverse relaxivity, which is rarely reported for QUAIPH. The QUAIPH nanorods started to transform to porous hematite nanostructures at ∼350 °C and phase transformation was completed at 600 °C. During the annealing, the crystal structure changed from monoclinic (akaganeite) to quasi-amorphous and rhombohedral (hematite). Unusually, the crystallite size first decreased (akaganeite → QUAIPH) and then increased (QUAIPH → hematite) during annealing whereas the nanorods retained particle shape. The magnetic properties of the samples changed from antiferromagnetic (akaganeite) to superparamagnetic with blocking temperature TB = 84 K (QUAIPH) and finally to weak-ferromagnetic with the Morin transition at TM = 244 K and high coercivity HC = 1652 Oe (hematite). The low-cytotoxicity and MRI relaxivity (r2 = 5.80 mM−1 s−1 (akaganeite), r2 = 4.31 mM−1 s−1 (QUAIPH) and r2 = 5.17 mM−1 s−1 (hematite)) reveal potential for biomedical applications.

Novel MR imaging nanoprobe for hepatocellular carcinoma detection based on manganese-zinc ferrite nanoparticles: in vitro and in vivo assessments.

Achieving new contrast enhancer agents that can produce high-resolution images in magnetic resonance imaging (MRI) with a minimum dose and side effects has always been important. Herein, the pegylated curcumin-coated manganese-zinc ferrite nanoparticles (MZF@CA-PEG-CUR NPs) have been reported as an MR imaging nanoprobe in hepatocellular carcinoma detection in the murine model for the first time.In vitrostudies were done on HEPA 1-6 cancer cells and L929 as normal cells, andin vivostudies were done on hepatocellular carcinoma (HCC) using xenograft models of HCC. The prepared NP had a diameter of 105nm with narrow size distribution and was superparamagnetic with a saturated magnetization (Ms) of 39emu/g. The NP was biocompatible without any significant hemolysis and cytotoxicity. Prussian blue staining showed more cellular uptake of HEPA 1-6 compared to L929 control cells after incubation (P < 0.05). The concentration of Fe in mice blood confirmed the plasma half-life of about 3h; it seems the PEGylation increased the circulation time. ICP-OES of Fe showed the highest tumor localization for MZF@CA-CUR-PEG NPs, due to passive accumulation, compared to the other mice studied organs. The r2 relaxivity of NPs was 134.89mM-1s-1, andin vitroMRI demonstrated better effects in HEPA 1-6 cells than in L929 (P < 0.05). Also,in vivoMR images showed signal enhancement efficacy in tumor-bearing mice. This study demonstrated that the MZF@CA-CUR-PEG nanoprobe could be a promising candidate as an MR imaging agent in hepatocellular carcinoma early detection.

Novel Salinomycin-Based Paramagnetic Complexes-First Evaluation of Their Potential Theranostic Properties.

Novel salinomycin (Sal)-based theranostic probes comprising two different paramagnetic metal ions, gadolinium(III) (Gd(III)) or manganese(II) (Mn(II)), as signal emitting motifs for MRI were synthesized and characterized by elemental analysis, infrared spectral analysis (IR), electroparamagnetic resonance (EPR), thermogravimetry (TG) differential scanning calorimetry (DSC) and electrospray ionization mass spectrometry (ESI-MS). To overcome the water insolubility of the two Sal-complexes, they were loaded into empty bacterial ghosts (BGs) cells as transport devices. The potential of the free and BGs-loaded metal complexes as theranostics was evaluated by in vitro relaxivity measurements in a high-field MR scanner and in cell culture studies. Both the free Sal-complexes (Gd(III) salinomycinate (Sal-Gd(III) and Mn(II) salinomycinate (Sal-Mn(II)) and loaded into BGs demonstrated enhanced cytotoxic efficacy against three human tumor cell lines (A549, SW480, CH1/PA-1) relative to the free salinomycinic acid (Sal-H) and its sodium complex (Sal-Na) applied as controls with IC50 in a submicromolar concentration range. Moreover, Sal-H, Sal-Gd(III), and Sal-Mn(II) were able to induce perturbations in the cell cycle of treated colorectal and breast human cancer cell lines (SW480 and MCF-7, respectively). The relaxivity (r1) values of both complexes as well as of the loaded BGs, were higher or comparable to the relaxivity values of the clinically applied contrast agents gadopentetate dimeglumine and gadoteridol. This research is the first assessment that demonstrates the potential of Gd(III) and Mn(II) complexes of Sal as theranostic agents for MRI. Due to the remarkable selectivity and mode of action of Sal as part of the compounds, they could revolutionize cancer therapy and allow for early diagnosis and monitoring of therapeutic follow-up.

Synergic control in asymptomatic welders during multi-finger force exertion and load releasing while standing

Motor synergies, i.e., neural mechanisms that organize multiple motor elements to ensure stability of actions, are affected by several neurological condition. Asymptomatic welders showed impaired synergy controlling the stability of multi-finger action compared to non-welders and this impairment was associated with microstructural damage in the globus pallidus. We further explored the effect of welding-related metal exposure on multi-finger synergy and extended our investigation to posture-stabilizing synergy during a standing task. Occupational, MRI, and performance-stabilizing synergies during multi-finger accurate force production and load releasing while standing were obtained from 29 welders and 19 age- and sex-matched controls. R2* and R1 relaxation rate values were used to estimate brain iron and manganese content, respectively, and diffusion tensor imaging was used to reflect brain microstructural integrity. Associations of brain MRI (caudate, putamen, globus pallidus, and red nucleus), and motor synergy were explored by group status. The results revealed that welders had higher R2* values in the caudate (p = 0.03), putamen (p = 0.01), and red nucleus (p = 0.08, trend) than controls. No group effect was revealed on multi-finger synergy index during steady-state phase of action (ΔVZss). Compared to controls, welders exhibited lower ΔVZss (−0.106 ± 0.084 vs. 0.160 ± 0.092, p = 0.04) and variance that did not affect the performance variable (VUCM, 0.022 ± 0.003 vs. 0.038 ± 0.007, p = 0.03) in the load releasing, postural task. The postural synergy index, ΔVZss, was associated negatively with higher R2* in the red nucleus in welders (r = −0.44, p = 0.03), but not in controls. These results suggest that the synergy index in the load releasing during a standing task may reflect welding-related neurotoxicity in workers with chronic metals exposure. This finding may have important clinical and occupational health implications.

Orientation dependence of R2 relaxation in the newborn brain

In MRI the transverse relaxation rate, R2 = 1/T2, shows dependence on the orientation of ordered tissue relative to the main magnetic field. In previous studies, orientation effects of R2 relaxation in the mature brain's white matter have been found to be described by a susceptibility-based model of diffusion through local magnetic field inhomogeneities created by the diamagnetic myelin sheaths. Orientation effects in human newborn white matter have not yet been investigated. The newborn brain is known to contain very little myelin and is therefore expected to exhibit a decrease in orientation dependence driven by susceptibility-based effects. We measured R2 orientation dependence in the white matter of human newborns. R2 data were acquired with a 3D Gradient and Spin Echo (GRASE) sequence and fiber orientation was mapped with diffusion tensor imaging (DTI). We found orientation dependence in newborn white matter that is not consistent with the susceptibility-based model and is best described by a model of residual dipolar coupling. In the near absence of myelin in the newborn brain, these findings suggest the presence of residual dipolar coupling between rotationally restricted water molecules. This has important implications for quantitative imaging methods such as myelin water imaging, and suggests orientation dependence of R2 as a potential marker in early brain development.

Comparison of Three Ultrasmall, Superparamagnetic Iron Oxide Nanoparticles for MRI at 3.0 T.

The ultrasmall, superparamagnetic iron oxide (USPIO) nanoparticle ferumoxytol has unique applications in cardiac, vascular, and body magnetic resonance imaging (MRI) due to its long intravascular half-life and suitability as a blood pool agent. However, limited availability and high cost have hindered its clinical adoption. A new ferumoxytol generic, and the emergence of MoldayION as an alternative USPIO, represent opportunities to expand the use of USPIO-enhanced MRI techniques. To compare in vitro and in vivo MRI relaxometry and enhancement of Feraheme, generic ferumoxytol, and MoldayION. Prospective. Ten healthy swine and six swine with artificially induced coronary narrowing underwent cardiac MRI. 3.0 T; T1-weighted (4D-MUSIC, 3D-VIBE, 2D-MOLLI) and T2-weighted (2D-HASTE) sequences pre- and post-contrast. We compared the MRI relaxometry of Feraheme, generic ferumoxytol, and MoldayION using saline, plasma, and whole blood MRI phantoms with contrast concentrations from 0.26 mM to 2.10 mM. In-vivo contrast effects on T1- and T2-weighted sequences and fractional intravascular contrast distribution volume in myocardium, liver, and spleen were evaluated. Analysis of variance and covariance were used for group comparisons. A P value <0.05 was considered statistically significant. The r1 relaxivities for Feraheme, generic ferumoxytol, and MoldayION in saline (22 °C) were 7.11 ± 0.13 mM-1 s-1 , 8.30 ± 0.29 mM-1 s-1 , 8.62 ± 0.16 mM-1 s-1 , and the r2 relaxivities were 111.74 ± 3.76 mM-1 s-1 , 105.07 ± 2.20 mM-1 s-1 , and 109.68 ± 2.56 mM-1 s-1 , respectively. The relationship between contrast concentration and longitudinal (R1) and transverse (R2) relaxation rate was highly linear in saline and plasma. The three agents produced similar in vivo contrast effects on T1 and T2 relaxation time-weighted sequences. Relative to clinically approved ferumoxytol formulations, MoldayION demonstrates minor differences in in vitro relaxometry and comparable in vivo MRI characteristics. 2 TECHNICAL EFFICACY: Stage 1.

Fucoidan-based dual-targeting mesoporous polydopamine for enhanced MRI-guided chemo-photothermal therapy of HCC via P-selectin-mediated drug delivery

The development of novel theranostic agents with outstanding diagnostic and therapeutic performances is still strongly desired in the treatment of hepatocellular carcinoma (HCC). Here, a fucoidan-modified mesoporous polydopamine nanoparticle dual-loaded with gadolinium iron and doxorubicin (FMPDA/Gd3+/DOX) was prepared as an effective theranostic agent for magnetic resonance imaging (MRI)-guided chemo-photothermal therapy of HCC. It was found that FMPDA/Gd3+/DOX had a high photothermal conversion efficiency of 33.4% and excellent T1−MRI performance with a longitudinal relaxivity (r1) value of 14.966 mM−1·s − 1. Moreover, the results suggested that FMPDA/Gd3+/DOX could effectively accumulate into the tumor foci by dual-targeting the tumor-infiltrated platelets and HCC cells, which resulted from the specific interaction between fucoidan and overexpressed p-selectin receptors. The excellent tumor-homing ability and MRI-guided chemo-photothermal therapy therefore endowed FMPDA/Gd3+/DOX with a strongest ability to inhibit tumor growth than the respective single treatment modality. Overall, our study demonstrated that FMPDA/Gd3+/DOX could be applied as a potential nanoplatform for safe and effective cancer theranostics

The r1 relaxivity and T1 imaging properties of dendrimer-based manganese and gadolinium chelators in magnetic resonance imaging

We report the preparation and characterization of gadolinium (Gd)- or manganese (Mn)-loaded dendrimers and Gd-loaded dendrimer-entrapped gold nanoparticles (Gd-Au DENPs) to examine the relationship between the number of metal ion chelators and r1 relaxivity. In this study, amine-terminated fifth-generation poly(amidoamine) dendrimers (G5.NH2) modified with different numbers of DOTA-NHS chelators were used to chelate Gd and Mn ions. The remaining amine groups were then acetylated completely, followed by the use of materials with better r1 relaxivities and T1-weighted imaging performances as templates to synthesize Gd-Au DENPs. The Gd and Mn chelators as well as Gd-Au DENPs were characterized via different techniques. We show that the r1 relaxivity and T1 imaging performance increase with loading of greater numbers of Gd and Mn ions on the G5.NH2 and that the acetylation process affects the relaxivity and imaging properties to a certain extent. After entrapment with Au NPs, the r1 relaxivity and T1-weighted imaging performance of Gd-Au DENPs decrease with greater loading of Au NPs. This systematic study of the relaxivities and T1-weighted imaging performances of Gd, Mn, and Gd-Au DENP chelators are expected to be a theoretical basis for developing multifunctional dual-mode contrast agents.

Fibrin-Targeted Nanoparticles for Finding, Visualizing and Characterizing Blood Clots in Acute Ischemic Stroke.

Recanalization of the occluded artery is the gold standard treatment for acute ischemic stroke, which includes enzymatic fibrinolytic treatment with the use of recombinant tissue plasminogen activators (rtPAs) to disrupt the occluding clot, the use of mechanical thrombectomy to physically remove the clot, or a combination of both. Fibrin is one of the main components of blood clots causing ischemic stroke and is the target of rtPA upon activation of plasminogen in the clot. In addition, fibrin content also influences the efficacy of mechanical thrombectomy. Current imaging methods can successfully identify occlusions in large vessels; however, there is still a need for contrast agents capable of visualizing small thrombi in ischemic stroke patients. In this work, we describe the synthesis and the in vitro characterization of a new diagnostic nanoparticle, as well as the in vivo evaluation in an animal model of thromboembolic stroke. Gd-labeled KCREKA peptides were synthesized and attached onto the surface of PEGylated superparamagnetic nanoparticles. Magnetic resonance imaging (MRI) of blood clots was performed in vitro and in vivo in animal models of thromboembolic stroke. KCREKA-NPs were synthesized by attaching the peptide to the amino (N) termini of the PEG-NPs. The sizes of the nanoparticles, measured via DLS, were similar for both KCREKA-NPs and PEG-NPs (23 ± 4 nm, PDI = 0.11 and 25 ± 8 nm, PDI = 0.24, respectively). In the same line, r2 relaxivities were also similar for the nanoparticles (149 ± 2 mM Fe s−1 and 151 ± 5 mM Fe s−1), whereas the r1 relaxivity was higher for KCREKA-NPs (1.68 ± 0.29 mM Fe s−1 vs. 0.69 ± 0.3 mM Fe s−1). In vitro studies showed that blood clots with low coagulation times were disrupted by rtPA, whereas aged clots were almost insensitive to the presence of rtPA. MRI in vitro studies showed a sharp decrease in the T1 × T2 signals measured for aged clots incubated with KCREKA-NPs compared with fresh clots (47% [22, 80] to 26% [15, 51]). Furthermore, the control blood showed a higher value of the T1 × T2 signal (39% [20, 61]), being the blood clots with low coagulation times the samples with the lowest values measured by MRI. In vivo studies showed a significant T1 × T2 signal loss in the clot region of 24% after i.v. injection of KCREKA-NPs. The thrombus age (2.5% ± 6.1% vs. 81.3% ± 19.8%, p < 0.01) confirmed our ability to identify in vivo fresh blood clots. In this study, we developed and tested a dual MRI nanoparticle, acting as T1 and T2 contrast agents in MRI analyses. The developed KCREKA-NPs showed affinity for the fibrin content of blood clots, and the MRI signals provided by the nanoparticles showed significant differences depending on the clot age. The developed KCREKA-NPs could be used as a tool to predict the efficacy of a recanalization treatment and improve the triage of ischemic stroke patients.

Tailoring the Magnetic and Structural Properties of Manganese/Zinc Doped Iron Oxide Nanoparticles through Microwaves-Assisted Polyol Synthesis.

Tuning the fundamental properties of iron oxide magnetic nanoparticles (MNPs) according to the required biomedical application is an unsolved challenge, as the MNPs’ properties are affected by their composition, their size, the synthesis process, and so on. In this work, we studied the effect of zinc and manganese doping on the magnetic and structural properties of MNPs synthesized by the microwave-assisted polyol process, using diethylene glycol (DEG) and tetraethylene glycol (TEG) as polyols. The detailed morpho-structural and magnetic characterization showed a correspondence between the higher amounts of Mn and smaller crystal sizes of the MNPs. Such size reduction was compensated by an increase in the global magnetic moment so that it resulted in an increase of the saturation magnetization. Saturation magnetization M values up to 91.5 emu/g and NMR transverse relaxivities r of 294 smM were obtained for Zn and Mn- doped ferrites having diameters around 10 nm, whereas Zn ferrites with diameters around 15 nm reached values of M 97.2 emu/g and of r∼ 467 smM, respectively. Both kinds of nanoparticles were synthesized by a simple, reproducible, and more sustainable method that makes them very interesting for diagnostic applications as MRI contrast agents.

Targeted Contrast Agents for Magnetic Resonance Molecular Imaging of Cancer.

Magnetic resonance imaging (MRI) is a clinical imaging modality that provides high-resolution images of soft tissues, including cancerous lesions. Stable gadolinium(III) chelates have been used as contrast agents (CA) in MRI to enhance the contrast between the tissues of interest and surrounding tissues for accurate diagnostic imaging. Magnetic resonance molecular imaging (MRMI) of cancer requires targeted CA to specifically elucidate cancer-associated molecular processes and can provide high-resolution delineation and characterization of cancer for precision medicine. The main challenge for MRMI is the lack of sufficient sensitivity to detect the low concentration of the cellular oncogenic markers. In addition, targeted CA must satisfy regulatory safety requirements prior to clinical development. Up to now, there is no FDA-approved targeted CA for MRMI of cancer.In this Account, we discuss the latest developments in the design and development of clinically translatable targeted CA for MRMI of cancer, with an emphasis on our own research. The primary limitation of MRMI can be overcome by designing small molecular targeted CA to target abundant cancer-specific targets found in the tumor microenvironment (TME). For example, aggressive tumors have a unique extracellular matrix (ECM) composed of oncoproteins, which can be used as targetable markers for MRMI. We have designed and prepared small peptide conjugates of clinical contrast agents, including Gd-DTPA and Gd-DOTA, to target fibrin-fibronectin clots in tumors. These small molecular CA have been effective in enhancing MRMI detection of solid tumors and have demonstrated the ability to detect submillimeter cancer micrometastases in mouse tumor models, exceeding the detection limit of current clinical imaging modalities. We have also identified extradomain B fibronectin (EDB-FN), an oncofetal subtype of fibronectin, as a promising TME target to leverage in the design and development of small peptide targeted CA for clinical translation. The expression level of EDB-FN is correlated with invasiveness of cancer cells and poor patient survival of multiple cancer types. ZD2 peptide with a sequence of seven amino acids (TVRTSAD) was identified to specifically bind to the EDB protein fragment. Several ZD2 conjugates of macrocyclic GBCA, including Gd-DOTA and Gd(HP-DO3A), have been synthesized and tested in mouse tumor models. ZD2-N3-Gd(HP-DO3A) (MT218) with a high r1 relaxivity was selected as the lead agent for clinical translation. The physicochemical properties and preclinical assessments of MT218 are summarized in this Account. MRMI of EDB-FN with MT218 can effectively detect invasive tumors of multiple cancers with risk-stratification and monitor tumor response to anticancer therapies in mouse models. Currently, MT218 is in clinical trials for precision cancer MRMI. Herein, we will show that using targeted MRI contrast agents specific to abundant TME biomarkers is a pragmatic solution for effective precision cancer imaging in high spatial resolution. And thus, we illustrate a replicable approach for CA development that is vital for cancer MRMI.

Efficient Synthesis of Macromolecular DO3A@Gn Derivatives for Potential Application in MRI Diagnostics: From Polymer Conjugates to Polymer Nanoparticles

AbstractHerein, the synthesis of three different macromolecular DO3A@Gn conjugates based on poly(2‐oxazoline)s is presented. Therefore, poly(2‐methyl‐2‐oxazoline) is synthesized by a ring‐opening, cationic polymerization and the polymerization is terminated with DO3A(tBu)3. The best results are obtained after 48 h at 120 °C with degree of termination of 86%. After deprotection of the DO3A ligand and complexation with Gn3+, relaxivity as measured with a magnetic field strength of 9.4 T (400 MHz) reveals values for r1 of up to 2.32 mm−1 s−1. The concept is extended to a block copolymer based on 2‐heptyl‐2‐oxazoline and 2‐methyl‐2‐oxazoline that is again terminated with DO3A(tBu)3 to form micelles with a size of 12.6 ± 0.7 nm after DO3A(tBu)3 termination and deprotection of the 1,4,7,10‐tetraazacyclododecane‐N,N,N,N‐tetraacetic acid ligand. After complexation with Gn3+, relaxivity r1 is 10.1 mm−1 s−1 as determined from the slope of the plot of 1/T1 against the gadolinium(III) concentration at 9.4 T. Finally, crosslinked nanoparticles are prepared from amphiphilic macro‐monomers that form micelles in water and are crosslinked throughout the core in the presence of azoisobutyronitrile (AIBN). The nanoparticle is 32.9 ± 7.8 nm in size after Gn3+ complexation and reveals a relaxivity r1 of 6.77 mm−1 s−1.

Effective R2 relaxation rate, derived from dual-contrast fast-spin-echo MRI, enables detection of hemisphere differences in iron level and dopamine function in Parkinson’s disease and healthy individuals

BackgroundClinical estimates of brain iron concentration are achievable with quantitative transverse relaxation rate R2, via time-consuming multiple spin-echo (SE) sequences. The objective of this study was to investigate whether quantitative iron-sensitive information may be derived from 3.0 T dual-contrast fast-spin-echo (FSE) sequences (typically employed in anatomical non-quantitative evaluations), as a routinely-collected alternative to evaluate iron levels in healthy (HC) and Parkinson’s disease (PD) brains. New methodMRI 3.0 T FSE data from the Parkinson’s Progression Markers Initiative (PPMI) (12 PD, 12 age- and gender-matched HC subjects) were cross-sectionally and longitudinally evaluated. A new measure, ‘effective R2’, was calculated for bilateral subcortical grey matter (caudate nucleus, putamen, globus pallidus, red nucleus, substantia nigra). Linear regression analysis was performed to correlate ‘effective R2’ with models of age-dependent brain iron concentration and striatal dopamine transporter (DaT) receptor binding ratio. ResultsEffective R2 was strongly correlated with estimated brain iron concentration. In PD, putaminal effective R2 difference was observed between the hemispheres contra-/ipsi-lateral to the predominantly symptomatic side at onset. This hemispheric difference was correlated with the putaminal DaT binding ratios in PD. Comparison with existing method(s)Effective R2, derived from rapid dual-contrast FSE sequences, showed viability as an alternative to R2 from SE sequences. Linear correlation of effective R2 with estimated iron concentration was comparable to documented iron-dependent R2. The effective R2 correlation coefficient was consistent with theoretical R2 iron-dependence at 3.0 T. ConclusionsEffective R2 has clinical potential as a fast quantitative method, as an alternative to R2, to aid evaluation of brain iron levels and DaT function.

Preparation and evaluation of bismuth sulfide and magnetite‐based theranostic nanohybrid as drug carrier and dual MRI/CT contrast agent

Due to the increased incidence and population growth that has been leading to growing number of cases worldwide, early diagnosis and treatment of cancer is crucial. Low density cancer tissue cannot be diagnosed before progressing toward a metastatic stage. Thus, theranostic systems play a significant role in assisting timely diagnosis and treatment. The combination of magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents in a single probe is of high importance and necessity, where individual strengths of each approach can be merged while shortcomings of each modality could be compensated. With this motivation, we have developed and synthesized Bi2S3@BSA‐Fe3O4 nanoparticles as a dual MRI/CT contrast agent and carrier of curcumin (CUR) as natural anticancer drug. The nanoparticles shortened both the longitudinal (T1) and transverse (T2), MRI relaxation times, with a more distinct effect on producing negative contrast (T2) images with a relaxivity (r2) of 54.73 mM−1 s−1. The magnetite/bismuth hybrid nanoparticle also was capable of increasing CT image contrast. Further, in vitro cytotoxicity assay showed high biocompatibility of the synthesized nanoparticles. Furthermore, in vitro cytotoxicity assay on cancer cells showed high anticancer activity of the synthesized nanoparticles.

Multifunctional nanocarriers of Fe3O4@PLA-PEG/curcumin for MRI, magnetic hyperthermia and drug delivery.

Background: Despite medicinal advances, cancer is still a big problem requiring better diagnostic and treatment tools. Magnetic nanoparticle (MNP)-based nanosystems for multiple-purpose applications were developed for these unmet needs. Methods: This study fabricated novel trifunctional MNPs of Fe3O4@PLA-PEG for drug release, MRI and magnetic fluid hyperthermia. Result: The MNPs provided a significant loading of curcumin (∼11%) with controllable release ability, a high specific absorption rate of 82.2W/g and significantly increased transverse relaxivity (r2=364.75mM-1 s-1). The in vivo study confirmed that the MNPs enhanced MRI contrast in tumor observation and low-field magnetic fluid hyperthermia could effectively reduce the tumor size in mice bearing sarcoma 180. Conclusion: The nanocarrier has potential for drug release, cancer treatment monitoring and therapy.

Magnetic Resonance Neuroimaging Contrast Agents of Nanomaterials.

Since the early 1980s when MRI imaging technology was put into clinical use, the number of MRI clinical tests has steadily increased by more than 10% every year. At the same time, exogenous MRI contrast agents have also been developed with the development of MRI technology. However, there are still challenges in the preparation of contrast agents for magnetic resonance imaging, such as how to prepare high-efficiency contrast agents with high stability and low biological toxicity. In order to study the contrast agent with simple preparation method, low cost, and good imaging effect, a magnetic resonance contrast agent was prepared by magnetic nanoparticles. By acting on magnetic resonance imaging detection method, and using polymer ligands to synthesize magnetic nanoparticles, experiments and tests of P(MA-alt-VAc) polymer ligand-modified magnetic nanoparticles were carried out. The experimental results showed that when nanoparticles containing different iron ion concentrations were incubated with DC 2.4 normal cells for 48 hours, the cell viability was still higher than 80% at concentrations up to 200 μm. It shows that the nanoparticle has high cell activity and good biological adaptability. The transverse relaxation (r2) value of the nanoparticles in aqueous solution at 37°C and 1.5 T magnetic field is 231.1 m−1 s−1, which is much higher than that of PTMP-PMAA (r2 = 35.1 mM−1 s−1), which is also more than five times the relaxation of SHU-555C (r2 = 44 mM−1 s−1). It shows that the nanoparticles prepared in this paper have good effect and can be used as a contrast agent in human brain for magnetic resonance imaging.

Role of Transmembrane Water Exchange in Glioma Invasion/Migration: In Vivo Preclinical Study by Relaxometry at Very Low Magnetic Field.

Simple SummarySince the pioneering work of Damadian (1971), the longitudinal T1-relaxation of nuclear magnetic resonance (NMR) has been reported to generate significant contrast between cancer and healthy tissues at low magnetic fields. However, low NMR sensitivity was a substantial obstacle. Fast field cycling NMR (FFC-NMR) can overcome this problem and is commercially available for physics/chemistry research since around the years 2000s. Herein, using FFC-NMR in vivo, we show that T1-relaxation measured at very low fields is sensitive to transmembrane water exchange, thus allowing the discrimination between glioma invasion/migration and proliferation. Aquaporins 4 and 1 are found to be upregulated in invasion/migration, indicating that water exchange modulates T1-relaxations in glioma, via these aquaporins action. Overall, results suggest that, by blocking the aquaporin functions, the T1-relaxation should decrease in invasion/migration glioma. Results also stipulate that the entire invasion/migration volume could be visualized by FFC imaging, noninvasively. This may impact the medical community since invasion/migration delineation remains challenging by any medical imaging modality.This work shows that the longitudinal relaxation differences observed at very low magnetic fields between invasion/migration and proliferation processes on glioma mouse models in vivo are related to differences in the transmembrane water exchange basically linked to the aquaporin expression changes. Three glioma mouse models were used: Glio6 and Glio96 as invasion/migration models and U87 as cell proliferation model. In vivo proton longitudinal relaxation-rate constants (R1) at very low fields were measured by fast field cycling NMR (FFC-NMR). The tumor contribution to the observed proton relaxation rate, R1tum (U87: 12.26 ± 0.64 s−1; Glio6: 3.76 ± 0.88 s−1; Glio96: 6.90 ± 0.64 s−1 at 0.01 MHz), and the intracellular water lifetime, τin (U87: 826 ± 19 ms; Glio6: 516 ± 8 ms; Glio96: 596 ± 15 ms), were found to be good diagnostic hallmarks to distinguish invasion/migration from proliferation (p < 0.01 and 0.001). Overexpression of AQP4 and AQP1 were assessed in invasion/migration models, highlighting the pathophysiological role of these two aquaporins in water exchange that, in turn, determine the lower values in the observed R1 relaxation rate constant in glioma invasion/migration. Overall, our findings demonstrate that τin and R1 (measured at very low fields) are relevant biomarkers, discriminating invasion/migration from proliferation in vivo. These results highlight the use of FFC-NMR and FFC-imaging to assess the efficiency of drugs that could modulate aquaporin functions.

A caspase-3-activatable bimodal probe for photoacoustic and magnetic resonance imaging of tumor apoptosis in vivo

Multimodal imaging probes have shown promise in both biomedical research and clinical diagnosis. However, the development of molecular probes capable of being switched on multimodality imaging signals in response to a biomarker of interest remains challenging. In this paper, we report a caspase-3-activatable small-molecule bimodal probe (Gd-IR780) for photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) of tumor apoptosis via caspase-3-triggered intramolecular macrocyclization and in situ self-assembly process. Upon interaction with caspase-3, Gd-IR780 can be efficiently converted into a macrocyclic product, Gd-IR780-MC, which subsequently self-assembles into near-infrared absorptive and paramagnetic nanoparticles (Gd-IR780-NPs), allowing to concurrently switch on PAI (∼4.3-fold at 855 nm) and MRI (r1 relaxivity increases from 7.98 ± 0.03 mM−1 s−1 to 19.66 ± 0.7 mM−1 s−1 at 0.5 T) bimodal signals in caspase buffer. Noninvasive in vivo imaging results show that Gd-IR780 can enter apoptotic U87MG tumor tissues after systemic administration, and produce markedly enhanced PAI and MRI signals for high sensitivity and spatial-resolution visualization of caspase-3 activity in the doxorubicin-treated apoptotic U87MG tumor tissues. Gd-IR780 holds a good potential to report tumor apoptosis via combined PAI and MRI, which is beneficial for the early evaluation of antitumor efficacy in vivo.

The application of magnetic resonance ultrasmall magnetic Fe3O4 nano bimodal contrast agent in rabbit orthotopic liver tumors

AbstractTo investigate the diagnostic value of ultra‐small superparamagnetic Fe3O4 nanoparticles as dual modal contrast agent in rabbit orthotopic liver tumor. Twenty‐four New Zealand rabbits with orthotopic liver tumor were randomly divided into experimental group and control group. The experimental group contained 12 rabbits which intravenously injected with Fe3O4 nanoparticles and the control group contained 12 rabbits which intravenously injected with Gd‐DTPA. After injection, the cross‐sectional T1 and T2‐weighted scan images of experimental group and cross‐sectional T1‐weighted scan images of control group were obtained at the different timepoints (including 0, 5, 15, 20, 30, 45, 60, 75, 90, 120, 180, and 240 min) with a clinical 3.0 T MRI scanner. The SNR value of the tumor site and the normal liver site at different time points were calculated, respectively, and then the signal change value (CNR) of the tumor relative to the normal liver tissue was obtained. The r1 value of Fe3O4 nanoparticles was significantly higher than Gd‐DTPA (6.97 mM−1 s−1 for Fe3O4 nanoparticles and 4.75 mM−1 s−1 for Gd‐DTPA and only Fe3O4 nanoparticles exhibited the r2 relaxation rate which was 22.53 mM−1 s−1). In addition, the r2/r1 ratio of Fe3O4 was 3.23 which also demonstrated the strong MR relaxation characteristics of Fe3O4 nanoparticles. Compare with clinical used MRI contrast agent (Gd‐DTPA), the ultra‐small magnetic Fe3O4 nanoparticles not only showed the better T1 contrast enhancement but also exhibited the T1/T2 dual‐modal enhanced contrast ability, which could improve the accuracy and sensitivity of MRI diagnosis and realize the early diagnosis of diseases in prospect.