Optimization of micelle-encapsulated extremely small sized iron oxide nanoparticles as a T1 contrast imaging agent: biodistribution and safety profile.

BACKGROUND: Iron oxide nanoparticles (IONPs) have been cleared by the Food and Drug Administration (FDA) for various clinical applications, such as tumor-targeted imaging, hyperthermia therapy, drug delivery, and live-cell tracking. However, the application of IONPs as T1 contrast agents has been restricted due to their high r2 values and r2/r1 ratios, which limit their effectiveness in T1 contrast enhancement. Notably, IONPs with diameters smaller than 5 nm, referred to as extremely small-sized IONPs (ESIONs), have demonstrated potential in overcoming these limitations. To advance the clinical application of ESIONs as T1 contrast agents, we have refined a scale-up process for micelle encapsulation aimed at improving the hydrophilization of ESIONs, and have carried out comprehensive in vivo biodistribution and preclinical toxicity assessments. RESULTS: The optimization of the scale-up micelle-encapsulation process, specifically employing Tween60 at a concentration of 10% v/v, resulted in ESIONs that were uniformly hydrophilized, with an average size of 9.35 nm and a high purification yield. Stability tests showed that these ESIONs maintained consistent size over extended storage periods and dispersed effectively in blood and serum-mimicking environments. Relaxivity measurements indicated an r1 value of 3.43 mM- 1s- 1 and a favorable r2/r1 ratio of 5.36, suggesting their potential as T1 contrast agents. Biodistribution studies revealed that the ESIONs had extended circulation times in the bloodstream and were primarily cleared via the hepatobiliary route, with negligible renal excretion. We monitored blood clearance and organ distribution using positron emission tomography and magnetic resonance imaging (MRI). Additionally, MRI signal variations in a dose-dependent manner highlighted different behaviors at varying ESIONs concentrations, implying that optimal dosages might be specific to the intended imaging application. Preclinical safety evaluations indicated that ESIONs were tolerable in rats at doses up to 25 mg/kg. CONCLUSIONS: This study effectively optimized a scale-up process for the micelle encapsulation of ESIONs, leading to the production of hydrophilic ESIONs at gram-scale levels. These optimized ESIONs showcased properties conducive to T1 contrast imaging, such as elevated r1 relaxivity and a reduced r2/r1 ratio. Biodistribution study underscored their prolonged bloodstream presence and efficient clearance through the liver and bile, without significant renal involvement. The preclinical toxicity tests affirmed the safety of the ESIONs, supporting their potential use as T1 contrast agent with versatile clinical application.

High SNR rapid T1 -weighted MPRAGE using spiral imaging with long readouts and improved deblurring.

PURPOSE: The goal of this work is to present the implementation of 3D spiral high-resolution MPRAGE and to demonstrate that SNR and scan efficiency increase with the increment of readout time. THEORY: Simplified signal equations for MPRAGE indicate that the T1 contrast can be kept approximately the same by a simple relationship between the flip angle and the TR. Furthermore, if T1 contrast remains the same, image SNR depends on the square root of the product of the total scan time and the readout time. METHODS: MPRAGE spiral sequences were implemented with distributed spirals and spiral staircase on 3 Tesla scanners. Brain images of three volunteers were acquired with different readout times. Spiral images were processed with a joint water-fat separation and deblurring algorithm and compared to Cartesian images. Pure noise data sets were also acquired for SNR evaluation. RESULTS: Consistent T1 weighting can be achieved with various spiral readout lengths, and between spiral MPRAGE imaging and the traditional Cartesian MPRAGE imaging. Noise performance analysis demonstrates higher SNR efficiency of spiral MPRAGE imaging with matched T1 contrast compared to the Cartesian reference imaging. CONCLUSION: Fast, high SNR MPRAGE imaging is feasible with long readout spiral trajectories.

Synthesis of Multifunctional Mn3O4-Ag2S Janus Nanoparticles for Enhanced T1-Magnetic Resonance Imaging and Photo-Induced Tumor Therapy.

The global burden of cancer is increasing rapidly, and nanomedicine offers promising prospects for enhancing the life expectancy of cancer patients. Janus nanoparticles (JNPs) have garnered considerable attention due to their asymmetric geometry, enabling multifunctionality in drug delivery and theranostics. However, achieving precise control over the self-assembly of JNPs in solution at the nanoscale level poses significant challenges. Herein, a low-temperature reversed-phase microemulsion system was used to obtain homogenous Mn3O4-Ag2S JNPs, which showed significant potential in cancer theranostics. Structural characterization revealed that the Ag2S (5-10 nm) part was uniformly deposited on a specific surface of Mn3O4 to form a Mn3O4-Ag2S Janus morphology. Compared to the single-component Mn3O4 and Ag2S particles, the fabricated Mn3O4-Ag2S JNPs exhibited satisfactory biocompatibility and therapeutic performance. Novel diagnostic and therapeutic nanoplatforms can be guided using the magnetic component in JNPs, which is revealed as an excellent T1 contrast enhancement agent in magnetic resonance imaging (MRI) with multiple functions, such as photo-induced regulation of the tumor microenvironment via producing reactive oxygen species and second near-infrared region (NIR-II) photothermal excitation for in vitro tumor-killing effects. The prime antibacterial and promising theranostics results demonstrate the extensive potential of the designed photo-responsive Mn3O4-Ag2S JNPs for biomedical applications.

Structure-Relaxivity Mechanism of an Ultrasmall Ferrite Nanoparticle T1 MR Contrast Agent: The Impact of Dopants Controlled Crystalline Core and Surface Disordered Shell.

Ultrasmall ferrite nanoparticles (UFNPs) have emerged as powerful magnetic resonance imaging (MRI) T1 nanoprobe for noninvasive visualization of biological events. However, the structure-relaxivity relationship and regulatory mechanism of UFNPs remain elusive. Herein, we developed chemically engineered 3.8 nm ZnxFe3-xO4@ZnxMnyFe3-x-yO4 (denoted as ZnxF@ZnxMnyF) nanoparticles with precise dopants control in both crystalline core and disordered shell as a model system to assess the impact of dopants on the relaxometric properties of UFNPs. It is determined that the core-shell dopant architecture allows the optimal tuning of r1 relaxivity for Zn0.4F@Zn0.4Mn0.2F up to 20.22 mM-1 s-1, which is 5.2-fold and 6.5-fold larger than that of the original UFNPs and the clinically used Gd-DTPA. Moreover, the high-performing UFNPs nanoprobe, when conjugated with a targeting moiety AMD3100, enables the in vivo MRI detection of small lung metastasis with greatly enhanced sensitivity. Our results pave the way toward the chemical design of ultrasensitive T1 nanoprobe for advanced molecular imaging.

B0-field dependence of MRI T1 relaxation in human brain.

Tissue longitudinal relaxation characterized by recovery time T1 or rate R1 is a fundamental MRI contrast mechanism that is increasingly being used to study the brain's myelination patterns in both health and disease. Nevertheless, the quantitative relationship between T1 and myelination, and its dependence on B0 field strength, is still not well known. It has been theorized that in much of brain tissue, T1 field-dependence is driven by that of macromolecular protons (MP) through a mechanism called magnetization transfer (MT). Despite the explanatory power of this theory and substantial support from in-vitro experiments at low fields (<3 â€‹T), in-vivo evidence across clinically relevant field strengths is lacking. In this study, T1-weighted MRI was acquired in a group of eight healthy volunteers at four clinically relevant field strengths (0.55, 1.5, 3 and 7 â€‹T) using the same pulse sequence at a single site, and jointly analyzed based on the two-pool model of MT. MP fraction and free-water pool T1 were obtained in several brain structures at 3 and 7 â€‹T, which allowed distinguishing between contributions from macromolecular content and iron to tissue T1. Based on this, the T1 of MP in white matter, indirectly determined by assuming a field independent T1 of free water, was shown to increase approximately linearly with B0. This study advances our understanding of the T1 contrast mechanism and its relation to brain myelin content across the wide range of currently available MRI strengths, and it has the potential to inform design of T1 mapping methods for improved reproducibility in the human brain.

Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups.

Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH2), are compared. Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r1 relaxivity of the Fe(L1)(OH2) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 °C in buffered solutions. However, variable-temperature 17O-NMR experiments show that the inner-sphere water of Fe(L1)(OH2) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH2) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH2) for development as an extracellular fluid contrast agent.

An efficient sequence for fetal brain imaging at 3T with enhanced T1 contrast and motion robustness.

PURPOSE: Ultrafast single-shot T2 -weighted images are common practice in fetal MR exams. However, there is limited experience with fetal T1 -weighted acquisitions. This study aims at establishing a robust framework that allows fetal T1 -weighted scans to be routinely acquired in utero at 3T. METHODS: A 2D gradient echo sequence with an adiabatic inversion was optimized to be robust to fetal motion and maternal breathing optimizing grey/white matter contrast at the same time. This was combined with slice to volume registration and super resolution methods to produce volumetric reconstructions. The sequence was tested on 22 fetuses. RESULTS: Optimized grey/white matter contrast and robustness to fetal motion and maternal breathing were achieved. Signal from cerebrospinal fluid (CSF) and amniotic fluid was nulled and 0.75 mm isotropic anatomical reconstructions of the fetal brain were obtained using slice-to-volume registration and super resolution techniques. Total acquisition time for a single stack was 56 s, all acquired during free breathing. Enhanced sensitivity to normal anatomy and pathology with respect to established methods is demonstrated. A direct comparison with a 3D spoiled gradient echo sequence and a controlled motion experiment run on an adult volunteer are also shown. CONCLUSION: This paper describes a robust framework to perform T1 -weighted acquisitions and reconstructions of the fetal brain in utero. Magn Reson Med 80:137-146, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

MnO nanoparticles with unique excitation-dependent fluorescence for multicolor cellular imaging and MR imaging of brain glioma.

The authors describe MnO nanoparticles (NPs) with unique excitation-dependent fluorescence across the entire visible spectrum. These NPs are shown to be efficient optical nanoprobe for multicolor cellular imaging. Synthesis of the NPs is accomplished by a thermal decomposition method. The MnO NPs exhibit a high r1 relaxivity of 4.68 mM-1 s-1 and therefore give an enhanced contrast effect in magnetic resonance (MR) studies of brain glioma. The cytotoxicity assay, hemolysis analysis, and hematoxylin and eosin (H&E) staining tests verify that the MnO NPs are biocompatible. In the authors' perception, the simultaneous attributes of multicolor fluorescence and excellent MR functionality make this material a promising dual-modal nanoprobe for use in bio-imaging. Graphical abstract A direct method to synthesize fluorescent MnO NPs is reported. The NPs are biocompatible and have been successfully applied for multicolor cellular imaging and MR detection of brain glioma.

Effects of magnetization transfer on T1 contrast in human brain white matter.

MRI based on T1 relaxation contrast is increasingly being used to study brain morphology and myelination. Although it provides for excellent distinction between the major tissue types of gray matter, white matter, and CSF, reproducible quantification of T1 relaxation rates is difficult due to the complexity of the contrast mechanism and dependence on experimental details. In this work, we perform simulations and inversion-recovery MRI measurements at 3T and 7T to show that substantial measurement variability results from unintended and uncontrolled perturbation of the magnetization of MRI-invisible (1)H protons of lipids and macromolecules. This results in bi-exponential relaxation, with a fast component whose relative contribution under practical conditions can reach 20%. This phenomenon can strongly affect apparent relaxation rates, affect contrast between tissue types, and result in contrast variations over the brain. Based on this novel understanding, ways are proposed to minimize this experimental variability and its effect on T1 contrast, quantification accuracy and reproducibility.

fMRI contrast at high and ultrahigh magnetic fields: insight from complementary methods.

This manuscript examines the origins and nature of the function-derived activation detected by magnetic resonance imaging at ultrahigh fields using different encoding methods. A series of preclinical high field (7 T) and ultra-high field (17.2 T) fMRI experiments were performed using gradient echo EPI, spin echo EPI and spatio-temporally encoded (SPEN) strategies. The dependencies of the fMRI signal change on the strength of the magnetic field and on different acquisition and sequence parameters were investigated. Artifact-free rat brain images with good resolution in all areas, as well as significant localized activation maps upon forepaw stimulation, were obtained in a single scan using fully refocused SPEN sequences devoid of T2* effects. Our results showed that, besides the normal T2-weighted BOLD contribution that arises in spin-echo sequences, fMRI SPEN signals contain a strong component caused by apparent T1-related effects, demonstrating the potential of such technique for exploring functional activation in rodents and on humans at ultrahigh fields.

Comparison of the Pharmacokinetics of Gadolinium-Based and Iron Oxide-Based Contrast Agents inside the Lymphatic Structure using Magnetic Resonance Lymphangiography.

PURPOSE: Gadolinium (Gd)-based contrast agents are primarily used for contrast-enhanced magnetic resonance lymphangiography (MRL). However, overcoming venous contamination issues remains challenging. This study aims to assess the MRL efficacy of the newly developed iron-based contrast agent (INV-001) that is specially designed to mitigate venous contamination issues. The study further explores the optimal dosage, including both injection volume and concentration, required to achieve successful visualization of the popliteal lymph nodes and surrounding lymphatic vessels. PROCEDURES: All animals utilized in this study were male Sprague-Dawley (SD) rats weighing between 250 and 300 g. The contrast agents prepared were injected intradermally in the fourth phalanx of both hind limbs using a 30-gauge syringe in SD rats. MRL was performed every 16 min on a coronal 3D time-of-flight sequence with saturation bands using a 9.4-T animal machine. RESULTS: Contrary to Gd-DOTA, which exhibited venous contamination in most animals irrespective of injection dosages and conditions, INV-001 showed no venous contamination. For Gd-DOTA, the popliteal lymph nodes and lymphatic vessels reached peak enhancement 16 min after injection from the injection site and then rapidly washed out. However, with INV-001, they reached peak enhancement between 16 and 32 min after injection, with prolonged visualization of the popliteal lymph node and lymphatic vessels. INV-001 at 0.45 µmol (15 mM, 30 µL) and 0.75 µmol (15 mM, 50 µL) achieved high scores for qualitative image analysis, providing good visualization of the popliteal lymph nodes and lymphatic vessels without issues of venous contamination, interstitial space enhancement, or lymph node enlargement. CONCLUSION: In MRL, INV-001, a novel T1 contrast agent based on iron, enables prolonged enhancement of popliteal lymph nodes and lymphatic vessels without venous contamination.

Protease-Mediated T1 Contrast Enhancement of Multilayered Magneto-Gadolinium Nanostructures for Imaging and Magnetic Hyperthermia.

In this work, we constructed a multifunctional composite nanostructure for combined magnetic hyperthermia therapy and magnetic resonance imaging based on T1 and T2 signals. First, iron oxide nanocubes with a benchmark heating efficiency for magnetic hyperthermia were assembled within an amphiphilic polymer to form magnetic nanobeads. Next, poly(acrylic acid)-coated inorganic sodium gadolinium fluoride nanoparticles were electrostatically loaded onto the magnetic nanobead surface via a layer-by-layer approach by employing a positively charged enzymatic-cleavable biopolymer. The positive-negative multilayering process was validated through the changes occurring in surface ζ-potential values and structural characterization by transmission electron microscopy (TEM) imaging. These nanostructures exhibit an efficient heating profile, in terms of the specific absorption rates under clinically accepted magnetic field conditions. The addition of protease enzyme mediates the degradation of the surface layers of the nanostructures with the detachment of gadolinium nanoparticles from the magnetic beads and exposure to the aqueous environment. Such a process is associated with changes in the T1 relaxation time and contrast and a parallel decrease in the T2 signal. These structures are also nontoxic when tested on glioblastoma tumor cells up to a maximum gadolinium dose of 125 µg mL-1, which also corresponds to a iron dose of 52 µg mL-1. Nontoxic nanostructures with such enzyme-triggered release mechanisms and T1 signal enhancement are desirable for tracking tumor microenvironment release with remote T1-guidance and magnetic hyperthermia therapy actuation to be done at the diseased site upon verification of magnetic resonance imaging (MRI)-guided release.

Naturally biocompatible melanin based iron-complex nanoparticles for pH-responsive magnetic resonance imaging.

The sensitivity and diagnostic accuracy of magnetic resonance imaging mainly depend on the relaxation capacity of contrast agents (CAs) and their accumulated amount at the pathological region. Due to the better biocompatibility and high-spin capacity, Fe-complexes have been studied widely as an alternative to replace popular Gd-based CAs associated with potential biotoxicity. Compared with a variety of Fe complex-based CAs, such as small molecular, macrocyclic, multinuclear complexes, the form of nanoparticle exhibits outstanding longitudinal relaxation, but the clinical transformation was still limited by the inconspicuous difference of contrast between tumor and normal tissue. The enhanced effect of contrast is a positive relation as relaxation of CAs and their concentration in desired region. To specifically improve the amount of CAs accumulated in the tumor, pH-responsive polymer poly(2-ethyl-2-oxazoline) (PEOz) was modified on melanin, a ubiquitous natural pigment providing much active sites for chelating with Fe(III). The Fe(III)-Mel-PEOz we prepared could raise the tumor cell endocytosis efficiency via switching surface charge from anion to cation with the stimuli of the decreasing pH of tumor microenvironment. The change of pH has negligible effect on ther1of Fe(III)-Mel-PEOz, which is always maintained at around 1.0 mM-1s-1at 0.5 T. Moreover, Fe(III)-Mel-PEOz exhibited low cytotoxicity, and satisfactory enhancement of positive contrast effectin vivo. The excellent biocompatibility and stable relaxation demonstrate the high potential of Fe(III)-Mel-PEOz in the diagnosis of tumor.

Preparation and performance of biocompatible gadolinium polymer as liver-targeting magnetic resonance imaging contrast agent.

A biocompatible macromolecule-conjugated gadolinium chelate complex (PAV2-EDA-DOTA-Gd) as a new liver-specific contrast agent for magnetic resonance imaging (MRI) was synthesized and evaluated. An aspartic acid-valine copolymer was used as a carrier and ethylenediamine as a chemical linker, and the aspartic acid-valine copolymer was covalently linked to the small molecule MRI contrast agent Gd-DOTA (Dotarem) to synthesize a large molecule contrast agent. In vitro MR relaxation showed that the T1-relaxivity of PAV2-EDA-DOTA-Gd (13.7 mmol-1 L s-1) was much higher than that of the small-molecule Gd-DOTA (4.9 mmol-1 L s-1). In vivo imaging of rats showed that the enhancement effect of PAV2-EDA-DOTA-Gd (55.37 ± 2.80%) on liver imaging was 2.6 times that of Gd-DOTA (21.12 ± 3.86%), and it produced a longer imaging window time (40-70 min for PAV2-EDA-DOTA-Gd and 10-30 min for Gd-DOTA). Preliminary safety experiments, such as cell experiments and tissue sectioning, showed that PAV2-EDA-DOTA-Gd had low toxicity and satisfactory biocompatibility. The results of this study indicated that PAV2-EDA-DOTA-Gd had high potential as a liver-specific MRI contrast agent.

Identification of Origin for Spinal Metastases from MR Images: Comparison Between Radiomics and Deep Learning Methods.

OBJECTIVE: To determine whether spinal metastatic lesions originated from lung cancer or from other cancers based on spinal contrast-enhanced T1 (CET1) magnetic resonance (MR) images analyzed using radiomics (RAD) and deep learning (DL) methods. METHODS: We recruited and retrospectively reviewed 173 patients diagnosed with spinal metastases at two different centers between July 2018 and June 2021. Of these, 68 involved lung cancer and 105 were other types of cancer. They were assigned to an internal cohort of 149 patients, randomly divided into a training set and a validation set, and to an external cohort of 24 patients. All patients underwent CET1-MR imaging before surgery or biopsy. We developed two predictive algorithms: a DL model and a RAD model. We compared performance between models, and against human radiological assessment, via accuracy (ACC) and receiver operating characteristic (ROC) analyses. Furthermore, we analyzed the correlation between RAD and DL features. RESULTS: The DL model outperformed RAD model across the board, with ACC/ area under the receiver operating characteristic curve (AUC) values of 0.93/0.94 (DL) versus 0.84/0.93 (RAD) when applied to the training set from the internal cohort, 0.74/0.76 versus 0.72/0.75 when applied to the validation set, and 0.72/0.76 versus 0.69/0.72 when applied to the external test cohort. For the validation set, it also outperformed expert radiological assessment (ACC: 0.65, AUC: 0.68). We only found weak correlations between DL and RAD features. CONCLUSION: The DL algorithm successfully identified the origin of spinal metastases from pre-operative CET1-MR images, outperforming both RAD models and expert assessment by trained radiologists.

Kinetically inert manganese (II)-based hybrid micellar complexes for magnetic resonance imaging of lymph node metastasis.

The localization and differential diagnosis of the sentinel lymph nodes (SLNs) are particularly important for tumor staging, surgical planning and prognosis. In this work, kinetically inert manganese (II)-based hybrid micellar complexes (MnCs) for magnetic resonance imaging (MRI) were developed using an amphiphilic manganese-based chelate (C18-PhDTA-Mn) with reliable kinetic stability and self-assembled with a series of amphiphilic PEG-C18 polymers of different molecular weights (C18En, n = 10, 20, 50). Among them, the probes composed by 1:10 mass ratio of manganese chelate/C18En had slightly different hydrodynamic particle sizes with similar surface charges as well as considerable relaxivities (∼13 mM-1 s-1 at 1.5 T). In vivo lymph node imaging in mice revealed that the MnC MnC-20 formed by C18E20 with C18-PhDTA-Mn at a hydrodynamic particle size of 5.5 nm had significant signal intensity brightening effect and shortened T1 relaxation time. At an imaging probe dosage of 125 µg Mn/kg, lymph nodes still had significant signal enhancement in 2 h, while there is no obvious signal intensity alteration in non-lymphoid regions. In 4T1 tumor metastatic mice model, SLNs showed less signal enhancement and smaller T1 relaxation time variation at 30 min post-injection, when compared with normal lymph nodes. This was favorable to differentiate normal lymph nodes from SLN under a 3.0-T clinical MRI scanner. In conclusion, the strategy of developing manganese-based MR nanoprobes was useful in lymph node imaging.

Tumor microenvironment-responsive histidine modified-hyaluronic acid-based MnO2 as in vivo MRI contrast agent.

Tumor microenvironment (TME)-responsive manganese dioxide (MnO2) nanoparticles as a good T1 contrast agent could reduce unwanted toxicity and improve the accuracy of cancer detection. Despite these distinct advantages of MnO2-based nanoparticles, their synthesis involves multi-step processes with relatively long synthesis times. In this study, we synthesized histidine-modified hyaluronic acid (HA-His), and the prepared HA-His conjugates quickly reduce permanganate to MnO2, leading to facile production of HA-His/MnO2 nanoparticles with good water-dispersibility and stability under biological conditions. The synthesized HA-His/MnO2 nanoparticles readily responded to the TME (low pH, high H2O2, and high glutathione), and they were internalized into SCC7 cells with high CD44 expression. Moreover, the systemically administered HA-His/MnO2 nanoparticles with biocompatibility were specifically accumulated in tumor tissues, thereby efficiently enhancing T1 contrast in MRI. Therefore, the HA-His/MnO2 nanoparticles synthesized herein can be used as a promising T1 contrast agent for tumor MR imaging.

Retinoic acid-conjugated chitosan/manganese porphyrin ionic-complex nanoparticles for improved T1 contrast MR imaging of hepatic fibrosis.

Noninvasive and precise diagnosis of hepatic fibrosis is very important for the preventive therapeutic regimen of hepatic cirrhosis and cancer. In this study, we fabricated T1 contrast Mn-porphyrin (MnTPPS4 )/retinoic acid-chitosan ionic-complex nanoparticles (MRC NPs). The functional properties of MRC NPs were evaluated via transmission electron microscopy (TEM) imaging, release study, cytotoxicity assay, hepatocyte-specific uptake assay, and magnetic resonance (MR) imaging study. TEM images confirmed the typical structure of an ionic-complex NPs with around 100-200 nm of diameter. MnTPPS4 is released from MRC NPs for up to 24 hr in controlled pattern which implies that more reliable and convenient hepatic MR imaging is possible using of MRC NPs in clinical practice. Hepatocytes uptake assay proved retinoic acid-specific targeting of MRC NPs. The same results were observed in animal pharmacokinetic studies. In vitro MR phantom study, MRC NPs showed an increased T1 relaxivity (r1  = 6.772 mM-1  s-1 ) in comparison with 3.242 mM-1  s-1 of MnTPPS4 . The result was confirmed again in vivo MR imaging studies. Taken together, MRC NPs displayed a potential for noninvasive diagnostic T1 MR imaging of hepatic fibrosis with improved target specificity and prolonged MR imaging time window.

Multimodal Magnetic Resonance and Photoacoustic Imaging of Tumor-Specific Enzyme-Responsive Hybrid Nanoparticles for Oxygen Modulation.

Multimodal imaging contrast agents for cancer that can not only perform diagnostic functions but also serve as tumor microenvironment-responsive biomaterials are encouraging. In this study, we report the design and fabrication of a novel enzyme-responsive T1 magnetic resonance imaging (MRI) contrast agent that can modulate oxygen in the tumor microenvironment via the catalytic conversion of H2O2 to O2. The T1 contrast agent is a core-shell nanoparticle that consists of manganese oxide and hyaluronic acid (HA)-conjugated mesoporous silica nanoparticle (HA-MnO@MSN). The salient features of the nanoparticle developed in this study are as follows: 1) HA serves as a targeting ligand for CD44-expressing cancer cells; 2) HA allows controlled access of water molecules to the MnO core via the digestion of enzyme hyaluronidase; 3) the generation of O2 bubbles in the tumor by consuming H2O2; and 4) the capability to increase the oxygen tension in the tumor. The r 1 relaxivity of HA-MnO@MSN was measured to be 1.29 mM-1s-1 at a magnetic field strength of 9.4 T. In vitro results demonstrated the ability of continuous oxygen evolution by HA-MnO@MSN. After intratumoral administration of HA-MnO@MSN to an HCT116 xenograft mouse model, T1 weighted MRI contrast was observed after 5 h postinjection and retained up to 48 h. In addition, in vivo photoacoustic imaging of HA-MnO@MSN demonstrated an increase in the tumor oxygen saturation over time after i. t. administration. Thus, the core-shell nanoparticles developed in this study could be helpful in tumor-targeted T1 MR imaging and oxygen modulation.

Engineering manganese ferrite shell on iron oxide nanoparticles for enhanced T1 magnetic resonance imaging.

Doping Mn (II) ions into iron oxide (IO) as manganese ferrite (MnIO) has been proved to be an effective strategy to improve T1 relaxivity of IO nanoparticle in recent years; however, the high T2 relaxivity of MnIO nanoparticle hampers its T1 contrast efficiency and remains a hurdle when developing contrast agent for early and accurate diagnosis. Herein, we engineered the interfacial structure of IO nanoparticle coated with manganese ferrite shell (IO@MnIO) with tunable thicknesses. The Mn-doped shell significantly improve the T1 contrast of IO nanoparticle, especially with the thickness of ∼0.8 nm. Compared to pristine IO nanoparticle, IO@MnIO nanoparticle with thickness of ∼0.8 nm exhibits nearly 2 times higher T1 relaxivity of 9.1 mM-1s-1 at 3 T magnetic field. Moreover, exclusive engineering the interfacial structure significantly lower the T2 enhancing effect caused by doped Mn (II) ions, which further limits the impairing of increased T2 relaxivity to T1 contrast imaging. IO@MnIO nanoparticles with different shell thicknesses reveal comparable T1 relaxation rates but obvious lower T2 relaxivities and r2/r1 ratios to MnIO nanoparticles with similar sizes. The desirable T1 contrast endows IO@MnIO nanoparticle to provide sufficient signal difference between normal and tumor tissue in vivo. This work provides a detailed instance of interfacial engineering to improve IO-based T1 contrast and a new guidance for designing effective high-performance T1 contrast agent for early cancer diagnosis.