Gold Nanorod-Loaded Nano-Contrast Agent with Composite Shell-Core Structure for Ultrasonic/Photothermal Imaging-Guided Therapy in Ischemic Muscle Disorders.

Purpose: This study aims to broaden the application of nano-contrast agents (NCAs) within the realm of the musculoskeletal system. It aims to introduce novel methods, strategies, and insights for the clinical management of ischemic muscle disorders, encompassing diagnosis, monitoring, evaluation, and therapeutic intervention. Methods: We developed a composite encapsulation technique employing O-carboxymethyl chitosan (OCMC) and liposome to encapsulate NCA-containing gold nanorods (GNRs) and perfluoropentane (PFP). This nanoscale contrast agent was thoroughly characterized for its basic physicochemical properties and performance. Its capabilities for in vivo and in vitro ultrasound imaging and photothermal imaging were authenticated, alongside a comprehensive biocompatibility assessment to ascertain its effects on microcirculatory perfusion in skeletal muscle using a murine model of hindlimb ischemia, and its potential to augment blood flow and facilitate recovery. Results: The engineered GNR@OCMC-liposome/PFP nanostructure exhibited an average size of 203.18±1.49 nm, characterized by size uniformity, regular morphology, and a good biocompatibility profile. In vitro assessments revealed NCA's potent photothermal response and its transformation into microbubbles (MBs) under near-infrared (NIR) irradiation, thereby enhancing ultrasonographic visibility. Animal studies demonstrated the nanostructure's efficacy in photothermal imaging at ischemic loci in mouse hindlimbs, where NIR irradiation induced rapid temperature increases and significantly increased blood circulation. Conclusion: The dual-modal ultrasound/photothermal NCA, encapsulating GNR and PFP within a composite shell-core architecture, was synthesized successfully. It demonstrated exceptional stability, biocompatibility, and phase transition efficiency. Importantly, it facilitates the encapsulation of PFP, enabling both enhanced ultrasound imaging and photothermal imaging following NIR light exposure. This advancement provides a critical step towards the integrated diagnosis and treatment of ischemic muscle diseases, signifying a pivotal development in nanomedicine for musculoskeletal therapeutics.

Facile Synthesis of Rigid Binuclear Manganese Complexes for Magnetic Resonance Angiography and SLC39A14-Mediated Hepatic Imaging.

Manganese(II)-based contrast agents (MBCAs) are potential candidates for gadolinium-free enhanced magnetic resonance imaging (MRI). In this work, a rigid binuclear MBCA (Mn2-PhDTA2) with a zero-length linker was developed via facile synthetic routes, while the other dimer (Mn2-TPA-PhDTA2) with a longer rigid linker was also synthesized via more complex steps. Although the molecular weight of Mn2-PhDTA2 is lower than that of Mn2-TPA-PhDTA2, their T1 relaxivities are similar, being increased by over 71% compared to the mononuclear Mn-PhDTA. In the presence of serum albumin, the relaxivity of Mn2-PhDTA2 was slightly lower than that of Mn2-TPA-PhDTA2, possibly due to the lower affinity constant. The transmetalation reaction with copper(II) ions confirmed that Mn2-PhDTA2 has an ideal kinetic inertness with a dissociation half-life of approximately 10.4 h under physiological conditions. In the variable-temperature 17O NMR study, both Mn-PhDTA and Mn2-PhDTA2 demonstrated a similar estimated q close to 1, indicating the formation of monohydrated complexes with each manganese(II) ion. In addition, Mn2-PhDTA2 demonstrated a superior contrast enhancement to Mn-PhDTA in in vivo vascular and hepatic MRI and can be rapidly cleared through a dual hepatic and renal excretion pattern. The hepatic uptake mechanism of Mn2-PhDTA2 mediated by SLC39A14 was validated in cellular uptake studies.

Surface ligand-regulated renal clearance of MRI/SPECT dual-modality nanoprobes for tumor imaging.

BACKGROUND: The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape. RESULTS: In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments. CONCLUSIONS: We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis.

Semiconducting Polymers Based on Asymmetric Thiadiazoloquinoxaline for Augmented In Vivo NIR-II Photoacoustic Imaging.

A photoacoustic (PA) imaging technique using the second near-infrared (NIR-II) window has attracted more and more attention because of its merits of deeper penetration depth and higher signal-to-noise (S/N) ratio than that using the first near-infrared (NIR-I) one. However, the design and development of high-performance PA imaging contrast agents in the NIR-II window is still a challenge. A semiconducting polymer, constructed by asymmetric units, exhibits regiorandom characteristics that effectively increase the distortion of the backbone. This increase in the degree of twist can regulate the twisted intramolecular charge transfer (TICT) effect, resulting in an enhancement of the PA signal. In this paper, an asymmetric structural acceptor strategy is developed to improve the PA signals of the resulting semiconducting polymer (PATQ-MP) in the NIR-II window with improved brightness, higher S/N ratio, and better photothermal conversion efficiency compared to polymers with the same main-chain structure containing a symmetric acceptor. DFT analysis showed that PATQ-MP containing an asymmetric acceptor monomer had a larger dihedral angle, which effectively improved the PA signal intensity by enhancing the TICT effect. The PEG-encapsulated PATQ-MP nanoparticles exhibit promising performance in the PA imaging of mouse tumors in vivo, demonstrating the clear identification of microvessels as small as 100 µm along with rapid metabolism within a span of 5 h. Therefore, this work provides a unique molecular design strategy for improving the signal intensity of PA imaging in the NIR-II window.

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.

An Indocyanine Green-Based Nanocluster for Imaging Orthodox Endometriosis Lesions with Negative Contrast.

Indocyanine green (ICG), as the sole near-infrared dye FDA-approved, is limited in biomedical applications because of its poor photostability, lack of targeting, and rapid removal in vivo. Herein, we presented a nanoformulation of poly-l-lysine-indocyanine green-hyaluronic acid (PIH) and demonstrated that it can image orthodox endometriosis (EM) lesions with a negative contrast. The PIH nanocluster, with an average diameter of approximately 200 nm, exhibited improved fluorescence photostability and antioxidant ability compared to free ICG. In the in vivo imaging, EM lesions were visualized, featuring apparent voids and clear boundaries. After colocalizing with the green fluorescent protein, we concluded that the contrast provided by PIH peaked at 4 h postinjection and was observable for at least 8 h. The negative contrast, clear boundaries, and enhanced observable time might be due to the low permeation of PIH to lesions and the enhanced retention on the surfaces of lesions. Thus, our findings suggest an ICG-based nanoprobe with the potential to diagnose abdominal diseases.

15N Hyperpolarization of Metronidazole Antibiotic in Aqueous Media Using Phase-Separated Signal Amplification by Reversible Exchange with Parahydrogen.

Metronidazole is a prospective hyperpolarized MRI contrast agent with potential hypoxia sensing utility for applications in cancer, stroke, neurodegenerative diseases, etc. We demonstrate a pilot procedure for production of ∼30 mM hyperpolarized [15N3]metronidazole in aqueous media by using a phase-separated SABRE-SHEATH hyperpolarization method, with nitrogen-15 polarization exceeding 2.2% on all three 15N sites achieved in less than 2 min. The 15N polarization T1 of ∼12 min is reported for the 15NO2 group at the clinically relevant field of 1.4 T in the aqueous phase, demonstrating a remarkably long lifetime of the hyperpolarized state. The produced aqueous solution of [15N3]metronidazole that contained only ∼100 µM of residual Ir was deemed biocompatible via validation through the MTT colorimetric test for assessing cell metabolic activity using human embryotic kidney HEK293T cells. This low-cost and ultrafast hyperpolarization procedure represents a major advance for the production of a biocompatible HP [15N3]metronidazole (and potentially other hyperpolarized drugs) formulation for MRI sensing applications.

Three musketeers of PDA-based MRI contrasting and therapy.

Polydopamine (PDA) stands as a versatile material explored in cancer nanomedicine for its unique properties, offering opportunities for multifunctional drug delivery platforms. This study explores the potential of utilizing a one-pot synthesis to concurrently integrate Fe, Gd and Mn ions into porous PDA-based theranostic drug delivery platforms called Ferritis, Gadolinis and Manganis, respectively. Our investigation spans the morphology, magnetic properties, photothermal characteristics and cytotoxicity profiles of those potent nanoformulations. The obtained structures showcase a spherical morphology, robust magnetic response and promising photothermal behaviour. All of the presented nanoparticles (NPs) display pronounced paramagnetism, revealing contrasting potential for MRI imaging. Relaxivity values, a key determinant of contrast efficacy, demonstrated competitive or superior performance compared to established, used contrasting agents. These nanoformulations also exhibited robust photothermal properties under near infra-red irradiation, showcasing their possible application for photothermal therapy of cancer. Our findings provide insights into the potential of metal-doped PDA NPs for cancer theranostics.

Development of Ln(III) Derivatives as 19F Parashift Probes.

19F parashift probes with paramagnetically shifted reporter nuclei provide attractive platforms to develop molecular imaging probes. These probes enable ratiometric detection of molecular disease markers using a direct detection technique. Here, we describe a series of trivalent lanthanide (Ln(III)) complexes that are structural analogues of the clinically approved MR contrast agent (CA) ProHance to obtain LnL 19F parashift probes. We evaluated trans-gadolinium paramagnetic lanthanides compared to diamagnetic YL for 19F chemical shift and relaxation rate enhancement. The paramagnetic contribution to chemical shift (δPCS) for paramagnetic LnL exhibited either shifts to lower frequency (δPCS < 0 for TbL, DyL, and HoL) or shifts to higher frequency (δPCS > 0 for ErL, TmL, and YbL) compared to YL 19F spectroscopic signal. Zero-echo time pulse sequences achieved 56-fold sensitivity enhancement for DyL over YL, while developing probe-specific pulse sequences with fast delay times and acquisition times achieved 0.6-fold enhancement in limit of detection for DyL. DyL provides an attractive platform to develop 19F parashift probes for ratiometric detection of enzymatic activity.

Preparation of Hematoporphyrin-Poly(Lactic Acid) Nanoparticles Encapsulated Perfluoropentane/Salicylic Acid for Enhanced US/CEST MR Bimodal Imaging.

Background: Medical imaging modalities, such as magnetic resonance imaging (MRI), ultrasound, and fluorescence imaging, have gained widespread acceptance in clinical practice for tumor diagnosis. Each imaging modality has its own unique principles, advantages, and limitations, thus necessitating a multimodal approach for a comprehensive disease understanding of the disease process. To enhance diagnostic precision, physicians frequently integrate data from multiple imaging modalities, driving research advancements in multimodal imaging technology research. Methods: In this study, hematoporphyrin-poly (lactic acid) (HP-PLLA) polymer was prepared via ring-opening polymerization and thoroughly characterized using FT-IR, 1H-NMR, XRD, and TGA. HP-PLLA based nanoparticles encapsulating perfluoropentane (PFP) and salicylic acid were prepared via emulsion-solvent evaporation. Zeta potential and mean diameter were assessed using DLS and TEM. Biocompatibility was evaluated via cell migration, hemolysis, and cytotoxicity assays. Ultrasonic imaging was performed with a dedicated apparatus, while CEST MRI was conducted using a 7.0 T animal scanner. Results: We designed and prepared a novel dual-mode nanoimaging probe SA/PFP@HP-PLLA NPs. PFP enhanced US imaging, while salicylic acid bolstered CEST imaging. With an average size of 74.43 ± 1.12 nm, a polydispersity index of 0.175 ± 0.015, and a surface zeta potential of -64.1 ± 2.11 mV. These NPs exhibit excellent biocompatibility and stability. Both in vitro and in vivo experiments confirmed the SA/PFP@HP-PLLA NP's ability to improve tumor characterization and diagnostic precision. Conclusion: The SA/PFP@HP-PLLA NPs demonstrate promising dual-modality imaging capabilities, indicating their potential for preclinical and clinical use as a contrast agent.

Construction of a Tumor-Targeting Nanobubble with Multiple Scattering Interfaces and its Enhancement of Ultrasound Imaging.

Introduction: Recently, nanobubbles (NBs) have gained significant traction in the field of tumor diagnosis and treatment owing to their distinctive advantages. However, the application of NBs is limited due to their restricted size and singular reflection section, resulting in low ultrasonic reflection. Methods: We synthesized a nano-scale ultrasound contrast agent (IR783-SiO2NPs@NB) by encapsulating SiO2 nanoparticles in an IR783-labeled lipid shell using an improved film hydration method. We characterized its physicochemical properties, examined its microscopic morphology, evaluated its stability and cytotoxicity, and assessed its contrast-enhanced ultrasound imaging capability both in vitro and in vivo. Results: The results show that IR783-SiO2NPs@NB had a "donut-type" composite microstructure, exhibited uniform particle size distribution (637.2 ± 86.4 nm), demonstrated excellent stability (30 min), high biocompatibility, remarkable tumor specific binding efficiency (99.78%), and an exceptional contrast-enhanced ultrasound imaging capability. Conclusion: Our newly developed multiple scattering NBs with tumor targeting capacity have excellent contrast-enhanced imaging capability, and they show relatively long contrast enhancement duration in solid tumors, thus providing a new approach to the structural design of NBs.

Structural and practical identifiability of contrast transport models for DCE-MRI.

Contrast transport models are widely used to quantify blood flow and transport in dynamic contrast-enhanced magnetic resonance imaging. These models analyze the time course of the contrast agent concentration, providing diagnostic and prognostic value for many biological systems. Thus, ensuring accuracy and repeatability of the model parameter estimation is a fundamental concern. In this work, we analyze the structural and practical identifiability of a class of nested compartment models pervasively used in analysis of MRI data. We combine artificial and real data to study the role of noise in model parameter estimation. We observe that although all the models are structurally identifiable, practical identifiability strongly depends on the data characteristics. We analyze the impact of increasing data noise on parameter identifiability and show how the latter can be recovered with increased data quality. To complete the analysis, we show that the results do not depend on specific tissue characteristics or the type of enhancement patterns of contrast agent signal.

Dynamic monitoring soft tissue healing via visualized Gd-crosslinked double network MRI microspheres.

By integrating magnetic resonance-visible components with scaffold materials, hydrogel microspheres (HMs) become visible under magnetic resonance imaging(MRI), allowing for non-invasive, continuous, and dynamic monitoring of the distribution, degradation, and relationship of the HMs with local tissues. However, when these visualization components are physically blended into the HMs, it reduces their relaxation rate and specificity under MRI, weakening the efficacy of real-time dynamic monitoring. To achieve MRI-guided in vivo monitoring of HMs with tissue repair functionality, we utilized airflow control and photo-crosslinking methods to prepare alginate-gelatin-based dual-network hydrogel microspheres (G-AlgMA HMs) using gadolinium ions (Gd (III)), a paramagnetic MRI contrast agent, as the crosslinker. When the network of G-AlgMA HMs degrades, the cleavage of covalent bonds causes the release of Gd (III), continuously altering the arrangement and movement characteristics of surrounding water molecules. This change in local transverse and longitudinal relaxation times results in variations in MRI signal values, thus enabling MRI-guided in vivo monitoring of the HMs. Additionally, in vivo data show that the degradation and release of polypeptide (K2 (SL)6 K2 (KK)) from G-AlgMA HMs promote local vascular regeneration and soft tissue repair. Overall, G-AlgMA HMs enable non-invasive, dynamic in vivo monitoring of biomaterial degradation and tissue regeneration through MRI, which is significant for understanding material degradation mechanisms, evaluating biocompatibility, and optimizing material design.

Modulating Nonlinear Acoustic Response of Phospholipid-Coated Microbubbles with pH for Ultrasound Imaging.

Activatable microbubble contrast agents for contrast-enhanced ultrasound have a potential role for measuring physiologic and pathologic states in deep tissues, including tumor acidosis. In this study, we describe a novel observation of increased harmonic oscillation of phosphatidylcholine microbubbles (PC-MBs) in response to lower ambient pH using a clinical ultrasound scanner. MB echogenicity and nonlinear echoes were monitored at neutral and acidic pH using B-mode and Cadence contrast pulse sequencing (CPS), a harmonic imaging technique at 7.0 and 1.5 MHz. A 3-fold increase in harmonic signal intensity was observed when the pH of PC-MB suspensions was decreased from 7.4 to 5.5 to mimic normal and pathophysiological levels that can be encountered in vivo. This pH-mediated activation is tunable based on the chemical structure and length of phospholipids composing the MB shell. It is also reliant on the presence of phosphate groups, as the use of lipids without phosphate instead of phospholipids completely abrogated this phenomenon. The increased harmonic signal likely is the result of increased MB oscillation caused by a decrease of the interfacial tension induced at a lower pH, altering the lipid conformation. While relative signal changes are interpreted clinically as mostly related to blood flow, pH effects could be significant contributors, particularly when imaging tumors. While our observation can be used clinically, it requires further research to isolate the effect of pH from other variables. These findings could pave the way toward for the development of new smart ultrasound contrast agents that expand the clinical utility of contrast-enhanced ultrasound.

Expression of concern: Gadolinium embedded iron oxide nanoclusters as T1-T2 dual-modal MRI-visible vectors for safe and efficient siRNA delivery.

Expression of concern for 'Gadolinium embedded iron oxide nanoclusters as T1-T2 dual-modal MRI-visible vectors for safe and efficient siRNA delivery' by Xiaoyong Wang et al., Nanoscale, 2013, 5, 8098-8104, https://doi.org/10.1039/C3NR02797J.

Photon-Counting Detector CT: Potential for 75% Reduction in Contrast Medium Amount: A Phantom Study.

This study aimed to evaluate the potential reduction in contrast medium utilization using photon-counting detector computed tomography (PCD-CT). One PCD-CT scan (CT1) and three conventional (non-PCD-CT) CT scans (CT2-CT4) were performed using a multi-energy CT phantom that contained eight rods with different iodine concentrations (0.2, 0.5, 1, 2, 5, 10, 15, and 20 mg/ml). The CT values of the seven groups (CT1 for 40, 50, 60, and 70 keV; and CT2-4) were measured. Noise and contrast-to-noise ratio (CNR) were assessed for the eight rods at various iodine concentrations. CT2 and CT1 (40 keV) respectively required 20 mg/ml and 5 mg/ml of iodine, indicating that a comparable contrast effect could be obtained with approximately one-fourth of the contrast medium amount. The standard deviation values increased at lower energy levels irrespective of the iodine concentration. The CNR exhibited a decreasing trend with lower iodine concentrations, while it remained relatively stable across all iodine levels (40-70 keV). This study demonstrated that virtual monochromatic 40 keV images offer a similar contrast effect with a reduced contrast medium amount when compared to conventional CT systems at 120 kV.

Fe3O4-Cy5.5-trastuzumab magnetic nanoparticles for magnetic resonance/near-infrared imaging targeting HER2 in breast cancer.

This study developed a probe Fe3O4-Cy5.5-trastuzumab with fluorescence and magnetic resonance imaging functions that can target breast cancer with high HER2 expression, aiming to provide a new theoretical method for the diagnosis of early breast cancer. Fe3O4-Cy5.5-trastuzumab nanoparticles were combined with Fe3O4for T2imaging and Cy5.5 for near-infrared imaging, and coupled with trastuzumab for HER2 targeting. We characterized the nanoparticles used transmission electron microscopy, hydration particle size, Zeta potential, UV and Fourier transform infrared spectroscopy, and examined its magnetism, fluorescence, and relaxation rate related properties. CCK-8 and blood biochemistry analysis evaluated the biosafety and stability of the nanoparticles, and validated the targeting ability of Fe3O4-Cy5.5 trastuzumab nanoparticles throughin vitroandin vivocell and animal experiments. Characterization results showed the successful synthesis of Fe3O4-Cy5.5-trastuzumab nanoparticles with a diameter of 93.72 ± 6.34 nm. The nanoparticles showed a T2relaxation rate 42.29 mM-1s-1, magnetic saturation strength of 27.58 emg g-1. Laser confocal and flow cytometry uptake assay showed that the nanoparticles could effectively target HER2 expressed by breast cancer cells. As indicated byin vitroandin vivostudies, Fe3O4-Cy5.5-trastuzumab were specifically taken up and effectively aggregated to tumour regions with prominent NIRF/MR imaging properties. CCK-8, blood biochemical analysis and histological results suggested Fe3O4-Cy5.5-trastuzumab that exhibited low toxicity to major organs and goodin vivobiocompatibility. The prepared Fe3O4-Cy5.5-trastuzumab exhibited excellent targeting, NIRF/MR imaging performance. It is expected to serve as a safe and effective diagnostic method that lays a theoretical basis for the effective diagnosis of early breast cancer. This study successfully prepared a kind of nanoparticles with near-infrared fluorescence imaging and T2imaging properties, which is expected to serve as a new theory and strategy for early detection of breast cancer.

Influence of SPION Surface Coating on Magnetic Properties and Theranostic Profile.

This study aimed to develop multifunctional nanoplatforms for both cancer imaging and therapy using superparamagnetic iron oxide nanoparticles (SPIONs). Two distinct synthetic methods, reduction-precipitation (MR/P) and co-precipitation at controlled pH (MpH), were explored, including the assessment of the coating's influence, namely dextran and gold, on their magnetic properties. These SPIONs were further functionalized with gadolinium to act as dual T1/T2 contrast agents for magnetic resonance imaging (MRI). Parameters such as size, stability, morphology, and magnetic behavior were evaluated by a detailed characterization analysis. To assess their efficacy in imaging and therapy, relaxivity and hyperthermia experiments were performed, respectively. The results revealed that both synthetic methods lead to SPIONs with similar average size, 9 nm. Mössbauer spectroscopy indicated that samples obtained from MR/P consist of approximately 11-13% of Fe present in magnetite, while samples obtained from MpH have higher contents of 33-45%. Despite coating and functionalization, all samples exhibited superparamagnetic behavior at room temperature. Hyperthermia experiments showed increased SAR values with higher magnetic field intensity and frequency. Moreover, the relaxivity studies suggested potential dual T1/T2 contrast agent capabilities for the coated SPpH-Dx-Au-Gd sample, thus demonstrating its potential in cancer diagnosis.

Using Chiral Auxiliaries to Mimic the Effect of Chiral Media on the Structure of Lanthanide(III) Complexes Common in Bioimaging and Diagnostic MRI.

[Ln·DOTA]- complexes and systems derived therefrom are commonly used in MRI and optical bioimaging. These lanthanide(III) complexes are chiral, and, in solution, they are present in four forms, with two sets of enantiomers, with the ligand donors arranged in either a square antiprismatic, SAP, or twisted square antiprismatic geometry, TSAP. This complicated speciation is found in laboratory samples. To investigate speciation in biological media, when Ln·DOTA-like complexes interact with chiral biomolecules, six Eu·DOTA-monoamide complexes were prepared and investigated by using 1D and 2D 1H NMR. To emulate the chirality of biological media, the amide pendant arm was modified with one or two chiral centers. It is known that a chiral center on the DOTA scaffold significantly influences the properties of the system. Here, it was found that chirality much further away from the metal center changes the available conformational space and that both chiral centers and amide cis/trans isomerism may need to be considered─a fact that, for the optically enriched materials, led to the conclusion that eight chemically different forms may need to be considered, instead of the four forms necessary for DOTA. The results reported here clearly demonstrate the diverse speciation that must be considered when correlating an observation to a structure of a lanthanide(III) complex.

Furin-Catalyzed Enhanced Magnetic Resonance Imaging Probe for Differential Diagnosis of Malignant Breast Cancers.

Molecular magnetic resonance imaging (mMRI) of biomarkers is essential for accurate cancer detection in precision medicine. However, the current clinically used contrast agents provide structural magnetic resonance imaging (sMRI) information only and rarely provide mMRI information. Here, a tumor-specific furin-catalyzed nanoprobe (NP) was reported for differential diagnosis of malignant breast cancers (BCs) in vivo. This NP with a compact structure of Fe3O4@Gd-DOTA NPs (FFG NPs) contains an "always-on" T2-weighted MR signal provided by the magnetic Fe3O4 core and a furin-catalyzed enhanced T1-weighted MR signal provided by the Gd-DOTA moiety. The FFG NPs were found to produce an activated T1 signal in the presence of furin catalysis and an "always-on" T2 signal, providing mMRI and sMRI information simultaneously. Ratiometric mMRI:sMRI intensity can be used for differential diagnosis of malignant BCs MDA-MB-231 and MCF-7, where the furin levels relatively differ. The proposed probe not only provides structural imaging but also enables real-time molecular differential visualization of BC through enzymatic activities of cancer tissues.