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.

Relaxivity Enhancement of Hybrid Micelles via Modulation of Water Coordination Numbers for Magnetic Resonance Lymphography.

Considerable efforts have been made to develop nanoparticle-based magnetic resonance contrast agents (CAs) with high relaxivity. The prolonged rotational correlation time (τR) induced relaxivity enhancement is commonly recognized, while the effect of the water coordination numbers (q) on the relaxivity of nanoparticle-based CAs gets less attention. Herein, we first investigated the relationship between T1 relaxivity (r1) and q in manganese-based hybrid micellar CAs and proposed a strategy to enhance the relaxivity by increasing q. Hybrid micelles with different ratios of amphiphilic manganese complex (MnL) and DSPE-PEG2000 were prepared, whose q values were evaluated by Oxygen-17-NMR spectroscopy. Micelles with lower manganese doping density exhibit increased q and enhanced relaxivity, corroborating the conception. In vivo sentinel lymph node (SLN) imaging demonstrates that DSPE-PEG/MnL micelles could differentiate metastatic SLN from inflammatory LN. Our strategy makes it feasible for relaxivity enhancement by modulating q, providing new approaches for the structural design of high-performance hybrid micellar CAs.

[Polyaspartic acid grafted dopamine polymer chelated Fe 3+ for magnetic resonance imaging visual photothermal therapy agent].

This study aims to explore the potential of polyaspartic acid grafted dopamine copolymer (PAsp- g-DA) chelated Fe 3+ for magnetic resonance imaging (MRI) visual photothermal therapy. Polyaspartic acid grafted copolymer of covalently grafted dopamine and polyethylene glycol (PAsp- g-DA/PEG) was obtained by the ammonolysis reaction of poly succinimide (PSI), and then chelated with Fe 3+ in aqueous solution. The relaxivity in vitro, magnetic resonance imaging enhancement in vivo and photothermal conversion effect at 808 nm were investigated. The results showed that polymeric iron coordination had good near-infrared absorption and photothermal conversion properties, good magnetic resonance enhancement effect, and good longitudinal relaxation efficiency under different magnetic field intensities. In summary, this study provides a new magnetic resonance visual photothermal therapeutic agent and a new research idea for the research in related fields.

[Research progress on the fluorescence resonance energy transfer-based polymer micelles as drug carriers].

Polymer micelles formed by self-assembly of amphiphilic polymers are widely used in drug delivery, gene delivery and biosensors, due to their special hydrophobic core/hydrophilic shell structure and nanoscale. However, the structural stability of polymer micelles can be affected strongly by environmental factors, such as temperature, pH, shear force in the blood and interaction with non-target cells, leading to degradations and drug leakage as drug carriers. Therefore, researches on the structural integrity and in vivo distribution of micelle-based carriers are very important for evaluating their therapeutic effect and clinical feasibility. At present, fluorescence resonance energy transfer (FRET) technology has been widely used in real-time monitoring of aggregation, dissociation and distribution of polymer micelles ( in vitro and in vivo). In this review, the polymer micelles, characteristics of FRET technology, structure and properties of the FRET-polymer micelles are briefly introduced. Then, methods and mechanism for combinations of several commonly used fluorescent probes into polymer micelles structures, and progresses on the stability and distribution studies of FRET-polymer micelles ( in vitro and in vivo) as drug carriers are reviewed, and current challenges of FRET technology and future directions are discussed.

Accurate identification of myocardial viability after myocardial infarction with novel manganese chelate-based MR imaging.

We developed a novel manganese (Mn2+ ) chelate for magnetic resonance imaging (MRI) assessment of myocardial viability in acute and chronic myocardial infarct (MI) models, and compared it with Gadolinium-based delay enhancement MRI (Gd3+ -DEMRI) and histology. MI was induced in 14 rabbits by permanent occlusion of the left circumflex coronary artery. Gd3+ -DEMRI and Mn2+ chelate-based delayed enhancement MRI (Mn2+ chelate-DEMRI) were performed at 7 days (acute MI, n = 8) or 8 weeks (chronic MI, n = 6) after surgery with sequential injection of 0.15 mmol/kg Gd3+ and Mn2+ chelate. The biodistribution of Mn2+ in tissues and blood was measured at 1.5 and 24 h. Blood pressure, heart rate (HR), left ventricular (LV) function, and infarct fraction (IF) were analyzed, and IF was compared with the histology. The Mn2+ chelate group maintained a stable hemodynamic status during experiment. For acute and chronic MI, all rabbits survived without significant differences in HR or LV function before and after injection of Mn2+ chelate or Gd3+ (p > 0.05). Mn2+ chelate mainly accumulated in the kidney, liver, spleen, and heart at 1.5 h, with low tissue uptake and urine residue at 24 h after injection. In the acute MI group, there was no significant difference in IF between Mn2+ chelate-DEMRI and histology (22.92 ± 2.21% vs. 21.79 ± 2.25%, respectively, p = 0.87), while Gd3+ -DEMRI overestimated IF, as compared with histology (24.54 ± 1.73%, p = 0.04). In the chronic MI group, there was no significant difference in IF between the Mn2+ chelate-DEMRI, Gd3+ -DEMRI, and histology (29.50 ± 11.39%, 29.95 ± 9.40%, and 29.00 ± 10.44%, respectively, p > 0.05), and all three were well correlated (r = 0.92-0.96, p < 0.01). We conclude that the use of Mn2+ chelate-DEMRI is reliable for MI visualization and identifies acute MI more accurately than Gd3+ -DEMRI.

Radiomics model of contrast-enhanced computed tomography for predicting the recurrence of acute pancreatitis.

OBJECTIVES: To predict the recurrence of acute pancreatitis (AP) by constructing a radiomics model of contrast-enhanced computed tomography (CECT) at AP first attack. METHODS: We retrospectively enrolled 389 first-attack AP patients (271 in the primary cohort and 118 in the validation cohort) from three tertiary referral centers; 126 and 55 patients endured recurrent attacks in each cohort. Four hundred twelve radiomics features were extracted from arterial and venous phase CECT images, and clinical characteristics were gathered to develop a clinical model. An optimal radiomics signature was chosen using a multivariable logistic regression or support vector machine. The radiomics model was developed and validated by incorporating the optimal radiomics signature and clinical characteristics. The performance of the radiomics model was assessed based on its calibration and classification metrics. RESULTS: The optimal radiomics signature was developed based on a multivariable logistic regression with 10 radiomics features. The classification accuracy of the radiomics model well predicted the recurrence of AP for both the primary and validation cohorts (87.1% and 89.0%, respectively). The area under the receiver operating characteristic curve (AUC) of the radiomics model was significantly better than that of the clinical model for both the primary (0.941 vs. 0.712, p = 0.000) and validation (0.929 vs. 0.671, p = 0.000) cohorts. Good calibration was observed for all the models (p > 0.05). CONCLUSIONS: The radiomics model based on CECT performed well in predicting AP recurrence. As a quantitative method, radiomics exhibits promising performance in terms of alerting recurrent patients to potential precautions. KEY POINTS: • The incidence of recurrence after an initial episode of acute pancreatitis is high, and quantitative methods for predicting recurrence are lacking. • The radiomics model based on contrast-enhanced computed tomography performed well in predicting the recurrence of acute pancreatitis. • As a quantitative method, radiomics exhibits promising performance in terms of alerting recurrent patients to the potential need to take precautions.

Lobe-Based Hepatic Uptake Index of Gd-EOB-DTPA on Contrast-Enhanced MRI to Quantitatively Discriminate between Compensated and Decompensated Hepatitis B-Related Cirrhosis.

Purpose: To use hepatic uptake index (HUI) of liver lobes on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) to discriminate between patients with hepatitis B-related cirrhosis in compensated and decompensated statuses. Methods: Forty-four consecutive patients with hepatitis B-related cirrhosis who underwent Gd-EOB-DTPA-enhanced MRI were divided into compensated and decompensated statuses based on clinical evaluation. Volume and signal intensity of individual lobes were retrospectively measured to calculate HUI of the right liver lobe (RHUI), medial (MHUI) and lateral (LHUI) left liver lobes, and caudate lobe (CHUI). Spearman's rank correlation analyses were performed to evaluate relationships of lobe-based HUI with Child-Pugh and model for end-stage liver disease (MELD) scoring system scores in compensated and decompensated statuses. The Mann-Whitney U-test was used to compare the lobe-based HUI between compensated and decompensated statuses. The performance of lobe-based HUI in distinguishing cirrhosis was evaluated using receiver operating characteristic (ROC) analysis, and the area under the ROC curve (AUC) was calculated as a measure of accuracy. Delong's method was used for statistical analysis to elucidate which HUI is optimal. Results: Compensated and decompensated liver cirrhosis were confirmed in 25 (56.82%) and 19 (43.18%) patients, respectively. According to Spearman's rank correlation analysis, RHUI, MHUI, LHUI, and CHUI were all significantly associated with Child-Pugh and MELD scores (all P values <0.05). Receiver operating characteristic analysis demonstrated that among all lobe-based HUI parameters, RHUI could best perform the previous discrimination with a cut-off of 485.73 and obtain an AUC of 0.867. The AUC of RHUI improved and was significantly different from that of MHUI, LHUI, and CHUI (P = 0.03, P = 0.007, and P < 0.001, respectively, Delong's test). Conclusions: The RHUI could help quantitatively discriminate hepatitis B-related cirrhosis between compensated and decompensated statuses.

MRI-guided photothermal/photodynamic immune activation combined with PD-1 inhibitor for the multimodal combination therapy of melanoma and metastases.

Non-invasive image-guided precise photothermal/photodynamic therapy (PTT/PDT) has been proven to be an effective local treatment modality but incompetent against metastases. Hence, the combination of local PTT/PDT and systemic immunotherapy would be a promising strategy for tumor eradication. Herein, a magnetic resonance imaging (MRI)-visualized PTT/PDT agent (SIDP NMs) was constructed, and the efficacy of its multimodal combination with a programmed cell death 1 (PD-1) inhibitor in the treatment of melanoma and metastases was studied. Due to the hydrophobic encapsulation of indocyanine green within the micellar core, SIDP NMs exhibited excellent photothermal/photodynamic properties and stability under an 808 nm near-infrared laser. In vitro cell experiments showed that SIDP NMs had a good killing effect. After incubating with B16-F10 cells for 24 h and irradiating with an 808-nm laser for 10 min, cell viability decreased significantly. Magnetic resonance imaging experiments in melanoma-bearing mice have shown that the dynamic distribution of SIDP NMs in tumor tissue could be monitored by T2WI and T2-MAP non-invasively due to the presence of superparamagnetic iron oxide nanocrystal in SIDP NMs. When the 808 nm laser was irradiated at the maximum focusing time point shown by MRI, the temperature of the tumor area rapidly increased from 32°C to 60.7°C in 5 min. In mouse melanoma ablation and distant tumor immunotherapy studies, SIDP NMs provided excellent MRI-guided PTT/PDT results and, when combined with PD-1 inhibitor, have great potential to cure primary tumors and eradicate metastases.

In situ self-assembly of amphiphilic dextran micelles and superparamagnetic iron oxide nanoparticle-loading as magnetic resonance imaging contrast agents.

Polymeric micelles have long been considered as promising nanocarrier for hydrophobic drugs and imaging probes, due to their nanoscale particle size, biocompatibility and ability to loading reasonable amount of cargoes. Herein, a facile method for dextran micelles preparation was developed and their performance as carriers of superparamagnetic iron oxide (SPIO) nanocrystals was evaluated. Amphiphilic dextran (Dex-g-OA) was synthesized via the Schiff base reactions between oxidized dextran and oleylamine, and self-assembled in situ into nano-size micelles in the reaction systems. The self-assembling behaviors of the amphiphilic dextran were identified using fluorescence resonance energy transfer technique by detection the energy transfer signal between the fluorophore pairs, Cy5 and Cy5.5. Hydrophobic SPIO nanoparticles (Fe3O4 NPs) were successfully loaded into the dextran micelles via the in situ self-assembly process, leading to a series of Fe3O4 NPs-loaded micelle nanocomposites (Fe3O4@Dex-g-OA) with good biocompatibility, superparamagnetism and strongly enhanced T 2 relaxivity. At the magnetic field of 0.5 T, the Fe3O4@Dex-g-OA nanocomposite with particle size of 116.2 ± 53.7 nm presented a higher T 2 relaxivity of 327.9 mM Fe - 1 ·s-1. The prepared magnetic nanocomposites hold the promise to be used as contrast agents in magnetic resonance imaging.

Superparamagnetic iron oxide nanoparticles target BxPC-3 cells and silence MUC4 for the treatment of pancreatic cancer.

PURPOSE: Superparamagnetic iron oxide nanoparticles (SPION) are excellent magnetic resonance imaging (MRI) contrast agents. Mucin 4 (MUC4) acts as pancreatic cancer (PC) tumor antigen and influences PC progression. Small interfering RNAs (siRNAs) are used as a gene-silencing tool to treat a variety of diseases. METHODS: We designed a therapeutic probe based on polyetherimide-superparamagnetic iron oxide nanoparticles (PEI-SPION) combined with siRNA nanoprobes (PEI-SPION-siRNA) to assess the contrast in MRI. The biocompatibility of the nanocomposite, and silencing of MUC4 were characterized and evaluated. RESULTS: The prepared molecular probe had a particle size of 61.7 ± 18.5 nm and a surface of 46.7 ± 0.8mV and showed good biocompatibility in vitro and T2 relaxation efficiency. It can also load and protect siRNA. PEI-SPION-siRNA showed a good silencing effect on MUC4. CONCLUSION: PEI-SPION-siRNA may be beneficial as a novel theranostic tool for PC.

Ultra-small superparamagnetic iron oxide nanoparticles for intra-articular targeting of cartilage in early osteoarthritis.

Early diagnosis of osteoarthritis (OA) is critical for effective cartilage repair. However, lack of blood vessels in articular cartilage poses a barrier to contrast agent delivery and subsequent diagnostic imaging. To address this challenge, we proposed to develop ultra-small superparamagnetic iron oxide nanoparticles (SPIONs, 4 nm) that can penetrate into the matrix of articular cartilage, and further modified with the peptide ligand WYRGRL (particle size, 5.9 nm), which allows SPIONs to bind to type II collagen in the cartilage matrix and increase the retention of probes. Type II collagen in the cartilage matrix is gradually lost with the progression of OA, consequently, the binding of peptide-modified ultra-small SPIONs to type II collagen in the OA cartilage matrix is less, thus presenting different magnetic resonance (MR) signals in OA group from the normal ones. By introducing the AND logical operation, damaged cartilage can be differentiated from the surrounding normal tissue on T1 and T2 AND logical map of MR images, and this was also verified in histology studies. Overall, this work provides an effective strategy for delivering nanosized imaging agents to articular cartilage, which could potentially be used to diagnosis joint-related diseases such as osteoarthritis.

Dopamine multivalent-modified polyaspartic acid for MRI-guided near-infrared photothermal therapy.

Nanophotothermal agents that provide efficient and precise treatment at tumor sites are attracting increasing attention in biomedicine. In particular, the method combination of nanophotothermal agents and magnetic resonance imaging (MRI) shows great promise for biomedical therapeutic applications. Herein, a simple nanophotothermal agent with dopamine multivalent-modified polyaspartic acid chelated superparamagnetic iron oxide (SPIO) and ferric ion (SPIO@PAsp-DAFe/PEG) was developed for MRI-guided near-infrared photothermal therapy (PTT). SPIO@PAsp-DAFe/PEG was random SPIO nanocluster with good water solubility, had a diameter of 57.8 ± 7.8 nm in dynamic light scattering, negatively charged surface (zeta potential = -11 mV), exhibited good stability and outstanding photothermal conversion efficiency (35.4%) and produced superior magnetic resonance enhanced imaging. In the experiment with tumor-bearing mice, the MRI not only monitored the accumulation of SPIO@PAsp-DAFe/PEG nanocomposites enhanced by near-infrared irradiation after intravenous administration but also determined the appropriate time window for PTT. With the use of MRI-guided near-infrared therapy, the SPIO@PAsp-DAFe/PEG nanocomposites provided excellent therapeutic effects, confirming their great potential as effective MRI/PTT therapeutic agents.

Gadolinium(III) Complex-Backboned Branched Polymers as Imaging Probes for Contrast-Enhanced Magnetic Resonance Angiography.

Compared to traditional branched polymers with Gd(III) chelates conjugated on their surface, branched polymers with Gd(III) chelates as the internal skeleton are considered to be a reasonable strategy for preparing efficient magnetic resonance imaging contrast agents. Herein, the Gd(III) ligand DOTA was chosen as the internal skeleton; four different molecular weights (3.5, 5.3, 8.6, and 13.1 kDa) and degrees of branching poly-DOTA branched polymers (P1, P2, P3, and P4) were synthesized by a simple "A2 + B4"-type one-pot polymerization. The Gd(III) chelates of these poly-DOTA branched polymers (P1-Gd, P2-Gd, P3-Gd, and P4-Gd) display excellent kinetic stability, which is significantly higher than those of linear Gd-DTPA and cyclic Gd-DOTA-butrol and slightly lower than that of cyclic Gd-DOTA. The T1 relaxivities of P1-Gd, P2-Gd, P3-Gd, and P4-Gd are 29.4, 38.7, 44.0, and 47.9 Gd mM-1 s-1, respectively, at 0.5 T, which are about 6-11 times higher than that of Gd-DOTA (4.4 Gd mM-1 s-1). P4-Gd was selected for in vivo magnetic resonance angiography (MRA) because of its high kinetic stability, T1 relaxivity, and good biosafety. The results showed excellent MRA effect, sensitive detection of vascular stenosis, and prolonged observation window as compared to Gd-DOTA. Overall, Gd(III) chelates of poly-DOTA branched polymers are good candidates of MRI probes, providing a unique design strategy in which Gd chelation can occur at both the interior and surface of the poly-DOTA branched polymers, resulting in excellent relaxivity enhancement. In vivo animal MRA studies of the probe provide possibilities in discovering small vascular pathologies.

Ultra-small manganese dioxide nanoparticles with high T1 relaxivity for magnetic resonance angiography.

Gadolinium (Gd)-based contrast agents (CAs) for clinical magnetic resonance imaging are facing the problems of low longitudinal relaxivity (r1) and toxicity caused by gadolinium deposition. Manganese-based small molecule complexes and manganese oxide nanoparticles (MONs) are considered as potential alternatives to Gd-based CAs due to their better biocompatibility, but their relatively low r1 values and complicated synthesis routes slow down their clinical translation. Herein, we presented a facile one-step co-precipitation method to prepare MONs using poly(acrylic acid) (PAA) as a coating agent (MnO2/PAA NPs), which exhibited good biocompatibility and high r1 values. A series of MnO2/PAA NPs with different particle sizes were prepared and the relationship between the particle size and r1 was studied, revealing that the MnO2/PAA NPs with a particle size of 4.9 nm exhibited higher r1. The finally obtained MnO2/PAA NPs had a high r1 value (29.0 Mn mM-1 s-1) and a low r2/r1 ratio (1.8) at 1.5 T, resulting in a strong T1 contrast enhancement. In vivo magnetic resonance angiography with Sprague-Dawley (SD) rats further proved that the MnO2/PAA NPs showed better angiographic performance at low-dosage administration than commercial Gadovist® (Gd-DO3A-Butrol). Moreover, the MnO2/PAA NPs could be rapidly cleared out after imaging, which effectively minimized the toxic side effects. The MnO2/PAA NPs are promising candidates for MR imaging of vascular diseases.

Tracking tumor cells in lymphatics in a mice xenograft model by magnetic resonance imaging.

To enrich our understanding of the mechanism of tumor lymphatic metastasis, we developed a model system for tracking metastatic tumor cells in the lymphatic system with cellular magnetic resonance imaging (MRI) in live mice to observe the interaction between tumor cells and the lymphatic system. Nude mice were inoculated subcutaneously with superparamagnetic iron oxide (SPIO)-labeled and unlabeled LOVO cells in the foot pad, groin, or axillary area. Serial 7 T MRI of the tumors and surrounding regions was performed in the following 2 weeks. After imaging, tumor tissues and regional lymph nodes were collected and subjected to immunohistologic analysis. T2/T2*-weighted MRIs showed the primary tumor growth and the draining lymphatic architecture, as well as the SPIO-labeled tumor cells metastasized into the regional lymph node at 8 days. MRIs also revealed information on sentinel lymph node mapping with high-resolution anatomic information. Histologic findings confirmed the in vivo MRI results and revealed lymphangiogenesis, angiogenesis, infiltration of macrophages, and expression of vascular endothelial growth factor C in tumor and draining lymph nodes as well. This technology provides a powerful tool for tracking SPIO-labeled cancer cells in the lymphatics by cellular MRI. There was a close relationship between tumor lymphatic metastasis and lymphangiogenesis.

T 1-T 2 dual-modal magnetic resonance contrast-enhanced imaging for rat liver fibrosis stage.

The development of an effective method for staging liver fibrosis has always been a hot topic of research in the field of liver fibrosis. In this paper, PEGylated ultrafine superparamagnetic iron oxide nanocrystals (SPIO@PEG) were developed for T 1-T 2 dual-modal contrast-enhanced magnetic resonance imaging (MRI) and combined with Matrix Laboratory (MATLAB)-based image fusion for staging liver fibrosis in the rat model. Firstly, SPIO@PEG was synthesized and characterized with physical and biological properties as a T 1-T 2 dual-mode MRI contrast agent. Secondly, in the subsequent MR imaging of liver fibrosis in rats in vivo, conventional T 1 and T 2-weighted imaging, and T 1 and T 2 mapping of the liver pre- and post-intravenous administration of SPIO@PEG were systematically collected and analyzed. Thirdly, by creative design, we fused the T 1 and T 2 mapping images by MATLAB and quantitively measured each rat's hepatic fibrosis positive pixel ratio (PPR). SPIO@PEG was proved to have an ultrafine core size (4.01 ± 0.16 nm), satisfactory biosafety and T 1-T 2 dual-mode contrast effects under a 3.0 T MR scanner (r 2/r 1 = 3.51). According to the image fusion results, the SPIO@PEG contrast-enhanced PPR shows significant differences among different stages of liver fibrosis (P < 0.05). The combination of T 1-T 2 dual-modal SPIO@PEG and MATLAB-based image fusion technology could be a promising method for diagnosing and staging liver fibrosis in the rat model. PPR could also be used as a non-invasive biomarker to diagnose and discriminate the stages of liver fibrosis.

PEGylated amphiphilic polymeric manganese(II) complexes as magnetic resonance angiographic agents.

Currently, the most commonly used clinical magnetic resonance imaging (MRI) contrast agents, Gd(III) chelates, have been found to be associated with nephrogenic systemic fibrosis (NSF) in renally compromised patients. Toxicity concerns related to Gd(III)-based agents prompted intensive research toward the development of safe, efficient, and long-cycle non-Gd contrast agents. Herein, three amphiphilic polymeric manganese (Mn) ligands (mPEG1k-P(L-a-HMDI)-mPEG1k, mPEG2k-P(L-a-HMDI)-mPEG2k and mPEG4k-P(L-a-HMDI)-mPEG4k) were synthesized, and then end-capped respectively with different molecular weights of polyethylene glycol monomethyl ether (mPEG 1 kD, 2 kD and 4 kD) to obtain amphiphilic polymer Mn ligands. After being chelated with Mn(II), these amphiphilic polymer Mn complexes show significantly higher T1 relaxivity than the small molecule Mn complex (MnL) at 0.5 T, 1.5 T and 3.0 T magnetic fields, respectively. Then, mPEG2k-P(MnL-a-HMDI)-mPEG2k with relatively high T1 relaxivities (23.2, 14.4 and 9.7 mM-1s-1 at 0.5 T, 1.5 T and 3.0 T, respectively), low CMC (4.7 mg L-1), reasonable size (48 nm) and excellent stability among these three polymer Mn complexes was selected for in vivo MR imaging of vascular vessels. The results suggest that mPEG2k-P(MnL-a-HMDI)-mPEG2k has an excellent and relatively long time-window vascular enhancement effect even at a low dose of 0.05 mmol Mn kg-1 BW, and could play a role in the diagnosis of vascular diseases (0.1 mmol Mn kg-1 BW). Therefore, mPEG2k-P(MnL-a-HMDI)-mPEG2k may be considered as a potential blood pool contrast agent.

Cisplatin and paclitaxel co-delivery nanosystem for ovarian cancer chemotherapy.

We have designed and developed an effective drug delivery system using biocompatible polymer of poly (ethylene glycol)-polyaspartic acid (mPEG-PAsp) for co-loading the chemotherapy drugs paclitaxel (PTX) and cisplatin (CP) in one nano-vehicle. This study aimed to improve the anti-cancer efficacy of combinations of chemotherapy drugs and reduce their side effects. mPEG-PAsp-(PTX/Pt) nano-micelles disperse well in aqueous solution and have a narrow size distribution (37.8 ± 3.2 nm) in dynamic light scattering (DLS). Drug release profiles found that CP released at pH 5.5 was significantly faster than that at pH 7.4. MPEG-PAsp-(PTX/Pt) nano-micelles displayed a significantly higher tumor inhibitory effect than mPEG-PAsp-PTX nano-micelles when the polymer concentrations reached 50 µg/mL. Our data indicated that polymer micelles of mPEG-PAsp loaded with the combined drug exert synergistic anti-tumor efficacy on SKOV3 ovarian cells via different action mechanisms. Results from our studies suggested that mPEG-PAsp-(PTX/Pt) nano-micelles are promising alternatives for carrying and improving the delivery of therapeutic drugs with different water solubilities.

Mn(II) Complex of Lipophilic Group-Modified Ethylenediaminetetraacetic Acid (EDTA) as a New Hepatobiliary MRI Contrast Agent.

Liver-specific contrast agents (CAs) can improve the Magnetic resonance imaging (MRI) detection of focal and diffuse liver lesions by increasing the lesion-to-liver contrast. A novel Mn(II) complex, Mn-BnO-TyrEDTA, with a lipophilic group-modified ethylenediaminetetraacetic acid (EDTA) structure as a ligand to regulate its behavior in vivo, is superior to Gd-EOB-DTPA in terms of a liver-specific MRI contrast agent. An MRI study on mice demonstrated that Mn-BnO-TyrEDTA can be rapidly taken up by hepatocytes with a combination of hepatobiliary and renal clearance pathways. Bromosulfophthalein (BSP) inhibition imaging, biodistribution, and cellular uptake studies confirmed that the mechanism of hepatic targeting of Mn-BnO-TyrEDTA is the hepatic uptake of the amphiphilic anion contrast agent mediated by organic anion transporting polypeptides (OATPs) expressed by functional hepatocytes.

Application of contrast-enhanced CT radiomics in prediction of early recurrence of locally advanced oesophageal squamous cell carcinoma after trimodal therapy.

BACKGROUND: Early recurrence of oesophageal squamous cell carcinoma (SCC) is defined as recurrence after surgery within 1 year, and appears as local recurrence, distant recurrence, and lymph node positive and disseminated recurrence. Contrast-enhanced computed tomography (CECT) is recommended for diagnosis of primary tumor and initial staging of oesophageal SCC, but it cannot be used to predict early recurrence. It is reported that radiomics can help predict preoperative stages of oesophageal SCC, lymph node metastasis before operation, and 3-year overall survival of oesophageal SCC patients following chemoradiotherapy by extracting high-throughput quantitative features from CT images. This study aimed to develop models based on CT radiomics and clinical features of oesophageal SCC to predict early recurrence of locally advanced cancer. METHODS: We collected electronic medical records and image data of 197 patients with confirmed locally advanced oesophageal SCC. These patients were randomly allocated to 137 patients in the training cohort and 60 in the test cohort. 352 radiomics features were extracted by delineating region-of-interest (ROI) around the lesion on CECT images and clinical signature was generated by medical records. The radiomics model, clinical model, the combined model of radiomics and clinical features were developed by radiomics features and/or clinical characteristics. Predicting performance of the three models was assessed with area under receiver operating characteristic curve (AUC), accuracy and F-1 score. RESULTS: Eleven radiomics features and/or six clinical signatures were selected to build prediction models related to recurrence of locally advanced oesophageal SCC after trimodal therapy. The AUC of integration of radiomics and clinical models was better than that of radiomics or clinical model for the training cohort (0.821 versus 0.754 or 0.679, respectively) and for the validation cohort (0.809 versus 0.646 or 0.658, respectively). Integrated model of radiomics and clinical features showed good performance in predicting early recurrence of locally advanced oesophageal SCC for both the training and validation cohorts (accuracy = 0.730 and 0.733, and F-1score = 0.730 and 0.778, respectively). CONCLUSIONS: The integrated model of CECT radiomics and clinical features may be a potential imaging biomarker to predict early recurrence of locally advanced oesophageal SCC after trimodal therapy.