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A biocompatible macromolecule-conjugated gadolinium chelate complex (PAV 2 -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 T 1 -relaxivity of PAV 2 -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 PAV 2 -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 PAV 2 -EDA-DOTA-Gd and 10–30 min for Gd-DOTA). Preliminary safety experiments, such as cell experiments and tissue sectioning, showed that PAV 2 -EDA-DOTA-Gd had low toxicity and satisfactory biocompatibility. The results of this study indicated that PAV 2 -EDA-DOTA-Gd had high potential as a liver-specific MRI contrast agent. • A macromolecular biocompatible MRI contrast agent was synthesized. • The T 1 -relaxivity of the contrast agent was much higher than that of the current clinical standard. • The contrast agent demonstrated biocompatibility and low toxicity. • The contrast agent targeted the liver, with a longer imaging time and stronger imaging signal than Gd-DOTA. [ABSTRACT FROM AUTHOR]

Tumor microenvironment (TME)-responsive manganese dioxide (MnO 2) nanoparticles as a good T 1 contrast agent could reduce unwanted toxicity and improve the accuracy of cancer detection. Despite these distinct advantages of MnO 2 -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 MnO 2 , leading to facile production of HA-His/MnO 2 nanoparticles with good water-dispersibility and stability under biological conditions. The synthesized HA-His/MnO 2 nanoparticles readily responded to the TME (low pH, high H 2 O 2 , and high glutathione), and they were internalized into SCC7 cells with high CD44 expression. Moreover, the systemically administered HA-His/MnO 2 nanoparticles with biocompatibility were specifically accumulated in tumor tissues, thereby efficiently enhancing T 1 contrast in MRI. Therefore, the HA-His/MnO 2 nanoparticles synthesized herein can be used as a promising T 1 contrast agent for tumor MR imaging. [ABSTRACT FROM AUTHOR]

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 T 1 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 T 1 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. [ABSTRACT FROM AUTHOR]

[Display omitted] Doping Mn (II) ions into iron oxide (IO) as manganese ferrite (MnIO) has been proved to be an effective strategy to improve T 1 relaxivity of IO nanoparticle in recent years; however, the high T 2 relaxivity of MnIO nanoparticle hampers its T 1 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 T 1 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 T 1 relaxivity of 9.1 mM−1s−1 at 3 T magnetic field. Moreover, exclusive engineering the interfacial structure significantly lower the T 2 enhancing effect caused by doped Mn (II) ions, which further limits the impairing of increased T 2 relaxivity to T 1 contrast imaging. IO@MnIO nanoparticles with different shell thicknesses reveal comparable T 1 relaxation rates but obvious lower T 2 relaxivities and r 2 / r 1 ratios to MnIO nanoparticles with similar sizes. The desirable T 1 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 T 1 contrast and a new guidance for designing effective high-performance T 1 contrast agent for early cancer diagnosis. [ABSTRACT FROM AUTHOR]

Accurate diagnosis with secure and target-specific drug delivery improves the success rate in cancer treatment and patient survival outcomes. The development of stimuli-responsive theranostic with the molecular computing ability could address all these criteria at a time. This work attempts to design a multifunctional biocomputing agent that can serve as a secure and target-specific drug carrier and simultaneously act as a molecular logic device. Hence, we developed holmium-doped carbon dot-gelatin nanoparticles (HoCDGNPs) by two-step desolvation methods and used them as fluorescence (FL) imaging and MRI contrast agents with effective pH and Cu2+ ion sensing ability. Furthermore, Boolean algebraic operations (NOR, OR, IMP, and NIMP) are executed on the HoCDGNP system using the FL/magnetic resonance (MR) response in the presence of different inputs (H+, OH–, and Cu2+ ions), and the results are mesmerizing. Moreover, the FL quenching phenomena of HoCDGNPs in the presence of Cu2+ ions by cupric-amine or cupric-carboxylate coordination formation are also exploited in the living HeLa cells. Finally, the resulting system is used for pH-responsive drug delivery of a model anticancer drug (5-fluorouracil), and the release profile is found selective and sustained over the pH range 6–7.4. Thus, it counters the shortcomings associated with the 5-fluorouracil drug administration (short lifetime and poor specificity at high doses). The cellular uptake and cell viability assessment are also accomplished in cancerous and noncancerous cell lines to ensure the acceptability of this multifunctional biocomputing system, and the results are pretty satisfactory. [ABSTRACT FROM AUTHOR]

The size and uniformity of magnetic nanoparticles are essential for biomedical performance. In this study, we successfully controlled the size and uniformity of magnetic nanomaterials by applying gradient magnetic fields during the solvothermal method. This regulation method conforms to the following laws: the size of the synthesized magnetic nanoparticles (MNPs) is smaller when the applied magnetic field is stronger, and the synthesized uniformity is better when the product of the applied field and its gradient is greater. In vitro and in vivo magnetic resonance imaging experiments show that magnetic field treatment resulted in uniform MNPs of 4.5 nm, which can significantly improve the T1 contrast performance. We further propose a dynamic process of field-induced reconfiguration for reverse micelles (re-micelles) to analyze how the gradient magnetic field affects MNP synthesis. [ABSTRACT FROM AUTHOR]

Abstract Manganese oxide (MnO) nanocubes were fabricated and their surface were modified by ligand encapsulation or ligand exchange, to render them water-soluble. And then, MnO formed the hollow structure by etching using acidic solution (phthalate buffer, pH 4.0). Depending on the ligand of the MnO surface, it increases the interaction between MnO and water molecules. Also, the hollow structure of MnO, as well as the ligand, can greatly enhance the accessibility of water molecules to metal ions by surface area-to-volume ratio. These factors provide high R1 relaxation, leading to strong T1 MRI signal. We have confirmed T1-weighted MR contrast effect using 4-kinds of MnO nanocubes (MnOEn, MnOEnHo, MnOEx and MnOExHo). They showed enough a MR contrast effect and biocompatibility. Especially, among them, MnOExHo exhibited high T1 relaxivity (r1) (6.02 mM−1 s−1), even about 1.5 times higher sensitivity than commercial T1 MR contrast agents. In vitro/in vivo studies have shown that MnOExHo provides highly sensitive T1-weighted MR imaging, thereby improving diagnostic visibility at the disease site.

Manganese oxide (MnO) nanocubes were fabricated and their surface were modified by ligand encapsulation or ligand exchange, to render them water-soluble. And then, MnO formed the hollow structure by etching using acidic solution (phthalate buffer, pH 4.0). Depending on the ligand of the MnO surface, it increases the interaction between MnO and water molecules. Also, the hollow structure of MnO, as well as the ligand, can greatly enhance the accessibility of water molecules to metal ions by surface area-to-volume ratio. These factors provide high R1 relaxation, leading to strong T1 MRI signal. We have confirmed T1-weighted MR contrast effect using 4-kinds of MnO nanocubes (MnOEn, MnOEnHo, MnOEx and MnOExHo). They showed enough a MR contrast effect and biocompatibility. Especially, among them, MnOExHo exhibited high T1 relaxivity (r1) (6.02 mM−1 s−1), even about 1.5 times higher sensitivity than commercial T1 MR contrast agents. In vitro/in vivo studies have shown that MnOExHo provides highly sensitive T1-weighted MR imaging, thereby improving diagnostic visibility at the disease site. [ABSTRACT FROM AUTHOR]

Ultrasmall iron oxide nanoparticles (USIONPs) have been recently developed as labeling probes for T2 magnetic resonance imaging contrast agents. However, their use in stem cell tracking has been limited, especially as T1 contrast agents. In this study, we studied the effects of USIONP surface coatings on proliferation, cellular uptake, and multipontency of established and primary neural stem cells (NSCs). USIONPs were functionalized with gluconic acid (GA), tannic acid (TA), and hyaluronic acid (HA) to label the NSCs. All functionalized USIONPs were characterized as T1 contrast agents via relaxivity measurements. Direct functionalization with TA and HA coating promoted NSC proliferation and enhanced cellular uptake in a dose-dependent manner compared to those with GA. Furthermore, HA coating showed enhanced cell proliferation and cellular uptake in primary NSCs depending on the HA molecular weight. Stem cell characteristics were well-maintained, verified by neurosphere formation and gene expression of stemness and differentiation markers. Collectively, we demonstrated that NSC proliferation, cellular uptake, and multipotency can be enhanced using various surface coating strategies of USIONPs. [ABSTRACT FROM AUTHOR]

Precise diagnosis and monitoring of cancer depend on the development of advanced technologies for in vivo imaging. Owing to the merits of outstanding spatial resolution and excellent soft-tissue contrast, the application of magnetic resonance imaging (MRI) in biomedicine is of great importance. Herein, Angiopep-2 (ANG), which can simultaneously help to cross the blood-brain barrier and target the glioblastoma cells, was rationally combined with the 3.3 nm-sized ultra-small iron oxide (Fe3O4) to construct high-performance MRI nanoprobes (Fe3O4-ANG NPs) for glioblastoma diagnosis. The in vitro experiments show that the resultant Fe3O4-ANG NPs not only exhibit favorable relaxation properties and colloidal stability, but also have low toxicity and high specificity to glioblastoma cells, which provide critical prerequisites for the in vivo tumor imaging. Furthermore, in vivo imaging results show that the Fe3O4-ANG NPs exhibit good targeting ability toward subcutaneous and orthotopic glioblastoma model, manifesting an obvious contrast enhancement effect on the T1-weighted MR image, which demonstrates promising potential in clinical application.

Glioblastoma multiforme is the most aggressive form of brain tumor. Early and accurate diagnosis of glioma and its borders is an important step for its successful treatment. One of the promising targets for selective visualization of glioma and its margins is connexin 43 (Cx43), which is highly expressed in reactive astrocytes and migrating glioma cells. The purpose of this study was to synthesize a Gd-based contrast agent conjugated with specific antibodies to Cx43 for efficient visualization of glioma C6 in vivo. We have prepared stable nontoxic conjugates of monoclonal antibody to Cx43 and polylysine-DTPA ligands complexed with Gd(III), which are characterized by higher T1 relaxivity (6.5 mM−1 s−1 at 7 T) than the commercial agent Magnevist® (3.4 mM−1 s−1). Cellular uptake of Cx43-specific T1 contrast agent in glioma C6 cells was more than four times higher than the nonspecific IgG-contrast agent, as detected by flow cytometry and confocal analysis. MRI experiments showed that the obtained agents could markedly enhance visualization of glioma C6 in vivo after their intravenous administration. Significant accumulation of Cx43-targeted contrast agents in glioma and the peritumoral zone led not only to enhanced contrast but also to improved detection of the tumor periphery. Fluorescence imaging confirmed notable accumulation of Cx43-specific conjugates in the peritumoral zone compared with nonspecific IgG conjugates at 24 h after intravenous injection. All these features of Cx43-targeted contrast agents might be useful for more precise diagnosis of glioma and its borders by MRI. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we synthesized hyaluronic acid-conjugated gadolinium (HA-diethylene triamine pentaacetic acid (DTPA)-Gd) and evaluated as hepatocyte-specific magnetic resonance imaging (MRI) contrast agent for the diagnosis of hepatic metastasis. Procedures: We conducted Fourier transform (FT)-IR analysis to determine the conjugation of HA and DTPA and performed cell viability assays using NIH3T3 and FL83B cell lines. We also conducted T1-weighted MRI of HA-DTPA-Gd and gadoxetic acid to compare the paramagnetic properties of both. Results: HA-DTPA-Gd had a higher efficiency in liver MRI compared with the commercially available liver-specific contrast agent ( p < 0.001). HA-DTPA-Gd, which possessed a higher T1 relaxivity, showed excellent capability for the diagnosis of hepatic metastasis through an in vivo MRI study in comparison with gadoxetic acid ( p < 0.001). Conclusion: Based on this study, we believe that HA-DTPA-Gd has promising potential for use as a contrast agent for liver MRI of hepatic metastases. [ABSTRACT FROM AUTHOR]

Precise diagnosis and monitoring of cancer depend on the development of advanced technologies for in vivo imaging. Owing to the merits of outstanding spatial resolution and excellent soft-tissue contrast, the application of magnetic resonance imaging (MRI) in biomedicine is of great importance. Herein, Angiopep-2 (ANG), which can simultaneously help to cross the blood-brain barrier and target the glioblastoma cells, was rationally combined with the 3.3 nm-sized ultra-small iron oxide (Fe 3 O 4 ) to construct high-performance MRI nanoprobes (Fe 3 O 4 -ANG NPs) for glioblastoma diagnosis. The in vitro experiments show that the resultant Fe 3 O 4 -ANG NPs not only exhibit favorable relaxation properties and colloidal stability, but also have low toxicity and high specificity to glioblastoma cells, which provide critical prerequisites for the in vivo tumor imaging. Furthermore, in vivo imaging results show that the Fe 3 O 4 -ANG NPs exhibit good targeting ability toward subcutaneous and orthotopic glioblastoma model, manifesting an obvious contrast enhancement effect on the T 1 -weighted MR image, which demonstrates promising potential in clinical application.

Ultrasmall ferrite nanoparticles (UFNPs) have emerged as powerful magnetic resonance imaging (MRI) T 1 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 Zn x Fe 3- x O 4 @Zn x Mn y Fe 3- x - y O 4 (denoted as Zn x F@Zn x Mn y F) 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 r 1 relaxivity for Zn 0.4 F@Zn 0.4 Mn 0.2 F 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 T 1 nanoprobe for advanced molecular imaging.

Ultra-small-sized iron oxide nanoparticles with good biocompatibility are regarded as promising alternatives for the gadolinium-based contrast agents, which are widely used as a positive contrast agent in magnetic resonance imaging (MRI). However, the current preparation of the iron oxide magnetic nanoparticles with small sizes usually involves organic solvents, increasing the complexity of hydrophilic ligand replacement and reducing the synthesis efficiency. It remains a great challenge to explore new iron oxide nanoparticles with good biocompatibility and a high T 1 contrast effect. Here, we reported a cage-like protein architecture self-assembled by approximately 6-7 BSA (bovine serum albumin) subunits. The BSA nanocage was then used as a biotemplate to synthesize uniformed and monodispersed Fe 2 O 3 @BSA nanoparticles with ultra-small sizes (∼3.5 nm). The Fe 2 O 3 @BSA nanoparticle showed a high r 1 value of 6.8 mM -1 s -1 and a low r 2 / r 1 ratio of 10.6 at a 3 T magnetic field. Compared to Gd-DTPA, the brighter signal and prolonged angiographic effect of Fe 2 O 3 @BSA nanoparticles could greatly benefit steady-state and high-resolution imaging. The further in vivo and in vitro assessments of stability, toxicity, and renal clearance indicated a substantial potential as a T 1 contrast agent in preclinical MRI.

A new strategy for designing contrast agents (CAs) based on geometrical confinement will become a competent way to improve the relaxivity of CAs. Herein, a magnetic resonance imaging (MRI) nanoconstruct is fabricated through loading Gd 2 O 3 nanoparticles into mesoporous carbon nanospheres, followed by conjugation of poly(ethylene glycol) (PEG) and the c(RGDyK) peptide (Gd 2 O 3 @OMCN-PEG-RGD), which could prolong the blood circulation half-life as well as improve the tumor-targeting ability. As a result, the Gd 2 O 3 @OMCN-PEG-RGD exhibits an outstandingly high relaxivity ( r 1 = 68.02 mM -1 s -1 ), which is ∼5.3 times higher than that of Gd 2 O 3 nanoparticles ( r 1 = 12.74 mM -1 s -1 ). Afterward, both the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test and H&E staining show that the Gd 2 O 3 @OMCN-PEG-RGD has wonderful biocompatibility in vitro and in vivo. Moreover, the in vivo MR images indicate that the Gd 2 O 3 @OMCN-PEG-RGD could accumulate in the tumor region more rapidly than Gd 2 O 3 @OMCN-PEG. This study presents a facile method to fabricate an MRI CA with excellent T 1 contrast ability based on geometrical confinement and excellent biocompatibility, which could act as an optimal contender for sensitive in vivo tumor imaging with outstanding targeting ability.

Glioblastoma multiforme is the most aggressive form of brain tumor. Early and accurate diagnosis of glioma and its borders is an important step for its successful treatment. One of the promising targets for selective visualization of glioma and its margins is connexin 43 (Cx43), which is highly expressed in reactive astrocytes and migrating glioma cells. The purpose of this study was to synthesize a Gd-based contrast agent conjugated with specific antibodies to Cx43 for efficient visualization of glioma C6 in vivo. We have prepared stable nontoxic conjugates of monoclonal antibody to Cx43 and polylysine-DTPA ligands complexed with Gd(III), which are characterized by higher T1 relaxivity (6.5 mM(-1) s(-1) at 7 T) than the commercial agent Magnevist® (3.4 mM(-1) s(-1)). Cellular uptake of Cx43-specific T1 contrast agent in glioma C6 cells was more than four times higher than the nonspecific IgG-contrast agent, as detected by flow cytometry and confocal analysis. MRI experiments showed that the obtained agents could markedly enhance visualization of glioma C6 in vivo after their intravenous administration. Significant accumulation of Cx43-targeted contrast agents in glioma and the peritumoral zone led not only to enhanced contrast but also to improved detection of the tumor periphery. Fluorescence imaging confirmed notable accumulation of Cx43-specific conjugates in the peritumoral zone compared with nonspecific IgG conjugates at 24 h after intravenous injection. All these features of Cx43-targeted contrast agents might be useful for more precise diagnosis of glioma and its borders by MRI., (Copyright © 2015 John Wiley & Sons, Ltd.)

Nanoprobes for MRI and optical imaging are demonstrated. Gd@C-dots possess strong fluorescence and can effectively enhance signals on T1 -weighted MR images. The nanoprobes have low toxicity, and, despite a relatively large size, can be efficiently excreted by renal clearance from the host after systemic injection., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)