Optical and magnetic resonance imaging of cell death and platelet activation using annexin a5-functionalized quantum dots

A quantum-dot-based nanoparticle is presented, allowing visualization of cell death and activated platelets with fluorescence imaging and MRI. The particle exhibits intense fluorescence and a large MR relaxivity (r1) of 3000-4500 mM-1 s-1 per nanoparticle due to a newly designed construct increasing the gadolinium-DTPA load. The nanoparticle is suitable for both anatomic and subcellular imaging of structures in the vessel wall and is a promising bimodal contrast agent for future in vivo imaging studies.     

Highly water-dispersible PEG surface modified ultra small superparamagnetic iron oxide nanoparticles useful for target-specific biomedical applications

For the application of superparamagnetic iron oxide nanoparticles in biomedical fields for target-specific purposes, they should be ultra small in diameter. We developed a simple one-step synthesis of surface modified ultra small superparamagnetic iron oxide nanoparticles (USPIONs) with an average particle diameter of 1.7?nm in a polar organic solvent. Polyethylene glycol diacid (PEG) surface modified USPIONs synthesized in triethylene glycol were nearly monodisperse in diameter and highly water-dispersible. The PEG surface modified USPIONs were tested for use as magnetic resonance (MR) contrast agents. They had a low r(2)/r(1) relaxivity ratio of 3.4 (r(1) = 4.46 and r(2) = 15.01?mM(-1)?s(-1)) and showed clear dose-dependent T(1) and T(2) map images, indicating that they will be useful as both target-specific T(1) and T(2) MR contrast agents due to their ultra small size.     

Synthesis and characterization of PVP-coated large core iron oxide nanoparticles as an MRI contrast agent

The purpose of this study was to synthesize biocompatible polyvinylpyrrolidone (PVP)-coated iron oxide (PVP-IO) nanoparticles and to evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The PVP-IO nanoparticles were synthesized by a thermal decomposition method and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and a superconducting quantum interface device (SQUID). The core size of the particles is about 8-10 nm and the overall size is around 20-30 nm. The measured r(2) (reciprocal of T(2) relaxation time) and r2? (reciprocal of T2? relaxation time) are 141.2 and 338.1 (s mM)(-1), respectively. The particles are highly soluble and stable in various buffers and in serum. The macrophage uptake of PVP-IO is comparable to that of Feridex as measured by a Prussian blue iron stain and phantom study. The signal intensity of a rabbit liver was effectively reduced after intravenous administration of PVP-IO. Therefore PVP-IO nanoparticles are potentially useful for T(2)-weighted MR imaging.     

Manganese Doped Fluorescent Paramagnetic Nanocrystals for Dual‐Modal Imaging

In this work, dual‐modal (fluorescence and magnetic resonance) imaging capabilities of water‐soluble, low‐toxicity, monodisperse Mn‐doped ZnSe nanocrystals (NCs) with a size (6.5 nm) below the optimum kidney cutoff limit (10 nm) are reported. Synthesizing Mn‐doped ZnSe NCs with varying Mn²⁺ concentrations, a systematic investigation of the optical properties of these NCs by using photoluminescence (PL) and time resolved fluorescence are demonstrated. The elemental properties of these NCs using X‐ray photoelectron spectroscopy and inductive coupled plasma‐mass spectroscopy confirming Mn²⁺ doping is confined to the core of these NCs are also presented. It is observed that with increasing Mn²⁺ concentration the PL intensity first increases, reaching a maximum at Mn²⁺ concentration of 3.2 at% (achieving a PL quantum yield (QY) of 37%), after which it starts to decrease. Here, this high‐efficiency sample is demonstrated for applications in dual‐modal imaging. These NCs are further made water‐soluble by ligand exchange using 3‐mercaptopropionic acid, preserving their PL QY as high as 18%. At the same time, these NCs exhibit high relaxivity (≈2.95 mM^?1 s^?1) to obtain MR contrast at 25 °C, 3 T. Therefore, the Mn²⁺ doping in these water‐soluble Cd‐free NCs are sufficient to produce contrast for both fluorescence and magnetic resonance imaging techniques.     

Gadonanotubes as ultrasensitive pH-smart probes for magnetic resonance imaging

With their nanoscalar, superparamagnetic Gd(3+)-ion clusters (1 x 5 nm) confined within ultrashort (20-80 nm) single-walled carbon nanotube capsules, gadonanotubes are high-performance T1-weighted contrast agents for magnetic resonance imaging (MRI). At 1.5 T, 37 degrees C, and pH 6.5, the r1 relaxivity (ca. 180 mM(-1) s(-1) per Gd(3+) ion) of gadonanotubes is 40 times greater than any current Gd(3+) ion-based clinical agent. Herein, we report that gadonanotubes are also ultrasensitive pH-smart probes with their r1/pH response from pH 7.0-7.4 being an order of magnitude greater than for any other MR contrast agent. This result suggests that gadonanotubes might be excellent candidates for the development of clinical agents for the early detection of cancer where the extracellular pH of tumors can drop to pH=7 or below. In the present study, gadonanotubes have also been shown to maintain their integrity when challenged ex vivo by phosphate-buffered saline solution, serum, heat, and pH cycling.     

Self-fluorescence of chemically crosslinked MRI nanoprobes to enable multimodal imaging of therapeutic cells

Old chemistry for novel materials: Self-fluorescent high-relaxivity T(2)-weighted magnetic resonance imaging (MRI) contrast agents are produced. They are a novel type of MR/optical dual-modality in vivo imaging nanoprobe using glutaraldehyde crosslinking chemistry, and they are used to label and monitor therapeutic cells both in vitro and in vivo.     

Hyperbranched Conjugated Polyelectrolyte for Dual‐modality Fluorescence and Magnetic Resonance Cancer Imaging

Herein is reported the synthesis of gadolinium ion (Gd(III))‐chelated hyperbranched conjugated polyelectrolyte (HCPE‐Gd) and its application in fluorescence and magnetic resonance (MR) dual imaging in live animals. The synthesized HCPE‐Gd forms nanospheres with an average diameter of ～42 nm measured by laser light scattering and a quantum yield of 10% in aqueous solution. The absorption spectrum of HCPE‐Gd has two maxima at 318 and 417 nm, and its photoluminescence maximum centers at 591 nm. Confocal laser scanning microscopy studies indicate that the HCPE‐Gd is internalized in MCF‐7 cancer cell cytoplasm with good photostability and low cytotoxicity. Further fluorescence and MR imaging studies on hepatoma H₂₂ tumor‐bearing mouse model reveal that HCPE‐Gd can serve as an efficient optical/MR dual‐modal imaging nanoprobe for in vivo cancer diagnosis.     

Biodegradable Polysilsesquioxane Nanoparticles as Efficient Contrast Agents for Magnetic Resonance Imaging

Polysilsesquioxane (PSQ) nanoparticles are crosslinked homopolymers formed by condensation of functionalized trialkoxysilanes, and provide an interesting platform for developing biologically and biomedically relevant nanomaterials. In this work, the design and synthesis of biodegradable PSQ particles with extremely high payloads of paramagnetic Gd(III) centers is explored, for use as efficient contrast agents for magnetic resonance imaging (MRI). Two new bis(trialkoxysilyl) derivatives of Gd(III) diethylenetriamine pentaacetate (Gd‐DTPA) containing disulfide linkages are synthesized and used to form biodegradable Gd‐PSQ particles by base‐catalyzed condensation reactions in reverse microemulsions. The Gd‐PSQ particles, PSQ‐ 1 and PSQ‐ 2 , carry 53.8 wt% and 49.3 wt% of Gd‐DTPA derivatives, respectively. In addition, the surface carboxy groups on the PSQ‐ 2 particles can be modified with polyethylene glycol (PEG) and the anisamide (AA) ligand to enhance biocompatibility and cell uptake, respectively. The Gd‐PSQ particles are readily degradable to release the constituent Gd(III) chelates in the presence of endogenous reducing agents such as cysteine and glutathione. The MR relaxivities of the Gd‐PSQ particles are determined using a 3T MR scanner, with r₁ values ranging from 5.9 to 17.8 mMs^?1 on a per‐Gd basis. Finally, the high sensitivity of the Gd‐PSQ particles as T₁‐weighted MR contrast agents is demonstrated with in vitro MR imaging of human lung and pancreatic cancer cells. The enhanced efficiency of the anisamide‐functionalized PSQ‐ 2 particles as a contrast agent is corroborated by both confocal laser scanning microscopy imaging and ICP‐MS analysis of Gd content in vitro.     

A Self‐Assembled Biocompatible Nanoplatform for Multimodal MR/Fluorescence Imaging Assisted Photothermal Therapy and Prognosis Analysis

The need for better imaging assisted cancer therapy calls for new biocompatible agents with excellent imaging and therapeutic capabilities. This study successfully fabricates albumin‐cooperated human serum albumin (HSA)‐GGD‐ICG nanoparticles (NPs), which are comprised of a magnetic resonance (MR) contrast agent, glycyrrhetinic‐acid‐modified gadolinium (III)‐1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetate (GGD), and a fluorescence (FL) dye, indocyanine green (ICG), for multimodal MR/FL imaging assisted cancer therapy. These HSA‐GGD‐ICG NPs with excellent biocompatibility are stable under physiological conditions, and exhibit enhanced T₁ contrast capability and improved fluorescence imaging capacity. In vitro experiments reveal an apparent effect of the NPs in killing tumor cells under low laser irradiation, due to the enhanced photothermal conversion efficiency (≈85.1%). Importantly, multimodal MR/FL imaging clearly shows the in vivo behaviors and the efficiency of tumor accumulation of HSA‐GGD‐ICG NPs, as confirmed by a pharmacokinetic study. With the guidance of multimodal imaging, photothermal therapy is subsequently conducted, which demonstrates again high photothermal conversion capability for eliminating tumors without relapse. Notably, real‐time monitoring of tumor ablation for prognosis and therapy evaluation is also achieved by MR imaging. This strategy of constructing nanoplatforms through albumin‐mediated methods is both convenient and efficient, which would enlighten the design of multimodal imaging assisted cancer therapy for potential clinical translation.     

Novel Magnetorheological Suspensions Based on Co-Phthalocyanine/Fe Nanocomposite Particles

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Impact of agglomeration on the relaxometric properties of paramagnetic ultra-small gadolinium oxide nanoparticles

Ultra-small gadolinium oxide nanoparticles (US-Gd(2)O(3)) are used to provide 'positive' contrast effects in magnetic resonance imaging (MRI), and are being considered for molecular and cellular imaging applications. However, these nanoparticles can aggregate over time in aqueous medium, as well as when internalized into cells. This study is aimed at measuring in vitro, in aqueous medium, the impact of aggregation on the relaxometric properties of paramagnetic US-Gd(2)O(3) particles. First, the nanoparticle core size as well as aggregation behaviour was assessed by HRTEM. DLS (hydrodynamic diameter) was used to measure the hydrodynamic diameter of nanoparticles and nanoaggregates. The relaxometric properties were measured by NMRD profiling, as well as with (1)H NMR relaxometers. Then, the positive contrast enhancement effect was assessed by using magnetic resonance scanners (at 1.5 and 7 T). At every magnetic field, the longitudinal relaxivity (r(1)) decreased upon agglomeration, while remaining high enough to provide positive contrast. On the other hand, the transverse relaxivity (r(2)) slightly decreased at 0.47 and 1.41 T, but it was enhanced at higher fields (7 and 11.7 T) upon agglomeration. All NMRD profiles revealed a characteristic relaxivity peak in the range 60-100 MHz, suggesting the possibility to use US-Gd(2)O(3) as an efficient 'positive-T(1)' contrast agent at clinical magnetic fields (1-3 T), in spite of aggregation.     

Controlled aggregation of superparamagnetic iron oxide nanoparticles for the development of molecular magnetic resonance imaging probes

A method for synthesizing superparamagnetic iron oxide (SPIO) multi-nanoparticle aggregates as molecular magnetic resonance imaging (MRI) contrast agents is described. The approach utilizes organic acid/base interactions in the colloid to induce highly controllable nanoparticle aggregation. Monodisperse aggregates with diameters as large as 100?nm are synthesized by manipulating the interfacial surface chemistry of the SPIO nanoparticles in tetrahydrofuran solvent. Subsequent phospholipid micelle encapsulation yields micellar multi-SPIO (mmSPIO) aggregates with enhanced T(2) relaxivity (368.0?s(-1)?mmol(-1)?Fe) as compared to micellar single particle SPIO (302.0?s(-1)?mmol(-1)?Fe). mmSPIO conjugated to anti-CA125 monoclonal antibodies were incubated with ovarian carcinoma cell lines to demonstrate targeted in vitro molecular MRI, resulting in a?66% shortening in T(2) time for CA125 positive NIH:OVCAR-3 cells and a less than?3% change in T(2) time for CA125 negative SK-OV-3 cells. The controllable aggregation of mmSPIO shows potential for the development of molecular MRI contrast agents with optimal sizes for specific diagnostic imaging applications.     

Facile synthesis of ultrasmall PEGylated iron oxide nanoparticles for dual-contrast T1- and T2-weighted magnetic resonance imaging

The development of new types of high-performance nanoparticulate MR contrast agents with either positive (T(1)) or dual-contrast (both positive and negative, T(1) + T(2)) ability is of great importance. Here we report a facile synthesis of ultrasmall PEGylated iron oxide nanoparticles for dual-contrast T(1)- and T(2)-weighted MRI. The produced superparamagnetic iron oxide nanoparticles (SPIONs) are of high crystallinity and size uniformity with an average diameter of 5.4 nm, and can be individually dispersed in the physiological buffer with high stability. The SPIONs reveal an impressive saturation magnetization of 94 emu g(-1) Fe(3)O(4), the highest r(1) of 19.7 mM(-1) s(-1) and the lowest r(2)/r(1) ratio of 2.0 at 1.5 T reported so far for PEGylated iron oxide nanoparticles. T(1)- and T(2)-weighted MR images showed that the SPIONs could not only improve surrounding water proton signals in the T(1)-weighted image, but induce significant signal reduction in the T(2)-weighted image. The good contrast effect of the SPIONs as T(1) + T(2) dual-contrast agents might be due to its high magnetization, optimal nanoparticle size for T(1) + T(2) dual-contrast agents, high size monodispersity and excellent colloidal stability. In vitro cell experiments showed that the SPIONs have little effect on HeLa cell viability.     

Preparation and properties of antiperovskite Mn3NiN thin film

The magnetic and electronic transport properties of the antiperovskite Mn₃NiN thin film deposited on quartz substrate using magnetron sputtering were investigated. The film shows a (100) preferred orientation. It is worthwhile noting that a positive magnetoresistance (MR) effect was found in the whole measured temperature region and the maximum MR value by 31% was obtained at about 300 K under 2 T. On the other hand, when cooling from room temperature, a spin-glass behavior was also observed in the Mn₃NiN film and the Tb shifted to lower temperature with increasing external magnetic field. In contrast to the bulk counterpart, the temperature dependent resistivity of the film shows a semiconductor-like behavior.     

Preoperative Detection and Intraoperative Visualization of Brain Tumors for More Precise Surgery: A New Dual‐Modality MRI and NIR Nanoprobe

In clinical practice, it is difficult to identify tumor margins during brain surgery due to its inherent infiltrative character. Herein, a unique dual‐modality nanoprobe (Gd‐DOTA‐Ag₂S QDs, referred as Gd‐Ag₂S nanoprobe) is reported, which integrates advantages of the deep tissue penetration of enhanced magnetic resonance (MR) imaging of Gd and the high signal‐to‐noise ratio and high spatiotemporal resolution of fluorescence imaging in the second near‐infrared window (NIR‐II) of Ag₂S quantum dots (QDs). Due to the abundant tumor angiogenesis and the enhanced permeability and retention effect in the tumor, a brain tumor (U87MG) in a mouse model is clearly delineated in situ with the help of the Gd assisted T1 MR imaging and the intraoperative resection of the tumor is precisely accomplished under the guidance of NIR‐II fluorescence imaging of Ag₂S QDs after intravenous injection of Gd‐Ag₂S nanoprobe. Additionally, no histologic changes are observed in the main organs of the mouse after administration of Gd‐Ag₂S nanoprobe for 1 month, indicating the high biocompatibility of the nanoprobe. We expect that such a novel “Detection and Operation” strategy based on Gd‐Ag₂S nanoprobe is promising in future clinical applications.     

Intracellular Construction of Cathepsin B-Guided Gadolinium Nanoparticles for Enhanced T2-Weighted MR Tumor Imaging

Magnetic resonance imaging (MRI) is a superior and noninvasive imaging technique with unlimited tissue penetration depth and superb spatiotemporal resolution, however, using intracellular self-assembly of Gd-containing nanoparticles to enhance the T₂-weighted MR contrast of cancer cells in vivo for precise tumor MRI is rarely reported. The lysosomal cysteine protease cathepsin B (CTSB) is regarded as an attractive biomarker for the early diagnosis of cancers and metastasis. Herein, taking advantage of a biocompatible condensation reaction, a “smart” Gd-based CTSB-responsive small molecular contrast agent VC-Gd-CBT is developed, which can self-assemble into large intracellular Gd-containing nanoparticles by glutathione reduction and CTSB cleavage to enhance the T₂-weighted MR contrast of CTSB-overexpressing MDA-MB-231 cells at 9.4 T. In vivo T₂-weighted MRI studies using MDA-MB-231 murine xenografts show that the T₂-weighted MR contrast change of tumors in VC-Gd-CBT-injected mice is distinctly larger than the mice injected with the commercial agent gadopentetate dimeglumine, or co-injected with CTSB inhibitor and VC-Gd-CBT, indicating that the accumulation of self-assembled Gd-containing nanoparticles at tumor sites effectively enhances the T₂-weighted MR tumor imaging. Hence, this CTSB-targeted small molecule VC-Gd-CBT has the potential to be employed as a T₂ contrast agent for the clinical diagnosis of cancers at an early stage.     

N-alkyl-polyethylenimine stabilized iron oxide nanoparticles as MRI visible transfection agents

An amphiphilic polymer, alkylated branched polyethylenimine (N-Alkyl-PEI), is synthesized and used for stabilization of hydrophobic superparamagnetic iron oxide (SPIO) nanocrystals in aqueous phase. Such composite particles are monodisperse without aggregation in physiological buffer as verified by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The nanocomposite system is capable of binding and delivering plasmid DNA for gene transfection while maintaining magnetic properties and biocompatibility. Transfection of cells showed that N-Alkyl-PEI2k stabilized magnetite nanoparticles were most effective in gene transfection comparing to unmodified PEI2k and PEI25k agents. Obvious MR signal darkening of transfected cells was observed under a clinical 3T MRI scanner. This multifunctional nanocomposite system provides a safe and efficient method for gene delivery with non-invasive imaging monitoring capability.     

Multiwall carbon nanotubes as MRI contrast agents for tracking stem cells

In this study we investigate the potential of multiwall carbon nanotubes (MWCNTs) with low metal impurities (2.57% iron) as magnetic resonance imaging (MRI) contrast agents. Taking into account probable aggregation at high MWCNTs concentration analysis shows that the r(2) relaxivity of MWCNTs in 1% agarose gels at 19?°C is 564 ± 41 s(-1) mM(-1); this is attributed to both the presence of iron oxide impurities and also to the carbon MWCNT structure itself. Stem cells were labelled with MWCNTs to demonstrate the effectiveness of MWCNTs as MRI contrast agents for cellular MRI. The MWCNTs did not impair cell viability or proliferation. These results suggest that the MRI contrast agent properties of the MWCNTs could be used in vivo for stem cell tracking/imaging and during MWCNT-mediated targeted electro-chemotherapy of tumours.     

AS1411 aptamer-conjugated Gd2O3:Eu nanoparticles for target-specific computed tomography/magnetic resonance/fluorescence molecular imaging

Europium-doped gadolinium oxide （Gd2O3：Eu） nanoparticles have been synthesized, and then their surfaces have been conjugated with nucleolin- targeted AS1411 aptamer to form functionalized target-specific Gd2OB：EU nanoparticles （A-GdO：Eu nanoparticles）. The A-GdO：Eu nanoparticles present strong fluorescence in the visible range, high magnetic susceptibility, X-ray attenuation and good biocompatibility. The A-GdO：Eu nanoparticles have been applied to test molecular expression of nucleolin highly expressed CL1-5 lung cancer cells under a confocal microscope. Fluorescence imaging clearly reveals that the nanoparticles can be applied as fluorescent tags for cancer-targeting molecular imaging. Furthermore, taking together their excellent T1 contrast and strong computed tomography （CT） signal, the A-GdO：Eu nanoparticles demonstrate a great capability for use as a dual modality contrast agent for CT and magnetic resonance （MR） molecular imaging. Animal experiments also show that the A-GdO：Eu nanoparticles are able to contrast the tissues of BALB/c mice using CT modality. Moreover, the obvious red fluorescence of A-GdO：Eu nanoparticles can be visualized in a tumor by the naked eye. Overall, our results demonstrate that the A-GdO：Eu nanoparticles can not only serve as new medical contrast agents but also as intraoperative fluorescence imaging probes for guided surgery in the near future.     

Conjugated polymer and gold nanoparticle co-loaded PLGA nanocomposites with eccentric internal nanostructure for dual-modal targeted cellular imaging

Herein is reported the one-step synthesis of an integrated nanocomposite with eccentrically loaded 5 nm gold nanoparticles (Au NPs) and conjugated polymer of poly[9,9-bis(6'-N,N,N-trimethylammonium)hexyl)fluorenyldivinylene-alt-4,7-(2,1,3,- benzothiadiazole) dibromide] (PFVBT). The nanocomposite is generated with surface-functionalized folic acid groups due to the matrix polymer of PLGA-PEG(2000) -folate used for encapsulation. The nanocomposite shows far-red fluorescence from PFVBT and scattering signal from Au NPs. Although Au NPs have been widely reported to quench the fluorescence of conjugated polymers, the PFVBT fluorescence is well maintained in the nanocomposite due to the eccentric location of Au NPs. The folic acid groups at the nanocomposite surface favor its cellular uptake by MCF-7 breast cancer cells, which have overexpressed folate receptors on the cell membranes. In conjugation with its low cytotoxicity, the folic-acid-functionalized nanocomposite has been successfully utilized for fluorescence and dark-field dual-modal targeted cellular imaging.