Hybrid Dextran-gadolinium Nano-suitcases as High-relaxivity MRI Contrast Agents

Dextran-poly（glycidyl methacrylate） （Dex-PGMA） nano-suitcases were synthesized efficiently via a graft copolymerization induced self-assembly （GISA） approach. On this basis, the Dex-PGMA nano-suitcases were modified with hydrazide, and the attachment of multiple chelated Gd（III） ions to the interior of the nano-suitcases affords nanoscale MRI contrast agents with high relaxivity values. The highly fenestrated dextran shell of the nano-suitcases assures water exchange which readily occurs between the surrounding environment and the Gd（III） ions encapsulated within the hybrid nano-suitcases. The complexation between the hydrophilic hydrazide interior of the nano-suitcases and Gd（III） ions results in an impressive Gd payload at 22.6 wt% in the hybrid nano-suitcases. The longitudinal relaxivity （rl） of the hybrid nano-suitcases is reported as 44.4 L/（mmol-s）, which is 9-14 folds of that of commercial Gd-DTPA agents. In vivo MRI studies demonstrate that the hybrid nano-suitcases accumulated in the lymph node of the rat due to their nanoscale dimensions and displayed strong signals in vivo. The results indicated that the hybrid nano-suitcases provide a promising platform for the diagnosis of lymph node related diseases.

Synthesis and in vitro Evaluation of Manganese（Ⅱ）-porphyrin Modified with Chitosan Oligosaccharides as Potential MRI Contrast Agents

Mn-TCPP-CSn（n=6,1 1,20） as a type of potential magnetic resonance imaging（MRI） contrast agents were synthesized via manganese（Ⅱ） meso-tetra（4-carboxyphenyl） porphyrin（Mn-TCPP） modified with chitosan oligosaccharides（CSn）.Experimental data of infared（IR）,UV-Vis,MS,inductively coupled plasma-atomic emission spectrometer（ICP-AES） and size exclusion chromatography evidenced the formation of Mn-TCPP-CSn-The stability results show that Mn-TCPP-CSn in aqueous solution was stable enough to prevent Mn（Ⅱ） ions from leaking.The magnetic properties in vitro indicate that Mn-TCPP-CS20 possesses higher longitudinal relaxivity（r1=10.38 L·mmol^-1·s^-1） in aqueous solution than unmodified porphyrin Mn-TCPPNa4[manganese（Ⅱ） meso-tetra（4-carboxyphenyl） porphyrin,tetrasodium salt]（r1=5.10 L·mmol^-1·s^-1） and the commercial contrast agent Gd-DTPA（r1=4.05 L·mmol^-1·s^-1）.The preliminary T1-weighted flash image studies in vitro show that the contrast and the imaging signal of Mn-TCPP-CSn were superior to those of Mn-TCPPNa4 and Gd-DTPA under the same conditions.The 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） assay shows that Mn-TCPP-CSn has a good biocompatibility.In addition,the thermodynamical parameters（ΔH〈0,ΔS〈0,ΔG〈0） of Mn-TCPP-CSn bound to bovine serum albumin（BSA） show that Mn-TCPP-CSn could bind to BSA spontaneously,where the binding complex was stabilized mainly by van der Waals interactions and hydrogen bonds.These results suggest that Mn-TCPP-CSn have the advantage of becoming a potential MRI contrast agent.

A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging

Nitroreductases(NTRs) are known to be able to metabolize nitro-substituted compounds in the presence of reduced nicotinamide adenine dinucleotide(NADH) as an electron donor. NTRs are present in a wide range of bacterial genera and, to a lesser extent, in eukaryotes hypoxic tumour cells and tumorous tissues, which makes it an appropriate biomarker for an imaging target to detect the hypoxic status of cancer cells and potential bacterial infections. To evaluate the specific activation level of NTR, great efforts have been devoted to the development of fluorescent probes to detect NTR activities using fluorogenic methods to probe its behaviour in a cellular context; however, NTR-responsive MRI contrast agents are still by far underexplored. In this study, para-nitrobenzyl substituted T_1-weighted magnetic resonance imaging(MRI)contrast agent Gd-DOTA-PNB(probe 1) has been designed and explored for the possible detection of NTR.Our experimental results show that probe 1 could serve as an MRI-enhanced contrast agent for monitoring NTR activity. The in vitro response and mechanism of the NTR catalysed reduction of probe 1 have been investigated through LC–MS and MRI. Para-nitrobenzyl substituted probe 1 was catalytically reduced by NTR to the intermediate para-aminobenzyl substituted probe which then underwent a rearrangement elimination reaction to Gd-DOTA, generating the enhanced T1-weighted MR imaging. Further, LC–MS and MRI studies of living Escherichia coli have confirmed the NTR activity detection ability of probe 1 at a cellular level. This method may potentially be used for the diagnosis of bacterial infections.

Synthesis and Relaxation Properties of Lanthanide(Gd ,Yb) Complexeswith Tris Modified DTPA

Synthesis and characterization of NMR T-1 relaxation properties of the title complexes and several transition metal-EDTA-bis[ tris(hydroxymethyl methylamide] complexes were performed for searching new contrast agents for magnetic resonance imaging(MRI). The ligands, abbr. to DTPA-BTris and EDTA-BTris, were obtained by modifying DTPA and EDTA with tris(hydroxymethyl) aminomethane. It was found that the relaxivities of solutions of the modified complexes in vitro are correspondingly greater than those of the parent complexes. For GdDTPA-BTris, MnEDTA-BTris, and FeEDTA-BTris, the relaxometry of lattice relaxation(R-1) is 5.4, 3.1, and 1.9 L.mmol(-1).s(-1) vs. 5.2, 2.8 and 1.7 L.mmol(-1).s(-1) for GdDTPA, MnEDTA, and FeEDTA, respectively. Additionally, the present complexes have the favorable properties such as high water solubility and chemical stability required of clinical useful contrast agent.

Synthesis, Characterization of α-Oxopentanedioic Acid-Isonicotinoyl (Hydrazone) Rare Earth-Complexes and Relaxivity of Gd-complex

Oxopentanedioic acid isonicotinoyl hydrazone (H_2L) and its five rare earth complexes were synthesized with a view to further investigating MRI activities of the polycarboxylic Schiff base complexes. The complexes were characterized on the basis of elemental analyses, IR, UV, (()~1H) NMR spectra and thermal analyses. The general formula of the complexes is [Ln(HL)(H_2O)_2]Cl_2·H_2O (where Ln(Ⅲ)=La, Pr, Nd, Eu and Gd). In addition, the relaxivity ( R _1) of the Gd-complex was determined by INVREC Au program.

TbF3 nanoparticles as dual-mode contrast agents for ultrahigh field magnetic resonance imaging and X-ray computed tomography

Considering the development of magnetic resonance imaging （MRI） under ultrahigh magnetic field （〉3 T）, the exploration of novel contrast agents （CAs） for ultrahigh field MRI is urgently needed. Herein, we report polyethyleneimine （PEI）-coated TbF3 nanoparticles （NPs）, which were synthesized by a facile solvothermal method, as potential dual-mode CAs for ultrahigh field MRI and X-ray computed tomography （CT）. Owing to their strong paramagnetism, the TbF3 NPs showed excellent transverse relaxivity （395.77 mM-l.s-1） and negligible longitudinal relaxivity under an ultrahigh magnetic field （7 T） with a great potential as a T2-weighted MRI contrast agent. Furthermore, by comparison with the clinically used CT CAs （iohexol）, the TbF3 NPs showed superior X-ray attenuation ability. The practical application for T2-weighted MRI and CT imaging was demonstrated with an animal model. Moreover, cell cytotoxicity and in vivo toxicity assessments implied the low toxicity of TbF3 NPs. In summary the above results indicate that TbF3 NPs are promising candidates for ultrahigh field MRI and CT dual-mode imaging.

Ultrasensitive iron-based magnetic resonance contrast agent constructed with natural polyphenol tannic acid for tumor theranostics

Because of the toxicity of Gd(Ⅲ)complexes and the poor T1 magnetic resonance imaging(MRI)contrast of superparamagnetic iron oxide,the development of new stable,non-toxic,and efficient contrast agents is desirable.Herein,tannic acid(TA),a large natural polyphenol,and bovine serum albumin(BSA)were used to construct non-toxic Fe(Ⅲ)complexes with increased relaxivity based on a strategy slowing the molecular spin.Compared with the commercial T1 contrast agent Magnevist■,TA-Fe@BSA not only exhibits comparable T1 MRI contrast enhancement under 0.5,1 and 7 T magnetic fields both in vitro and in vivo,but also has better stability and biocompatibility.Moreover,TA-Fe@BSA with near-infrared(NIR)absorption demonstrates efficient tumor ablation via photothermal effects.These results demonstrate their strong potential as an alternative T1 MRI contrast agent and tumor theranostics agent in clinical settings.

Preparation and MRI performances of core-shell structural PEG salicylic acid-gadolinium composite nanoparticles

Gadolinium(Ⅲ)-based T_(1) contrast agents have been widely used in clinical MRI.In this study,salicylic acid-gadolinium chelate was prepared via directly coordination reaction of gadolinium ion and salicylic acid.Then,three polyethylene glycols with different molecular weight were modified on the surface of salicylic acid-gadolinium by simple chemical coupling to construct three core-shell structural Gd based composites.The scanning electron microscopy(SEM)and transmission electron microscopy(TEM)characterization results show that the composite is a spherical particle with a diameter of about 100-200 nm.The longitudinal relaxation rate r_(1) of the Gal-PEG-2000 is 11.097(mmol/L)^(-1)/s,and the ratio of r_(2)/r_(1) is as low as 2.53.The composite shows good liver and intestines MRI performances after being used in in vivo imaging,showing a good prospect of biological application.

Recent advances in gadolinium-based MRI metal responsive agent

Smart magnetic resonance imaging(MRI) contrast agent has the ability to increase or decrease the signal intensity through response to certain analyte. Among the growing class of responsive agent, imaging probes based on gadolinium ion are developing fast in the last decade since they play an important role in physiological and pathology process in living system. This minireview would highlight recent progress in metal responsive gadolinium-based MRI contrast agent.

Cell-assembled （Gd-DOTA）i-triphenylphosphonium （TPP） nanoclusters as a T2 contrast agent reveal in vivo fates of stem cell transplants

A simple and straightforward strategy for magnetic resonance imaging （MRI） of stem cell transplants in terms of their viability, migration and homing, and differentiation has been pursued over the years. Herein we couple Gd-DOTA with triphenylphosphonium （TPP） to yield small molecule （Gd-DOTA）i-TPP （i = 1,4） agents and show that labeling cells with （Gd-DOTA）i-TPP via electro- poration （EP） results in two distinct cellular distributions of （Gd-DOTA）i-TPP： freely and evenly distributed in the cytosol or cell-assembled nanoclusters in the cytoplasm. The two distinct cellular distributions contribute in different ways to MRI signals in vitro and in vivo. Importantly, we present a detailed interpretation of MRI results based on the signal intensity equation and cellular longitudinal （T1-） and transverse （Ta-） relaxation rates of water protons. We demonstrate that cell-assembled （Gd-DOTA）i-TPP nanoclusters not only promote its intracellular retention time but also induce significant MRI signal reduction, which act as an excellent T2 contrast agent and allows for unambiguous reporting of in vivo viability and migration of cell transplants under T2-weighted MRI over a long period. Notably,（Gd-DOTA）i-TPP agents released as a result of exocytosis or cell death induce signal enhancement in the surrounding tissue such that the labeled cells can be unambiguously discriminated from its host tissue. The labeling and imaging strategy provides abundant information on the in vivo fates of stem cell transplants. The strategy features a single contrast, single imaging mode with dual signal output.

FOLATE-TARGETED OPTICAL AND MAGNETIC RESONANCE DUAL-MODALITY PCL-b-PEG MICELLES FOR TUMOR IMAGING

A biodegradable tumor targeting nano-probe based on poly（ε-caprolactone）-b-poly（ethylene glycol） block copolymer （PCL-b-PEG）micelle functionalized with a magnetic resonance imaging （MRI） contrast agent diethylenetriaminepentaacetic acid-gadolinium （DTPA-Gd＋） on the shell and a near-infrared （NIR） dye in the core for magnetic resonance and optical dual-modality imaging was prepared. The longitudinal relaxivity （rl） of the PCL-b-PEG- DTPA-Gd3＋ micelle was 13.4 （mmol/L）^-1s^-1, three folds of that of DTPA-Gd3＋, and higher than that of many polymeric contrast agents with similar structures. The in vivo optical imaging of a nude mouse bearing xenografied breast tumor showed that the dual-modality micelle preferentially accumulated in the tumor via the folic acid-mediated active targeting and the passive accumulation by the enhanced permeability and retention （EPR） effect. The results indicated that the dualmodality micelle is a promising nano-probe for cancer detection and diagnosis.

Controlled temperature-mediated curcumin release from magneto-thermal nanocarriers to kill bone tumors

Systemic chemotherapy has lost its position to treat cancer over the past years mainly due to drug resistance,side effects,and limited survival ratio.Among a plethora of local drug delivery systems to solve this issue,the combinatorial strategy of chemo-hyperthermia has recently received attention.Herein we developed a magneto-thermal nanocarrier consisted of superparamagnetic iron oxide nanoparticles(SPIONs)coated by a blend formulation of a three-block copolymer Pluronic F127 and F68 on the oleic acid(OA)in which Curcumin as a natural and chemical anti-cancer agent was loaded.The subsequent nanocarrier SPION@OA-F127/F68-Cur was designed with a controlled gelation temperature of the shell,which could consequently control the release of curcumin.The release was systematically studied as a function of temperature and pH,via response surface methodology(RSM).The bone tumor killing efficacy of the released curcumin from the carrier in combination with the hyperthermia was studied on MG-63 osteosarcoma cells through Alamar blue assay,live-dead staining and apoptosis caspase 3/7 activation kit.It was found that the shrinkage of the F127/F68 layer stimulated by elevated temperature in an alternative magnetic field caused the curcumin release.Although the maximum release concentration and cell death took place at 45℃,treatment at 41℃ was chosen as the optimum condition due to considerable cell apoptosis and lower side effects of mild hyperthermia.The cell metabolic activity results confirmed the synergistic effects of curcumin and hyperthermia in killing MG-63 osteosarcoma cells.

Fabrication of carbon coated gadolinia particles for dual-mode magnetic resonance and fluorescence imaging

In the present study,we report a fabrication of dual-mode carbon coated gadolinia C@Gd_(2)O_(3)particles by a facile hydrothermal synthesis method without using any organic solvents.The prepared C@Gd_(2)O_(3)particles have a core-shell structure and a narrow size distribution in the range of 261±27 nm.The fluorescent properties of the prepared C@Gd_(2)O_(3)particles were accessed by a room-temperature photoluminescence study,while the longitudinal relaxivity(r1)was examined by using a clinical 1.5 T MRI scanner.A murine fibroblast L-929 cell line was used to examine the cytotoxicity and capability of the prepared C@Gd_(2)O_(3)particles for the fluorescent labeling.The obtained results show that the prepared C@Gd_(2)O_(3)particles could be used as a dual-mode contrast agent for magnetic resonance and fluorescence imaging.