Gd Chelates Research Articles

Ultra-wide range field-dependent measurements of the relaxivity of Gd1\u2212xEuxVO4 nanoparticle contrast agents using a mechanical sample-shuttling relaxometer

The current trend for Magnetic Resonance Imaging points towards higher magnetic fields. Even though sensitivity and resolution are increased in stronger fields, T1 contrast is often reduced, and this represents a challenge for contrast agent design. Field-dependent measurements of relaxivity are thus important to characterize contrast agents. At present, the field-dependent curves of relaxivity are usually carried out in the field range of 0 T to 2 T, using fast field cycling relaxometers. Here, we employ a high-speed sample shuttling device to switch the magnetic fields experienced by the nuclei between virtually zero field, and the center of any commercial spectrometer. We apply this approach on rare-earth (mixed Gadolinium-Europium) vanadate nanoparticles, and obtain the dispersion curves from very low magnetic field up to 11.7 T. In contrast to the relaxivity profiles of Gd chelates, commonly used for clinical applications, which display a plateau and then a decrease for increasing magnetic fields, these nanoparticles provide maximum contrast enhancement for magnetic fields around 1–1.5 T. These field-dependent curves are fitted using the so-called Magnetic Particle (MP) model and the extracted parameters discussed as a function of particle size and composition. We finally comment on the new possibilities offered by this approach.

Gadolinium-Loaded Poly(N-vinylcaprolactam) Nanogels: Synthesis, Characterization, and Application for Enhanced Tumor MR Imaging.

We report the synthesis of poly(N-vinylcaprolactam) nanogels (PVCL NGs) loaded with gadolinium (Gd) for tumor MR imaging applications. The PVCL NGs were synthesized via precipitation polymerization using the monomer N-vinylcaprolactam (VCL), the comonomer acrylic acid (AAc), and the degradable cross-linker 3,9-divinyl-2,4,8,10-tetraoxaspiro-[5,5]-undecane (VOU) in aqueous solution, followed by covalently binding with 2,2',2″-(10-(4-((2-aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (NH2-DOTA-GA)/Gd complexes. We show that the formed Gd-loaded PVCL NGs (PVCL-Gd NGs) having a size of 180.67 ± 11.04 nm are water dispersible, colloidally stable, uniform in size distribution, and noncytotoxic in a range of the studied concentrations. The PVCL-Gd NGs also display a r1 relaxivity (6.38-7.10 mM-1 s-1), which is much higher than the clinically used Gd chelates. These properties afforded the use of the PVCL-Gd NGs as an effective positive contrast agent for enhanced MR imaging of cancer cells in vitro as well as a subcutaneous tumor model in vivo. Our study suggests that the developed PVCL-Gd NGs could be applied as a promising contrast agent for T1-weighted MR imaging of diverse biosystems.

Poly(glycerol) Used for Constructing Mixed Polymeric Micelles as T1 MRI Contrast Agent for Tumor-Targeted Imaging.

There was much interest in the development of nanoscale delivery vehicles based on polymeric micelles to realize the diagnostic and therapeutic applications in biomedicine. Here, with the purpose of constructing a micellar magnetic resonance imaging (MRI) contrast agent (CA) with well biocompatibility and targeting specificity, two types of amphiphilic diblock polymers, mPEG-PG(DOTA(Gd))-b-PCL and FA-PEG-b-PCL, were synthesized to form mixed micelles by coassembly. The nanostructure of the resulting micellar system consisted of poly(caprolactone) (PCL) as core and poly(glycerol) (PG) and poly(ethylene glycol) (PEG) as shell, simultaneously modified with DOTA(Gd) chelates and folic acid (FA), which afforded functions of MRI contrast enhancement and tumor targeting. The mixed micelles in aqueous solution presented a hydrodynamic diameter of about 85 nm. Additionally, this mixed micelles exhibited higher r1 relaxivity (14.01 mM-1 S1-) compared with commercial Magnevist (3.95 mM-1 S1-) and showed negligible cytotoxicity estimated by WST assay. In vitro and in vivo MRI experiments revealed excellent targeting specificity to tumor cells and tissue. Furthermore, considerably enhanced signal intensity and prominent positive contrast effect were achieved at tumor region after tumor-bearing mice were intravenously injected with the mixed micelles. These preliminary results indicated the potential of the mixed micelle as T1 MRI CA for tumor-targeted imaging.

Gadolinium-Functionalized Peptide Amphiphile Micelles for Multimodal Imaging of Atherosclerotic Lesions.

The leading causes of morbidity and mortality globally are cardiovascular diseases, and nanomedicine can provide many improvements including disease-specific targeting, early detection, and local delivery of diagnostic agents. To this end, we designed fibrin-binding, peptide amphiphile micelles (PAMs), achieved by incorporating the targeting peptide cysteine-arginine-glutamic acid-lysine-alanine (CREKA), with two types of amphiphilic molecules containing the gadoliniuim (Gd) chelator diethylenetriaminepentaacetic acid (DTPA), DTPA-bis(stearylamide)(Gd), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[(poly(ethylene glycol) (PEG))-2000]-DTPA(Gd) (DSPE-PEG2000-DTPA(Gd)). The material characteristics of the resulting nanoparticle diagnostic probes, clot-binding properties in vitro, and contrast enhancement and safety for dual, optical imaging–magnetic resonance imaging (MRI) were evaluated in the atherosclerotic mouse model. Transmission electron micrographs showed a homogenous population of spherical micelles for formulations containing DSPE-PEG2000-DTPA(Gd), whereas both spherical and cylindrical micelles were formed upon mixing DTPA-BSA(Gd) and CREKA amphiphiles. Clot-binding assays confirmed DSPE-PEG2000-DTPA(Gd)-based CREKA micelles targeted clots over 8-fold higher than nontargeting (NT) counterpart micelles, whereas no difference was found between CREKA and NT, DTPA-BSA(Gd) micelles. However, in vivo MRI and optical imaging studies of the aortas and hearts showed fibrin specificity was conferred by the peptide ligand without much difference between the nanoparticle formulations or shapes. Biodistribution studies confirmed that all micelles were cleared through both the reticuloendothelial system and renal clearance, and histology showed no signs of necrosis. In summary, these studies demonstrate the successful synthesis, and the molecular imaging capabilities of two types of CREKA-Gd PAMs for atherosclerosis. Moreover, we demonstrate the differences in micelle formulations and shapes and their outcomes in vitro versus in vivo for site-specific, diagnostic strategies, and provide the groundwork for the detection of thrombosis via contrast-enhancing agents and concurrent therapeutic delivery for theranostic applications.

Nanodiamond-Gadolinium(III) Aggregates for Tracking Cancer Growth In Vivo at High Field.

The ability to track labeled cancer cells in vivo would allow researchers to study their distribution, growth, and metastatic potential within the intact organism. Magnetic resonance (MR) imaging is invaluable for tracking cancer cells in vivo as it benefits from high spatial resolution and the absence of ionizing radiation. However, many MR contrast agents (CAs) required to label cells either do not significantly accumulate in cells or are not biologically compatible for translational studies. We have developed carbon-based nanodiamond-gadolinium(III) aggregates (NDG) for MR imaging that demonstrated remarkable properties for cell tracking in vivo. First, NDG had high relaxivity independent of field strength, a finding unprecedented for gadolinium(III) [Gd(III)]-nanoparticle conjugates. Second, NDG demonstrated a 300-fold increase in the cellular delivery of Gd(III) compared to that of clinical Gd(III) chelates without sacrificing biocompatibility. Further, we were able to monitor the tumor growth of NDG-labeled flank tumors by T1- and T2-weighted MR imaging for 26 days in vivo, longer than was reported for other MR CAs or nuclear agents. Finally, by utilizing quantitative maps of relaxation times, we were able to describe tumor morphology and heterogeneity (corroborated by histological analysis), which would not be possible with competing molecular imaging modalities.

Difference in the intratumoral distributions of extracellular-fluid and intravascular MR contrast agents in glioblastoma growth.

Contrast enhancement by an extracellular-fluid contrast agent (CA) (Gd-DOTA) depends primarily on the blood-brain-barrier permeability (bp), and transverse-relaxation change caused by intravascular T2 CA (superparamagnetic iron oxide nanoparticles, SPIONs) is closely associated with the blood volume (BV). Pharmacokinetic (PK) vascular characterization based on single-CA-using dynamic contrast-enhanced MRI (DCE-MRI) has shown significant measurement variation according to the molecular size of the CA. Based on this recognition, this study used a dual injection of Gd-DOTA and SPIONs for tracing the changes of bp and BV in C6 glioma growth (Days 1 and 7 after the tumor volume reached 2mL). bp was quantified according to the non-PK parameters of Gd-DOTA-using DCE-MRI (wash-in rate, maximum enhancement ratio and initial area under the enhancement curve (IAUC)). BV was estimated by SPION-induced ΔR2 * and ΔR2 . With validated measurement reliability of all the parameters (coefficients of variation ≤10%), dual-contrast MRI demonstrated a different region-oriented distribution between Gd-DOTA and SPIONs within a tumor as follows: (a) the BV increased stepwise from the tumor center to the periphery; (b) the tumor periphery maintained the augmented BV to support continuous tumor expansion from Day 1 to Day 7; (c) the internal tumor area underwent significant vascular shrinkage (i.e. decreased ΔR2 and ΔR2 ) as the tumor increased in size; (d) the tumor center showed greater bp-indicating parameters, i.e. wash-in rate, maximum enhancement ratio and IAUC, than the periphery on both Days 1 and 7 and (e) the tumor center showed a greater increase of bp than the tumor periphery in tumor growth, as suggested to support tumor viability when there is insufficient blood supply. In the MRI-histologic correlation, a prominent BV increase in the tumor periphery seen in MRI was verified with increased fluorescein isothiocyanate-dextran signals and up-regulated immunoreactivity of CD31-VEGFR. In conclusion, the spatiotemporal alterations of BV and bp in glioblastoma growth, i.e. augmented BV in the tumor periphery and increased bp in the center, can be sufficiently evaluated by MRI with dual injection of extracellular-fluid Gd chelates and intravascular SPION.

High Performance Anion Chromatography of Gadolinium Chelates.

High performance anion chromatography (HPIC) method to separate ionic Gd chelates, [Formula: see text], [Formula: see text], [Formula: see text] and free matrix anions was developed. At alkaline pHs, polydentate complexing agents such as ethylene-diamine-tetraacetate, diethylene-triamine pentaacetate and trans-1,2-diamine-cyclohexane-tetraacetate tend to form stable Gd chelate anions and can be separated by anion exchange. Separations were studied in the simple isocratic chromatographic run over the wide range of pH and concentration of carbonate eluent using suppressed conductivity detection. The ion exchange and complex forming equilibria were quantitatively described and demonstrated in order to understand major factors in the control of selectivity of Gd chelates. Parameters of optimized resolution between concurrent ions were presented on a 3D resolution surface. The applicability of the developed method is represented by the simultaneous analysis of Gd chelates and organic/inorganic anions. Inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis was used for confirmation of HPIC results for Gd. Collection protocols for the heart-cutting procedure of chromatograms were applied. SPE procedures were also developed not only to extract traces of free gadolinium ions from samples, but also to remove the high level of interfering anions of the complex matrices. The limit of detection, the recoverability and the linearity of the method were also presented.

Field Dependence Study of Commercial Gd Chelates With SQUID Detection

The contrast agents (CAs), which can enhance the image contrast by changing the relaxation times in the target locations, are widely used in clinical high-field magnetic resonance imaging (MRI). However, the commercial clinical CAs have attracted little attention in ultralow field (ULF) MRI, whose measurement field is four orders of magnitude lower than that of the clinical high-field counterpart. In this paper, we measure the relaxivity levels of three gadolinium (Gd)-based commercial CAs (Gd-DTPA, Gd-EOB-DTPA, and Gd-DTPA-BMA) with our four-channel magnetically unshielded ULF-MRI system using low- $T_{{c}}$ superconducting quantum interference devices as detectors. The system has a 0.65-T permanent-magnet pair as prepolarization field $B_{{p}}$ and applies a static $B_{0}$ field of 129 uT. We compare the longitudinal relaxivity levels of the CAs at $B_{{p}}$ and $B_{0}$ field strengths, as well as the reported values at 1.5 T. The results show that the relaxivity levels of three commercial CAs at 129 uT are all about twice those at high fields, which demonstrates one particular advantage of ULF-MRI.

PEGylated polyethylenimine-entrapped gold nanoparticles loaded with gadolinium for dual-mode CT/MR imaging applications.

To synthesize and characterize cost-efficient polyethylenimine-entrapped gold nanoparticles loaded with gadolinium (Gd@Au PENPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging applications. PEGylated PEI modified with gadolinium (Gd) chelator (DOTA) was used as a template to synthesize the Gd@Au PENPs and the particles were well characterized in terms of their physicochemical properties, cytotoxicity and performances in CT and MR imaging in vitro and in vivo. The formed Gd@Au PENPs with low cytotoxicity can be used as a highly efficient contrast agent for dual-mode CT/MR imaging of blood pool and major organs of animals. The designed Gd@Au PENPs may be used as a versatile nanoplatform for dual-mode CT/MR imaging of different biological systems.

A Novel Liposomal Nanoparticle for the Imaging of Amyloid Plaque by Magnetic Resonance Imaging.

Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy. Upon intravenous injection, the particles successfully traversed the blood-brain barrier in these mice, and bound to the plaques. Magnetic resonance imaging (T1-MRI) conducted 4 days after injection demonstrated elevated signal in the brains of mice with amyloid plaques present. No signal was observed in amyloid-negative mice, or in amyloid-positive mice injected with an untargeted version of the same agent. The MRI results were confirmed by immunohistochemical and fluorescent microscopic examination of mouse brain sections, showing colocalization of the fluorescent tags and amyloid deposits.

Stimuli-Responsive Biodegradable Hyperbranched Polymer-Gadolinium Conjugates as Efficient and Biocompatible Nanoscale Magnetic Resonance Imaging Contrast Agents.

The efficacy and biocompatibility of nanoscale magnetic resonance imaging (MRI) contrast agents depend on optimal molecular structures and compositions. Gadolinium [Gd(III)] based dendritic macromolecules with well-defined and tunable nanoscale sizes are excellent candidates as multivalent MRI contrast agents. Here, we propose a novel alternate preparation of biodegradable hyperbranched polymer-gadolinium conjugates via a simple strategy and report potentially efficient and biocompatible nanoscale MRI contrast agents for cancer diagnosis. The enzyme-responsive hyperbranched poly(oligo-(ethylene glycol) methacrylate)-gadolinium conjugate (HB-POEGMA-Gd) was prepared via one-step reversible addition-fragmentation chain transfer (RAFT) polymerization and Gd(III) chelating, and the cRGDyK functionalized polymer (HB-POEGMA-cRGD-Gd) was obtained via click chemistry. By using an enzyme similar to lysosomal cathepsin B, hyperbranched conjugates of high molecular weights (MW) (180 and 210 kDa) and nanoscale sizes (38 and 42 nm) were degraded into low MW (25 and 30 kDa) and smaller products (4.8 and 5.2 nm) below the renal threshold. Conjugate-based nanoscale systems had three-fold more T1 relaxivity compared to clinical agent diethylenediaminepentaacetic acid (DTPA)-Gd. Animal studies with the nanoscale system offered greater tumor accumulation and enhanced signal intensity (SI) in mouse U87 tumors of which the greatest activity was conferred by the cRGDyK moiety functionalized hyperbranched conjugate. In vitro cytotoxicity, hemocompatibility and in vivo toxicity studies confirmed no adverse events. This design strategy for multifunctional Gd(III)-labeled biodegradable dendritic macromolecules may have significant potential as future efficient, biocompatible polymeric nanoscale MRI diagnostic contrast agents for cancer.

Anthropogenic gadolinium anomalies and rare earth elements in the water of Atibaia River and Anhumas Creek, Southeast Brazil.

The concentrations of rare earth elements (REE), measured in water samples from Atibaia River and its tributary Anhumas Creek, Brazil, present excess of dissolved gadolinium. Such anthropogenic anomalies of Gd in water, already described in other parts of the world, result from the use of stable and soluble Gd chelates as contrast agents in magnetic resonance imaging. Atibaia River constitutes the main water supply of Campinas Metropolitan area, and its basin receives wastewater effluents. The REE concentrations in water samples were determined in 0.22-μm pore size filtered samples, without and after preconcentration by solid-phase extraction with bis-(2-ethyl-hexyl)-phosphate. This preconcentration method was unable to retain the anthropogenic Gd quantitatively. The probable reason is that the Gd chelates dissociate slowly in acidic media to produce the free ion that is retained by the phosphate ester. Strong correlations between Gd and constituents or parameters associated with effluents confirmed the source of most Gd in water samples as anthropogenic. The shale-normalized REE patterns of Atibaia River and Anhumas Creek water samples showed light and heavy REE enrichment trends, respectively. Also, positive Ce anomalies in many Atibaia River samples, as well as the strong correlations of the REE (except Gd) with terrigenous elements, imply that inorganic colloidal particles contributed to the REE measured values.

Nano assembly and encapsulation; a versatile platform for slowing the rotation of polyanionic Gd(3+) -based MRI contrast agents.

Encapsulating discrete Gd(3+) chelates in nano-assembled capsules (NACs) is a simple and effective method of preparing an MRI contrast agent capable of delivering a large payload of high relaxivity imaging agent. The preparation of contrast agent containing NACs had previously focussed on preparations incorporating GdDOTP(5-) into the internal aggregate. In this report we demonstrate that other Gd(3+) chelates bearing overall charges as low as 2- can also be used to prepare NACs. This discovery opens up the possibility of using Gd(3+) chelates that have inner-sphere water molecules that could further increase the relaxivity enhancement associated with the long τR that arises from encapsulation. However, encapsulation of the q = 1 chelate GdDTPA(2-) did not give rise to a significant increase in relaxivity relative to encapsulation of the outer-sphere chelate GdTTHA(3-). This leads us to the conclusion that in the NAC interior proton transport is not mediated by movement of whole water molecules and the enhanced relaxivity of Gd(3+) chelate encapsulated within NACs arises primarily from second sphere effects.

DNA–gadolinium–gold nanoparticles for in vivo T1 MR imaging of transplanted human neural stem cells

The unambiguous imaging of transplanted cells remains a major challenge to understand their biological function and therapeutic efficacy. In vivo imaging of implanted cells is reliant on tagging these to differentiate them from host tissue, such as the brain. We here characterize a gold nanoparticle conjugate that is functionalized with modified deoxythymidine oligonucleotides bearing Gd(III) chelates and a red fluorescent Cy3 moiety to visualize in vivo transplanted human neural stem cells. This DNA-Gd@Au nanoparticle (DNA-Gd@AuNP) exhibits an improved T1 relaxivity and excellent cell uptake. No significant effects of cell uptake have been found on essential cell functions. Although T1 relaxivity is attenuated within cells, it is sufficiently preserved to afford the in vivo detection of transplanted cells using an optimized voxel size. In vivo MR images were corroborated by a post-mortem histological verification of DNA-Gd@AuNPs in transplanted cells. With 70% of cells being correctly identified using the DNA-Gd-AuNPs indicates an overall reliable detection. Less than 1% of cells were false positive for DNA-Gd@AuNPs, but a significant number of 30% false negatives reveals a dramatic underestimation of transplanted cells using this approach. DNA-Gd@AuNPs therefore offer new opportunities to visualize transplanted cells unequivocally using T1 contrast and use cellular MRI as a tool to derive biologically relevant information that allows us to understand how the survival and location of implanted cells determines therapeutic efficacy.

Tumor Detection at 3 Tesla with an Activatable Cell Penetrating Peptide Dendrimer (ACPPD-Gd), a T1 Magnetic Resonance (MR) Molecular Imaging Agent.

PurposeThe ability to detect small malignant lesions with magnetic resonance imaging (MRI) is limited by inadequate accumulations of Gd with standard chelate agents. To date, no T1-targeted agents have proven superiority to Gd chelates in their ability to detect small tumors at clinically relevant field strengths. Activatable cell-penetrating peptides and their Gd-loaded dendrimeric form (ACPPD-Gd) have been shown to selectively accumulate in tumors. In this study we compared the performance of ACPPD-Gd vs. untargeted Gd chelates to detect small tumors in rodent models using a clinical 3T-MR system.Materials and MethodsThis study was approved by the Institutional-Animal Care-and-Use Committee. 2 of 4 inguinal breast fat pads of 16 albino-C57BL/6 mice were inoculated with tumor Py8119 cells and the other 2 with saline at random. MRI at 3T was performed at 4, 9, and 14 days after inoculation on 8 mice 24-hours after injection of 0.036mmol Gd/kg (ACPPD-Gd), and before and 2–3 minutes after 0.1 mmol/kg gadobutrol on the other 8 mice. T1-weighted (T1w) tumor signal normalized to muscle, was compared among the non-contrast, gadobutrol, and ACPPD-Gd groups using ANOVA. Experienced and trainee readers blinded to experimental conditions assessed for the presence of tumor in each of the 4 breast regions. Receiver operator characteristic (ROC) curves and area-under-curve (AUC) values were constructed and analyzed.ResultsTumors ≥1mm3 were iso-intense to muscle without contrast on T1w sequences. They enhanced diffusely and homogeneously by 57±20% (p<0.001) 24 hours after ACPPD-Gd and by 25±13% (p<0.001) immediately after gadobutrol. The nearly 2-fold difference was similar for small tumors (1-5mm3) (45±19% vs. 19±18%, p = 0.03). ACPPD-Gd tended to improve tumor detection by an experienced reader (AUC 0.98 vs 0.91) and significantly more for a trainee (0.93 vs. 0.82, p = 0.02) compared to gadobutrol. This improvement was more pronounced when obvious tumors (>5mm3) were removed from the ROC analysis for both the experienced observer (0.96 vs. 0.86) and more so for the trainee (0.86 vs. 0.69, p = 0.04).ConclusionACPPD-Gd enhances MMP-expressing tumors of any size at 3T 24 hours after administration, improving their detection by blinded observers when compared to non-contrast and contrast groups given commercial Gd-chelates and imaged during the equilibrium phase.

Gadolinium-functionalised multi-walled carbon nanotubes as a T1 contrast agent for MRI cell labelling and tracking

The development of efficient contrast agents for cell labelling coupled with powerful medical imaging techniques is of great interest for monitoring cell trafficking with potential clinical applications such as organ repair and regenerative medicine. In this paper, functionalised multi-walled carbon nanotubes (MWNTs) were engineered for cell labelling in T1-weighted MRI applications. These sophisticated constructs were covalently functionalised with the gadolinium (Gd) chelating agent, diethylene triamine pentaacetic acid (DTPA), enabling tight attachment of Gd atoms onto the nanotube surface. The resulting Gd-labelled MWNTs were found to be stable over 2weeks in water and mouse serum and high payload of Gd atoms could be loaded onto the nanotubes. The r1 relaxivity of the Gd-MWNTs was a 3-fold higher than of the clinically approved T1 contrast agent Magnevist at a magnetic field strength of 7T. The contrast efficiency, expressed as the r1 relaxivity, of the Gd-MWNTs in Human Umbilical Vein Endothelial cells (HUVEC) was investigated at 7T and was found to be around 6.6mM−1s−1. There was no reduction of the contrast efficiency after internalisation in HUVECs, which was imparted to the ability of carbon nanotubes to translocate the cell membrane.

Synthesis and Evaluation of Gd(III) -Based Magnetic Resonance Contrast Agents for Molecular Imaging of Prostate-Specific Membrane Antigen.

Magnetic resonance (MR) imaging is advantageous because it concurrently provides anatomic, functional, and molecular information. MR molecular imaging can combine the high spatial resolution of this established clinical modality with molecular profiling in vivo. However, as a result of the intrinsically low sensitivity of MR imaging, high local concentrations of biological targets are required to generate discernable MR contrast. We hypothesize that the prostate-specific membrane antigen (PSMA), an attractive target for imaging and therapy of prostate cancer, could serve as a suitable biomarker for MR-based molecular imaging. We have synthesized three new high-affinity, low-molecular-weight Gd(III) -based PSMA-targeted contrast agents containing one to three Gd(III) chelates per molecule. We evaluated the relaxometric properties of these agents in solution, in prostate cancer cells, and in an in vivo experimental model to demonstrate the feasibility of PSMA-based MR molecular imaging.

Multimeric Near IR-MR Contrast Agent for Multimodal In Vivo Imaging.

Multiple imaging modalities are often required for in vivo imaging applications that require both high probe sensitivity and excellent spatial and temporal resolution. In particular, MR and optical imaging are an attractive combination that can be used to determine both molecular and anatomical information. Herein, we describe the synthesis and in vivo testing of two multimeric NIR–MR contrast agents that contain three Gd(III) chelates and an IR-783 dye moiety. One agent contains a PEG linker and the other a short alkyl linker. These agents label cells with extraordinary efficacy and can be detected in vivo using both imaging modalities. Biodistribution of the PEGylated agent shows observable fluorescence in xenograft MCF7 tumors and renal clearance by MR imaging.

Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer.

BackgroundGene therapy is a very promising technology for treatment of pancreatic ductal adenocarcinoma (PDAC). However, its application has been limited by the abundant stromal response in the tumor microenvironment. The aim of this study was to prepare a dendrimer-based gene-free loading vector with high permeability in the tumor stroma and explore an imaging-guided local gene delivery strategy for PDAC to promote the efficiency of targeted gene delivery.MethodsThe experimental protocol was approved by the animal ethics committee of Zhongshan Hospital, Fudan University. Third-generation dendrigraft poly-L-lysines was selected as the nanocarrier scaffold, which was modified by cell-penetrating peptides and gadolinium (Gd) chelates. DNA plasmids were loaded with these nanocarriers via electrostatic interaction. The cellular uptake and loaded gene expression were examined in MIA PaCa-2 cell lines in vitro. Permeability of the nanoparticles in the tumor stroma and transfected gene distribution in vivo were studied using a magnetic resonance imaging-guided delivery strategy in an orthotopic nude mouse model of PDAC.ResultsThe nanocarriers were synthesized with a dendrigraft poly-L-lysine to polyethylene glycol to DTPA ratio of 1:3.4:8.3 and a mean diameter of 110.9±7.7 nm. The luciferases were strictly expressed in the tumor, and the luminescence intensity in mice treated by Gd-DPT/plasmid luciferase (1.04×104±9.75×102 p/s/cm2/sr) was significantly (P<0.05) higher than in those treated with Gd-DTPA (9.56×102±6.15×10 p/s/cm2/sr) and Gd-DP (5.75×103± 7.45×102 p/s/cm2/sr). Permeability of the nanoparticles modified by cell-penetrating peptides was superior to that of the unmodified counterpart, demonstrating the improved capability of nanoparticles for diffusion in tumor stroma on magnetic resonance imaging.ConclusionThis study demonstrated that an image-guided gene delivery system with a stroma-permeable gene vector could be a potential clinically translatable gene therapy strategy for PDAC.

Multifunctional gold nanostar-based nanocomposite: Synthesis and application for noninvasive MR-SERS imaging-guided photothermal ablation

We report here the design and facile synthesis of multifunctional gold nanostars based nanocomposites (MGSNs) through direct organosilica coating onto anisotropic gold nanostars followed by the conjugation of Gd chelates. The as-synthesized MGSNs possess strong NIR absorbance, SERS signal and enhanced T1-MR imaging capability with excellent dispersivity and uniform size, as well as great photothermal stability and Raman stability under photothermal conditions. Importantly, MGSNs present excellent performance in vivo after their intravenous injection for both MR and SERS imaging and the high efficiency for killing tumor cells through photothermal ablation with NIR irradiation. A combination of the high spatial resolution of MR and the exciting sub-cell-level sensitivity and resolution of SERS can provide comprehensive information about the tumor to achieve the optimized therapeutic outcome. Therefore, MGSNs are of great potential as a multifunctional nanoplatform for MR-SERS bimodal imaging-guided, focused photothermal tumor therapy.