T1-weighted MRI Contrast Agent Research Articles

Folate Receptor Targeting Mn(II) Complex Encapsulated Porous Silica Nanoparticle as an MRI Contrast Agent for Early-State Detection of Cancer.

Cancer is recognized as one of the major causes of mortality, however, early-stage detection can increase the survival chance greatly. It is recognized that folate receptors are gradually overexpressed in the cellular membrane with the progress of cancer from stage 1 to stage 4. Utilizing the fact, herein, developed a porous silica nanoparticle system C1@SiO2-FA-NP; A) impregnated with thermodynamically stable Mn(II) complex (1) molecules within the core of the nanoparticle, and B) surface functionalized with folate units. It exhibited a high longitudinal relaxivity value r1 = 21.45 mM-1s-1 that substantially increased to r1 = 40.97 mM-1s-1 in the presence of 0.67mM concentration of BSA under the physiological condition. The in vitro fluorescent images after surface conjugation of C1@SiO2-FA-NP with FITC (fluorescein isothiocyanate) buttressed the inclusion of the nanoparticle exclusively within the cancerous HeLa cells than that of healthy HEK293 cells. The importance of the surface-bound folate unit in the nanoparticle is further established by comparing the fluorescent images of HeLa cells in the absence of the group. Finally, the applicability of C1@SiO2-FA-NP as the T1-weighted MRI contrast agent for early-stage cancer diagnosis is established within C57BL/6 mice after infecting the mice with HeLa cells.

Development of multifunctional MnO2-based nanoplatforms for hypoxia modulation/T1-weighted MRI/ optical biosensing and targeted drug delivery

TME-responsive MnO2 nanorod-based platform was synthesized through the simple and eco-friendly hydrothermal approach. Then, chitosan cross-linked tripolyphosphate (Chi-TPP) was applied to coat the surface of the MnO2 nanorod to enhance the biocompatibility of bare nanostructures. The high specific surface area (51.966 m2/g) and heterogeneous nature of MnO2@Chi-TPP nanoplatforms demonstrated a significant physical loading capacity of pharmaceutical cargo (97.116 mg/g). In-vitro release profiles demonstrated that the release of DOX and the Fenton-like reaction for enhanced therapeutic effect were induced by the demolition of MnO2 nanorod to Mn2+ under acidic conditions and high glutathione (GSH), high temperature, and high concentration of H2O2. Additionally, Mn2+ ions could function as a T1-weighted MRI contrast agent. As-synthesized nanoplatforms not only serve as a TME-responsive nanocarrier but also introduces a TME-modulating agent to produce molecular O2 and simultaneously decrease tumor hypoxia. To precise detection of the tumor microenvironment, fluorescein isothiocyanate (FITC) was well labeled on the MnO2@Chi-TPP nanoplatform. The MnO2 nanorods are known as a fluorescence signal quencher regardless of the wide absorption band in the visible spectrum through the fluorescence resonance energy transfer (FRET) effect. The in-vitro analysis proved the TME-responsiveness of the MnO2@Chi-TPP@FITC nanosystem. The recovery of the fluorescence signal in the TME introduced the MnO2@Chi-TPP@FITC nanosystem as a “turn off-on” sensor.

Doping engineering of iron oxide nanoparticles towards high performance and biocompatible T1-weighted MRI contrast agents

Doping engineering of iron oxide nanoparticles towards high performance and biocompatible T1-weighted MRI contrast agents

Fast detection of liver fibrosis with collagen-binding single-nanometer iron oxide nanoparticles via T1-weighted MRI

SNIO-CBP, a single-nanometer iron oxide (SNIO) nanoparticle functionalized with a type I collagen-binding peptide (CBP), was developed as a T1-weighted MRI contrast agent with only endogenous elements for fast and noninvasive detection of liver fibrosis. SNIO-CBP exhibits 6.7-fold higher relaxivity compared to a molecular gadolinium-based collagen-binding contrast agent CM-101 on a per CBP basis at 4.7T. Unlike most iron oxide nanoparticles, SNIO-CBP exhibits fast elimination from the bloodstream with a 5.7min half-life, high renal clearance, and low, transient liver enhancement in healthy mice. We show that a dose of SNIO-CBP that is 2.5-fold lower than that for CM-101 has comparable imaging efficacy in rapid (within 15min following intravenous injection) detection of hepatotoxin-induced liver fibrosis using T1-weighted MRI in a carbon tetrachloride-induced mouse liver injury model. We further demonstrate the applicability of SNIO-CBP in detecting liver fibrosis in choline-deficient L-amino acid-defined high-fat diet mouse model of nonalcoholic steatohepatitis. These results provide a platform with potential for the development of high relaxivity, gadolinium-free molecular MRI probes for characterizing chronic liver disease.

The electrostatic confinement of aquated monocationic Gd(III) complex-molecules within the inner core of porous silica nanoparticles creates a highly efficient T1 contrast agent for magnetic resonance imaging.

Contrast-agent enhanced magnetic resonance imaging (MRI) has been under continuous investigation for the conspicuous imaging of lesions and the early-stage detection of tumors. To achieve the development of a T1-weighted contrast agent with a high relaxivity value, herein, porous silica nanoparticles that had internalized about 20 aquated cationic Gd(III) complexes (1) of the hexadentate hydroxyethyl-appended picolinate-based ligand H2hbda were demonstrated. Complex 1 exhibited a longitudinal relaxivity value per mM Gd(III) ions, r1, of 9.05 mM-1 s-1 (pH 7.4, 37 °C, 1.41 T), which increased to 86.41 mM-1 s-1 because of the grafting of complex 1 in the inner core of porous silica nanospheres through electrostatic interactions between the anionic silica surface and the cationic complex 1 molecules. A further augmentation in the relaxivity value to 118.32 mM-1 s-1 was realized because of the interaction of the complex 1@SiO2NPs with serum albumin protein. The synthesized nanosystem was impervious to physiologically available anions (HPO42- and HCO31-) and also kinetically inert, as evidenced via a transmetallation experiment in the presence of Zn(II) ions. The developed complex-incorporated nanomaterial was bio- and hemo-compatible. Cellular uptake measurements employing HeLa cells and the concentration-dependent enhancement in the brightness of in vitro phantom images, recorded under a clinical scanner at 1.5 T, demonstrated that the developed biocompatible 1@SiO2NP complex has promising diagnostic applications as a T1-weighted MRI contrast agent.

Synthesis and Evaluation of a Gd (III) Complex as T1-Weighted MRI Contrast Agent

Synthesis and Evaluation of a Gd (III) Complex as T1-Weighted MRI Contrast Agent

The Gadonanotubes as High-Performance MRI Contrast Agents: The Unappreciated Role of the Carbon Nanotube Component at Low Magnetic Fields

The Gadonanotubes (GNTs) are the highest-performing T1-weighted MRI contrast agent material known with a relaxivity of ∼160 mM−1s−1 per Gd3+ ion at 1.5 T. In this work, the contribution of carbon-based free radicals at defect sites on the sidewalls of the ultra-short carbon nanotube (US-tube) component of the GNTs to the T1 relaxation time has been investigated by Nuclear Magnetic Resonance Dispersion (NMRD) and Electron Paramagnetic Resonance (EPR) studies. The NMRD results indicate that carbon-based radicals of the US-tube structure substantially shorten water proton spin-lattice relaxation times at low frequencies (< 1 MHz) and that the high water proton relaxation rate for the GNTs at these fields does not result from the Gd3+ ion alone. Furthermore, a computational study suggests that the defect sites of the US-tube structure increase nanotube strain and create new interband electronic states. While the presence of Gd3+ ions at the defect sites for the GNTs do not induce new electronic states, they do introduce a shift in the Fermi level to higher energy (0.4 eV).

Hyaluronic acid-coated nanoparticles for targeted photodynamic therapy of cancer guided by near-infrared and MR imaging

In this study, the multifaceted properties of hyaluronic acid (HA) were used for the targeted therapy of cancer by photodynamic therapy (PDT) guided by molecular imaging. Near-infrared (NIR) photosensitizers (Chlorin e6; Ce6) were encapsulated into poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) coated with HA that can act as CD44 targeting ligand. The abundant carboxylate groups of HA also enabled the chelation of gadolinium ions (Gd3+), T1-weighted MRI contrast agents, on the surface of PLGA NPs. Through both in vitro and in vivo fluorescence and MRI signal analysis, we confirmed that the HA-Gd-Ce6-PLGA NPs (HAGCP-NPs) could efficiently target CD44-overexpressing A549 cancer cells. When an NIR laser was illuminated to irradiate A549 tumor-bearing mice, the groups treated with HAGCP-NPs showed remarkable delays in tumor growth or tumor regression. Taken together, the HAGCP-NPs are expected to be used as a theranostic platform for the dual modal (MR/NIR) imaging and PDT of cancer.

Indocyanine green-loaded polydopamine-iron ions coordination nanoparticles for photoacoustic/magnetic resonance dual-modal imaging-guided cancer photothermal therapy.

Multi-modal imaging-guided cancer photothermal therapy (PTT) with advanced theranostic nanoagents can efficiently improve therapeutic efficacy and reduce treatment side effects. Herein, we have developed a theranostic nanoagent based on indocyanine green (ICG)-loaded polydopamine (PDA)-iron ions coordination nanoparticles (PDA-Fe3+-ICG NPs), which are used for photoacoustic (PA) and magnetic resonance (MR) dual-modal imaging-guided cancer PTT treatments. In this nanoplatform, ICG molecules, the U.S. Food and Drug Administration approved near-infrared (NIR) dye, absorbing on PDA NPs (a melanin-like biopolymer) to significantly increase the NIR optical absorption of PDA NPs nearly 6 times and decreases their fluorescence emission, which can improve the PA contrast ability and promote the photothermal conversion efficiency of PDA NPs. Meanwhile, Fe3+ ions chelated on the PDA NPs act as a T1-weighted MRI contrast agent (r1 = 14 mM-1 s-1). In a mouse 4T1 breast tumor model, PA/MRI dual-modal imaging and highly efficient PTT treatments with low laser density were achieved with remarkable therapeutic efficiency and minimal side effects. This study illustrates that the highly integrated and biocompatible PDA-based NPs can serve as a versatile nanoplatform by loading different imaging molecules and drugs for multi-modal imaging and cancer combination therapy.

Paramagnetic lanthanide chelates for multicontrast MRI.

The preparation of a paramagnetic chelator that serves as a platform for multicontrast MRI, and can be utilized either as a T1-weighted, paraCEST or (19)F MRI contrast agent is reported. Its europium(iii) complex exhibits an extremely slow water exchange rate which is optimal for the use in CEST MRI. The potential of this platform was demonstrated through a series of MRI studies on tube phantoms and animals.

Synthesis and Evaluation of Neutral Gd(III), Mn(II) Complexes From DTPA-Bisamide Derivative as Potential MRI Contrast Agents

A strong chelating ligand was synthesized through the modification of DTPA by bioactive 5-fluorouracil derivatives and characterized by means of mass spectra, Fourier transform infrared spectra, elemental analysis, and nuclear magnetic resonance spectroscopy. Its complexes of Gd(III) and Mn(II) were designed as potential MRI contrast agents. Thermodynamic stability constant of the complexes indicated that they were stable enough to prevent the metal ions from releasing. Relaxivity studies showed that the two complexes provided higher T1-weighted relaxivity than that of commercial contrast agent Gd-DTPA and the Mn(II) complex owned much higher T2-weighted relaxation property. Both the Gd(III) and Mn(II) complexes had the advantage of becoming promising T1-weighted MRI contrast agents.

Mesoporous manganese silicate coated silica nanoparticles as multi-stimuli-responsive T1-MRI contrast agents and drug delivery carriers

A novel kind of monodisperse mesoporous manganese silicate coated silica nanoparticle (MMSSN) as a highly efficient T1-weighted MRI contrast agent (CA) and drug carrier for cancer diagnosis and chemotherapy has been constructed by a modified “SiO2 sacrifice and in situ silicate growth” approach under a relatively low hydrothermal temperature and alkali-free condition. The mesoporous manganese silicate shell provides a large specific surface area and abundant exposed Mn paramagnetic centers to water molecules, which endows the MMSSNs with extraordinarily high longitudinal relaxivity. Meanwhile, the MMSSNs presented an efficient pH/redox-responsive T1-MRI feature based on the significant enhancement of relaxation rate (r1) stimulated by mild acidic environment or reducing agent (GSH) both in vitro and in vivo. Furthermore, the mesoporous structure and negatively charged pore surface of the manganese silicate shell enable the MMSSNs to attain anti-cancer drug (DOX) storage and a pH-responsive release, which is suitable for on-demand drug release for the chemotherapy of tumors. Therefore, the mesoporous manganese silicate-based nanomaterial is a promising candidate as T1-MRI CAs and anticancer-drug delivery carriers for the theranostics of tumor in an intelligent and on-demand manner. Statement of significanceMRI is one of the most frequently used imaging techniques in daily clinics for cancer diagnosis. Using contrast agents (CAs) in MRI can afford much clearer and enlarged images of detectable organs. Gadolinium (Gd3+)-based T1-positive CAs are widely used but associated with the risk of nephrogenic systemic fibrosis. To achieve much safer CAs, various Mn2+-based T1-positive CAs have been reported, such as MnO or core-shell MnOx-based nanoparticles. However, the efficiency of these CAs is still lower. Herein, we report a novel kind of mesoporous manganese silicate coated silica nanoparticle as CA and anti-cancer drug carrier. Results obtained from this study, especially the pH/redox-responsive T1-MRI feature are helpful for us to further design efficient MnSiO3-based materials for clinical MRI applications.

Self-organized Mn2+-Block Copolymer Complexes and Their Use for In Vivo MR Imaging of Biological Processes.

Manganese-block copolymer complexes (MnBCs) that contain paramagnetic Mn ions complexed with ionic-nonionic poly(ethylene oxide-b-poly(methacrylate) have been developed for use as a T1-weighted MRI contrast agent. By encasing Mn ion within ionized polymer matrices, r1 values could be increased by 250-350 % in comparison with free Mn ion at relative high fields of 4.7 to 11.7 T. MnBCs were further manipulated by treatment with NaOH to achieve more stable complexes (iMnBCs). iMnBCs delayed release of Mn2+ which could be accelerated by low pH, indeed by cellular uptake via endocytosis into acidic compartments. Both complexes exhibited good T1 contrast signal enhancement in liver following intravenous infusion. The contrast was observed in gallbladder due to the clearance of Mn ion from liver to biliary process. iMnBCs, notably, showed a delayed contrast enhancement profile in gallbladder, which was interpreted to be due to degradation and excretion of Mn2+ ions into the gallbladder. Intracortical injection of iMnBCs into the rat brain also led to delayed neuronal transport to thalamus. The delayed enhancement feature may have benefits for targeting MRI contrast to specific cells and surface receptors that are known to be internalized by endocytosis.

Iron-Loaded Magnetic Nanocapsules for pH-Triggered Drug Release and MRI Imaging.

Magnetic nanocapsules were synthesized for controlled drug release, magnetically assisted delivery, and MRI imaging. These magnetic nanocapsules, consisting of a stable iron nanocore and a mesoporous silica shell, were synthesized by controlled encapsulation of ellipsoidal hematite in silica, partial etching of the hematite core in acid, and reduction of the core by hydrogen. The iron core provided a high saturation magnetization and was stable against oxidation for at least 6 months in air and 1 month in aqueous solution. The hollow space between the iron core and mesoporous silica shell was used to load anticancer drug and a T1-weighted MRI contrast agent (Gd-DTPA). These multifunctional monodispersed magnetic “nanoeyes” were coated by multiple polyelectrolyte layers of biocompatible poly-l-lysine and sodium alginate to control the drug release as a function of pH. We studied pH-controlled release, magnetic hysteresis curves, and T1/T2 MRI contrast of the magnetic nanoeyes. They also served as MRI contrast agents with relaxivities of 8.6 mM–1 s–1 (r1) and 285 mM–1 s–1 (r2).

Biocompatible and high-performance amino acids-capped MnWO4 nanocasting as a novel non-lanthanide contrast agent for X-ray computed tomography and T1-weighted magnetic resonance imaging

In the present work, a novel non-lanthanide dual-modality contrast agent, manganese tungstate (MnWO4), has been successfully constructed by a facile and versatile hydrothermal route. With the merits of a high atomic number and a well-positioned K-edge energy of tungsten, our well-prepared non-lanthanide nanoprobes provide a higher contrast efficacy than routine iodine-based agents in clinics. Additionally, the presence of Mn in these nanoparticles endow them with excellent T1-weighted MR imaging capabilities. As an alternative to T2-weighted MRI and CT dual-modality contrast agents, the nanoprobes can provide a positive contrast signal, which prevents confusion with the dark signals from hemorrhage and blood clots. To the best of our knowledge, this is the first report that a non-lanthanide imaging nanoprobe is applied for CT and T1-weighted MRI simultaneously. Moreover, comparing with gadolinium-based T1-weighted MRI and CT dual-modality contrast agents that were associated with nephrogenic systemic fibrosis (NSF), our contrast agents have superior biocompatibility, which is proved by a detailed study of the pharmacokinetics, biodistribution, and in vivo toxicology. Together with excellent dispersibility, high biocompatibility and superior contrast efficacy, these nanoprobes provide detailed and complementary information from dual-modality imaging over traditional single-mode imaging and bring more opportunities to the new generation of non-lanthanide nanoparticulate-based contrast agents.

Bisphosphonate-anchored PEGylation and radiolabeling of superparamagnetic iron oxide: long-circulating nanoparticles for in vivo multimodal (T1 MRI-SPECT) imaging.

The efficient delivery of nanomaterials to specific targets for in vivo biomedical imaging is hindered by rapid sequestration by the reticuloendothelial system (RES) and consequent short circulation times. To overcome these two problems, we have prepared a new stealth PEG polymer conjugate containing a terminal 1,1-bisphosphonate (BP) group for strong and stable binding to the surface of ultrasmall-superparamagnetic oxide nanomaterials (USPIOs). This polymer, PEG(5)-BP, can be used to exchange the hydrophobic surfactants commonly used in the synthesis of USPIOs very efficiently and at room temperature using a simple method in 1 h. The resulting nanoparticles, PEG(5)-BP-USPIOs are stable in water or saline for at least 7 months and display a near-zero ζ-potential at neutral pH. The longitudinal (r1) and transverse (r2) relaxivities were measured at a clinically relevant magnetic field (3 T), revealing a high r1 of 9.5 mM–1 s–1 and low r2/r1 ratio of 2.97, making these USPIOs attractive as T1-weighted MRI contrast agents at high magnetic fields. The strong T1-effect was demonstrated in vivo, revealing that PEG(5)-BP-USPIOs remain in the bloodstream and enhance its signal 6-fold, allowing the visualization of blood vessels and vascular organs with high spatial definition. Furthermore, the optimal relaxivity properties allow us to inject a dose 4 times lower than with other USPIOs. PEG(5)-BP-USPIOs can also be labeled using a radiolabeled-BP for visualization with single photon emission computed tomography (SPECT), and thus affording dual-modality contrast. The SPECT studies confirmed low RES uptake and long blood circulation times (t1/2 = 2.97 h). These results demonstrate the potential of PEG(5)-BP-USPIOs for the development of targeted multimodal imaging agents for molecular imaging.

Dual purpose Prussian blue nanoparticles for cellular imaging and drug delivery: a new generation of T1-weighted MRI contrast and small molecule delivery agents

A simple and improved aqueous synthetic procedure using flash heating for preparing biocompatible Prussian blue nanoparticles (PBNPs) with the single-crystal-like feature was developed. This method entailed the use of citric acid as a chelator to complex ferric ions in the precursor and as an in situ capping agent to prevent the PB nanoparticles formed in solution from aggregation. The citrate-coated PBNPs, which can be surface functionalized with small molecules, were readily internalized by cells and exhibited no detectable cytotoxicity. Furthermore, such nanoparticles do not trigger the production of reactive oxygen species (ROS) in cells via the Fenton reaction. The potential of using such PBNPs as an effective T1-weighted cellular MRI contrast agent has also been demonstrated. These properties suggest that PBNPs are an attractive dual purpose nanoplatform for developing the next generation of nanoparticle-based T1-weighted MRI contrast agents as well as delivery vehicles for small molecules.

Biocompatible Prussian blue nanoparticles: Preparation, stability, cytotoxicity, and potential use as an MRI contrast agent

Abstract A simple synthetic procedure for preparing biocompatible superparamagnetic Prussian blue (PB) nanoparticles is reported. The stability, cytotoxicity and ability for PB nanoparticles to penetrate cells are investigated. The potential of using PB nanoparticles as the T1-weighted MRI contrast agent is demonstrated.