Supramolecular aggregates of amphiphilic gadolinium complexes as blood pool MRI/MRA contrast agents: physicochemical characterization

In this paper, we present the development of a new potential blood pool contrast agent for magnetic resonance imaging applications (MRA/MRI) based on gadolinium complexes containing amphiphilic supramolecular aggregates. A novel amphiphilic unimer, containing the DTPAGlu chelating agent covalently bound to two C18 alkylic chains, has been synthesized. DTPAGlu is a well-known chelating agent for a wide number of ions such as the paramagnetic metal ion Gd3+ used as contrast agent in MRA/MRI. The wide aggregation behavior of this surfactant, as free base or as gadolinium complex, has been studied and compared by means of dynamic light scattering, small-angle neutron scattering and cryogenic transmission electron microscopy techniques. Near neutral pH in both cases, the dominant aggregates are micelles.The high negative actual charge of the surfactant headgroup causes a strong headgroups repulsion, promoting the formation of large and high curvature aggregates. By decreasing pH and less markedly increasing the ionic strength, we observe a micelle-to-vesicle transition driven by a decreased electrostatic repulsion. A straightforward switch between different aggregation states can be particularly useful in the development of pH-responsive MRA/MRI contrast agents.     

Polymeric micelles in diagnostic imaging

The results are presented describing the use of polymeric micelles for gamma, magnetic resonance (MR), and computed tomography (CT) imaging. Micelle-forming diacyllipid-PEG conjugates were loaded with monomeric and polymeric amphiphilic chelates, containing entrapped metals, such as 111-In or Gd, and used for the experimental gamma and MR imaging of lymphatics in rabbits. The method is described to prepare polymeric iodine-containing PEG-based micelles which may act as a long-circulating blood pool imaging agent for CT. Experimental CT-imaging performed in mice and rabbits demonstrated high potential of a micellar contrast agent.     

Preparation and in vitro evaluation of a novel amphiphilic GdPCTA-[12] derivative; a micellar MRI contrast agent

A novel amphiphilic GdPCTA-[12] derivative has been prepared. The complex formed micelles in aqueous solution with a relatively low CMC, 0.15 mM (25 degrees C). The concentration dependent T1-relaxivity (r1) of the system has been described. The maximum T1-relaxivity, 29.2 s-1 mM-1 (20 MHz, 25 degrees C), was higher than for previously described micellar MRI contrast agents. This high T1-relaxivity is a consequence of the favourable water residence time (tau M) and the fact that the complex is heptadentate allowing two water molecules to coordinate to the gadolinium ion (q = 2).     

Synthesis of amphiphilic silver nanoparticles in nanoreactors from invertible polyester

A silver complex is transformed into amphiphilic nanoparticles at room temperature using nanoreactors formed from an amphiphilic polyester. It takes a few minutes to form silver nanocolloids with a narrow particle size distribution. Developed silver forms a stable dispersion in both polar and nonpolar media. The amphiphilic polyester acts as a reducing and stabilizing agent simultaneously. The size of the synthesized amphiphilic silver nanoparticles depends on the concentration of the invertible polyester and solvent polarity.     

Thermal activation of polyethylene@silica particles: towards ceramic surfactants

The fabrication of “switch-on” amphiphilic submicrometer hybrid particles of cross-linked polyethylene (XPE)@silica is described. The synthesis of the particles is based on the simultaneous cross-linking of PE and the polycondensation of tetraethoxysilane in hot, surfactant-stabilized O/W micelles. Thermal activation of the particles results in particles with amphiphilic behavior. It is proposed that the thermal activation triggers partial phase-separation which pushes some of the PE chain to the surface, in a heterogeneous way. By this, on each particle two halves can be identified which differ in their degree of hydrophobicity (“Janus” structure), thus giving rise to the surfactant activity. The particles were intensively characterized before and after the thermal activation and their amphiphilic behavior was demonstrated. By the approach described in the paper it is in principle possible to design a library of functionalities out of a single surface active agent species. This was demonstrated by the thermal activation of functionalized composite particles of dyes@XPE@silica and of the triple hybrid Ag@XPE@silica. Full material characterization is provided, including SEM, TGA, surface area analysis, antibacterial tests and zeta potential measurements.     

Long-circulating gadolinium-loaded liposomes: potential use for magnetic resonance imaging of the blood pool

In our previous paper, we reported a method of liposome loading with Gadolinium (Gd) via so called polychelating amphiphilic polymer (PAP). A novel Gd-containing polymeric probe, suitable for the incorporation into the liposomal membrane, was prepared from a low-molecular-weight DTPA-polylysine by linking its N-terminus to a lipid anchor, NGPE-PE. When compared with known membranotropic MR probes, such as Gd-DTPA-SA and Gd-DTPA-PE, liposomes containing new membrane-bound polychelator possess enhanced relaxivity for water protons resulting in an increase of tissue signal intensity on MR images. In this study, we developed the optimized protocol to prepare a liposomal MR contrast agent with high relaxivity and narrow size distribution. Gd-containing liposomes were additionally modified with PEG to provide longevity in vivo. We also demonstrated that upon intravenous administration in rabbit and dog, the new preparation causes a prolonged decrease in the blood T₁ value (reflecting the proton relaxation rate in the blood) and may be considered as a potential contrast agent for MRI of the blood pool.     

Relaxometric investigations and MRI evaluation of a liposome-loaded pH-responsive gadolinium(III) complex

Accurate measurement of the tissue pH in vivo by MRI may be of clinical value for both diagnosis and selection/monitoring of therapy. To act as pH reporters, MRI contrast agents have to provide responsiveness to pH that does not require prior knowledge of the actual concentration of the contrast agent. This work deals with the use of a paramagnetic gadolinium(III) complex, loaded into liposomes, whose relaxometric properties are affected by the pH of the medium. In this system, the amphiphilic metal complex, which contains a moiety whose protonation changes the coordination properties of the metal chelate, experiences a different intraliposomial distribution depending on the pH conditions. The pH of the solution can be unambiguously identified by exploiting the peculiar characteristics of the resulting NMRD profiles, and a ratiometric pH-responsive method has been set up by comparing the relaxation enhancement at different magnetic field strengths.     

Facile, efficient conjugation of a trifunctional lanthanide chelate to a peripheral benzodiazepine receptor ligand

[reaction: see text] Receptor-mediated imaging and therapy of diseased tissue is rapidly gaining favor in the medical community. The synthesis and facile aqueous/organic coupling of a peripheral-type benzodiazepine receptor ligand to a cyclen-based fluorophore is described herein. The contrast agent QM-CTMC-PK11195, when chelated with lanthanides, produces bright luminescence and good MRI contrast and can potentially serve as an imaging and demarcation agent for certain types of cancers.     

Spontaneous formation and characterization of silica mesoporous crystal spheres with reverse multiply twinned polyhedral hollows

A crystal is an object with translational symmetry. Basic research into and production of new materials necessitates the preparation of crystals of a particular morphology and with well-defined crystal defects. In this work, we found novel silica mesoporous crystal spheres with polyhedral hollows (icosahedral, such as those observed for proteins of virus capsids, decahedral, Wulff polyhedral, etc.) formed by the reverse multiply twinned bicontinuous double diamond mesostructure. Vesicles with a low-curvature lamellar structure were first formed by the self-assembly of amphiphilic carboxylic acid molecules in the presence of a nonionic surfactant and then underwent a structural transformation process that gave a reverse multiply twinned mesoporous shell while maintaining the hollow shape. These polyhedral hollow crystals showed an enhanced contrast of backscattering signatures relative to the incident acoustic signals and thus could be used as a potential contrast agent in medical ultrasonography with drug loadings in the mesopores.     

Synthesis, characterization, and pharmacokinetic evaluation of a potential MRI contrast agent containing two paramagnetic centers with albumin binding affinity

A dinuclear gadolinium(III) complex of an amphiphilic chelating ligand, containing two diethylenetriamine-N,N,N',N',N'-pentaacetate (DTPA) moieties bridged by a bisindole derivative with three methoxy groups, has been synthesized and evaluated as a potential magnetic resonance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37 degrees C the dinuclear gadolinium(III) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s(-1) mmol(-1)). The higher relaxivity of the dinuclear gadolinium(III) complex can be related to its reduced motion and larger rotational correlation time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the noncovalently bound dinuclear complex increases to 15.2 s(-1) per mmol of Gd3+, due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (Ka) was found to be 10(4) M(-1). Because of its interaction with HSA, the dinuclear complex exhibits a longer elimination half-life from the plasma, and a better confinement to the vascular space compared to the commercially available [Gd(DTPA)] contrast agent. Transmetalation of the dinuclear gadolinium(III) complex by zinc(II) has been investigated. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepatobiliary route. In vivo studies indicated that half of the normal dose of the gadolinium(III) complex enhanced the contrast in hepatic tissues around 40 % more effectively than [Gd(DTPA)]. The dinuclear gadolinium(III) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis-targeting properties.     

Self‐emulsion polymerization of amphiphilic monomers—a green route to synthesis of polymeric nanoscaffolds

Self‐emulsion polymerization (SEP), a green route developed by us for the polymerization of amphiphilic monomers, does not require any emulsifier or an organic solvent except that the water‐soluble initiators such as 2,2′‐azobis[2‐(2‐imidazolin‐2‐yl)propane]dihydrochloride (VA‐044) and potassium persulfate (KPS) are only used. We report here the polymer nanoscaffolds from a number of amphiphilic monomers, which can be used for in situ encapsulation of a variety of nanoparticles. As a demonstration of the efficacy of these nanoscaffolds, the synthesis of a biocompatible hybrid nanoparticle (nanohybrid), prepared by encapsulating Fe₃O₄ magnetic nanoparticle (Fe₃O₄ MNPs) in poly(2‐hydroxyethyl methacrylate) in water, for MRI application is presented. The nanohybrid prepared following the SEP in the form of an emulsion does not involve the use of any stabilizing agent, crosslinker, polymeric emulsifier, or surfactant. This water‐soluble, spherical, and stable nanohybrid containing Fe₃O₄ MNPs of average size 10 ± 2 nm has a zeta potential value of ?41.89 mV under physiological conditions. Magnetic measurement confirmed that the nanohybrid shows typical magnetic behavior having a saturation magnetization (Ms) value of 32.3 emu/g and a transverse relaxivity (r2) value of 29.97 mM^?1 s^?1, which signifies that it can be used as a T2 contrast agent in MRI. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019     

Crowding effect induced phase transition of amphiphilic diblock copolymer in solution

The crowding agent induced phase transition of amphiphilic block copolymers in solution was explicitly considered. The influence of the size and the volume fraction of the crowding agent on the phase separation of amphiphilic diblock copolymers is investigated by using self-consistent field theory (SCFT) method. The concentration of the disorder to order transition of the block copolymer decreases when the size of the crowding agent is larger than that of the solvent. The higher volume fraction of the crowding agent will induce the transition of the block copolymer from disorder to order state at a lower concentration. The relation between the size and the volume fraction of the crowding agent is elucidated. When the size of the crowding agent is larger, its volume fraction of the disorder to order transition of the block copolymer will be lower. The conformation of the crowding agent considered as a polymer chain is also studied and compared.     

两亲性RAFT试剂存在下丙烯酸六氟丁醋和苯乙烯的无皂乳液聚合

合成了具有两亲性结构的可逆加成断裂链转移(RAFT)试剂,在RAFT试剂的作用下,通过无皂乳液聚合方法合成了丙烯酸六氟丁酯与苯乙烯的共聚物.研究了RAFT试剂浓度和聚合温度对聚合动力学、聚合反应可控性及乳胶粒粒径的影响.通过红外光谱(FTIR)、核磁共振谱(1H NMR)、示差扫描量热仪(DSC)、凝胶渗透色谱仪(GPC)及表面张力仪表征了共聚物的结构、玻璃化转变温度(Tg)、分子量和分子量分布及乳胶膜表面性能.结果表明,得到的苯乙烯和丙烯酸六氟丁酯共聚物无皂乳液的乳胶粒粒径在100 nm左右且呈单分散分布.当RAFT试剂浓度高于0.016 mol/L时聚合体系有较好的可控性.共聚物乳液的乳胶膜对水和二碘甲烷的接触角都很高.     

Gd‐DTPA‐Dopamine‐Bisphytanyl Amphiphile: Synthesis,Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents

Here, a new amphiphilic magnetic resonance imaging (MRI) contrast agent, a Gd^III‐chelated diethylenetriaminepentaacetic acid conjugated to two branched alkyl chains via a dopamine spacer, Gd‐DTPA‐dopamine‐bisphytanyl (Gd‐DTPA‐Dop‐Phy), which is readily capable of self‐assembling into liposomal nanoassemblies upon dispersion in an aqueous solution, is reported. In vitro relaxivities of the dispersions were found to be much higher than Magnevist, a commercially available contrast agent, at 0.47 T but comparable at 9.40 T. Analysis of variable temperature ¹⁷O NMR transverse relaxation measurements revealed the water exchange of the nanoassemblies to be faster than that previously reported for paramagnetic liposomes. Molecular reorientation dynamics were probed by ¹H NMRD profiles using a classical inner and outer sphere relaxation model and a Lipari–Szabo “model‐free” approach. High payloads of Gd^III ions in the liposomal nanoassemblies made solely from the Gd‐DTPA‐Dop‐Phy amphiphiles, in combination with slow molecular reorientation and fast water exchange makes this novel amphiphile a suitable candidate to be investigated as an advanced MRI contrast agent.     

Highly Loaded Semipermeable Nanocapsules for Magnetic Resonance Imaging

Magnetic resonance imaging has become an essential tool in medicine for the investigation of physiological processes. The key issues related to contrast agents, i.e., substances that are injected in the body for imaging, are the efficient enhancement of contrast, their low toxicity, and their defined biodistribution. Polyurea nanocapsules containing the gadolinium complex Gadobutrol as a contrast agent in high local concentration and high relaxivity up to 40 s⁻¹ mmol⁻¹ L are described. A high concentration of the contrast agent inside the nanocapsules can be ensured by increasing the crystallinity in the shell of the nanocapsules. Nanocapsules from aliphatic polyurea are found to display higher crystallinity and higher relaxivity at an initial Gadobutrol concentration of 0.1 m than aromatic polyurea nanocapsules. The nanocapsules and the contrast agent are clearly identified in cells. After injection, the nanocarriers containing the contrast agent are mostly found in the liver and in the spleen, which allow for a significant contrast enhancement in magnetic resonance imaging.     

Structural, kinetic, and thermodynamic characterization of the interconverting isomers of MS-325, a gadolinium(III)-based magnetic resonance angiography contrast agent

The amphiphilic gadolinium complex MS-325 ((trisodium-{(2-(R)-[(4,4-diphenylcyclohexyl) phosphonooxymethyl] diethylenetriaminepentaacetato) (aquo)gadolinium(III)}) is a contrast agent for magnetic resonance angiography (MRA). MS-325 comprises a GdDTPA core with an appended phosphodiester moiety linked to a diphenylcyclohexyl group to facilitate noncovalent binding to serum albumin and extension of the plasma half-life in vivo. The chiral DTPA ligand (R) was derived from L-serine, and upon complexation with gadolinium, forms two interconvertible diastereomers, denoted herein as isomers A and B. X-ray crystallography of the tris(ethylenediamine)cobalt(III) salt derivative of isomer A revealed a structure in the polar acentric space group P32. The structure consisted of three independent molecules of the gadolinium complex in the asymmetric unit along with three Delta-[Co(en)3]3+ cations, and it represents an unusual example of spontaneous Pasteur resolution of the cobalt cation. The geometry of the coordination core was best described as a distorted trigonal prism, and the final R factor was 5.6%. The configuration of the chiral central nitrogen of the DTPA core was S. The Gd-water (2.47-2.48 A), the Gd-acetate oxygens (2.34-2.42 A), and the Gd-N bond distances (central N, 2.59-2.63 A; terminal N, 2.74-2.80 A) were similar to other reported GdDTPA structures. The structurally characterized single crystal was one of two interconvertable diastereomers (isomers A and B) that equilibrated to a ratio of 1.81 to 1 at pH 7.4 and were separable at elevated pH by ion-exchange chromatography. The rate of isomerization was highly pH dependent: k1 = (1.45 +/- 0.08) x 102[H+] + (4.16 +/- 0.30) x 105[H+]2; k-1 = (2.57 +/- 0.17) x 102[H+] + (7.54 +/- 0.60) x 105[H+]2.     

Facile synthesis of core‐surface crosslinked nanoparticles by interblock RAFT polymerization

A new, efficient method for synthesizing stable nanoparticles with poly(ethylene oxide) (PEO) functionalities on the core surface, in which the micellization and crosslinking reactions occur in one pot, has been developed. First, amphiphilic PEO‐b‐PS copolymers were synthesized by reversible addition fragmentation chain transfer (RAFT) radical polymerization of styrene using (PEO)‐based trithiocarbonate as a macro‐RAFT agent. The low molecular weight PEO‐b‐PS copolymer was dissolved in isopropyl alcohol where the block copolymer self‐assembled as core‐shell micelles, and then the core‐shell interface crosslink was performed using divinylbenzene as a crosslinking agent and 2,2′‐azobisisobutyronitrile as an initiator. The design of the amphiphilic RAFT agent is critical for the successful preparation of core‐shell interface crosslinked micellar nanoparticles, because of RAFT functional groups interconnect PEO and polystyrene blocks. The PEO functionality of the nanoparticles surface was confirmed by ¹H NMR and FTIR. The size and morphology of the nanoparticles was confirmed by scanning electron microscopy, transmission electron microscopy, and dynamic laser light scattering analysis. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

PEGylated calix[4]arene as a carrier for a Bodipy-based photosensitizer

Heavy atom substituted Bodipy compounds, unlike the parent chromophore, undergo rapid intersystem crossing to generate singlet oxygen, which is the primary cytotoxic agent exploited in PDT. In this work, we show that an organic soluble calix[4]arene can be functionalized by Knoevenagel reaction and then converted into an amphiphilic photosensitizer in a few steps. In addition to generating a potentially useful photosensitizer, the sequence of reactions is the first use of a Bodipy dye as a chromophoric/fluorogenic label without the typical reactive functional groups.     

Studies on the Electrochemical Properties of Amphiphilic Ferrocenylimines Compounds

A series of amphiphilic ferrocenylimine compounds (four amphiphilic ferrocenylimines and four corresponding palladium complexes) were synthesized and their electrochemical characters were also investigated in detail. The results revealed that the redox of ferrocene derivatives was assumed by the ferrocene group and affected by substituent groups. Some effect rules were discovered and are described here. Moreover, the dynamics parameters of the electrode process were detected by several electrochemistry techniques.     

两亲性RAFT试剂存在下丙烯酸六氟丁醋和苯乙烯的无皂乳液聚合

合成了具有两亲性结构的可逆加成断裂链转移(RAFT)试剂,在RAFT试剂的作用下,通过无皂乳液聚合方法合成了丙烯酸六氟丁酯与苯乙烯的共聚物.研究了RAFT试剂浓度和聚合温度对聚合动力学、聚合反应可控性及乳胶粒粒径的影响.通过红外光谱(FTIR)、核磁共振谱(1H NMR)、示差扫描量热仪(DSC)、凝胶渗透色谱仪(GP...