New insights into water‐soluble and water‐coordinated copper 15‐metallacrown‐5 gadolinium complexes designed for high‐field magnetic resonance imaging applications

The development of contrast agents specifically designed for high‐field magnetic resonance imaging (MRI) is required because the relaxation efficiency of classic Gd(III) contrast agents significantly decreases with increasing magnetic field strengths. With an idea of exploring the unique structure of lanthanide (Ln) 15‐MC‐5 metallacrowns, we developed a series of water‐soluble Gd(III) aqua‐complexes, bearing aminohydroxamate (glycine, α‐alanine, α‐phenylalanine and α‐tyrosine) ligands, with increasing number of water molecules directly coordinated to the Gd(III) ion: Gd(H₂O)₄[15‐MC_Cu(II)Glyha‐5](Cl)₃ ( 1 (Gd)), Gd(H₂O)₄[15‐MC_Cu(II)Alaha‐5](Cl)₃ ( 2 (Gd)), Gd(H₂O)₃[15‐MC_{Cu(II)Phalaha}‐5](Cl)₃ ( 3 (Gd)) and Gd(H₂O)₃[15‐MC_Cu(II)Tyrha‐5](Cl)₃ ( 4 (Gd)). In these systems, the Ln(III) central ion is coordinated by five oxygen donor atoms of the ligands and three or four inner‐sphere water molecules. The X‐ray crystal structure of metallacrown Ln(H₂O)_3,4[15‐MC_Cu(II)Rha‐5]³⁺ agrees with density functional theory predictions. The calculations demonstrate that the exchange of coordinated water molecules can proceed easily, resulting in increased relaxivity parameters. The longitudinal relaxivities (r₁) of 1 (Gd)– 4 (Gd) in water at ultrahigh magnetic field of 9.4 T were determined to be 11.5, 14.8, 13.9 and 12.2 mM^?1 s^?1, respectively. The ability to increase the number of Ln(III) inner‐sphere water molecules up to four, the planar metallacrown structure and the rich hydration shell due to strong hydrogen bonds between the [15‐MC‐5] moiety and bulk water molecules provide new opportunities for potential MRI applications.     

Ultrasmall Superparamagnetic Iron Oxide Nanoparticles with Europium(III) DO3A as a Bimodal Imaging Probe

A new prototype consisting of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles decorated with europium(III) ions encapsulated in a DO3A organic scaffold was designed as a platform for further development of bimodal contrast agents for MRI and optical imaging. The USPIO nanoparticles act as negative MRI contrast agents, whereas the europium(III) ion is a luminophore that is suitable for use in optical imaging detection. The functionalized USPIO nanoparticles were characterized by TEM, DLS, XRD, FTIR, and TXRF analysis, and a full investigation of the relaxometric and optical properties was conducted. The typical luminescence emission of europium(III) was observed and the main red emission wavelength was found at 614 nm. The relaxometric study of these ultrasmall nanoparticles showed r₂ values of 114.8 mm ^?1_Fes^?1 at 60 MHz, which is nearly double the r₂ relaxivity of Sinerem^®.     

Highly Water‐Dispersible Surface‐Modified Gd2O3 Nanoparticles for Potential Dual‐Modal Bioimaging

Water‐dispersible and luminescent gadolinium oxide (GO) nanoparticles (NPs) were designed and synthesized for potential dual‐modal biological imaging. They were obtained by capping gadolinium oxide nanoparticles with a fluorescent glycol‐based conjugated carboxylate (H L ). The obtained nanoparticles (GO‐ L ) show long‐term colloidal stability and intense blue fluorescence. In addition, L can sensitize the luminescence of europium(III) through the so‐called antenna effect. Thus, to extend the spectral ranges of emission, europium was introduced into L‐ modified gadolinium oxide nanoparticles. The obtained Eu^III‐doped particles (Eu:GO‐ L ) can provide visible red emission, which is more intensive than that without L capping. The average diameter of the monodisperse modified oxide cores is about 4 nm. The average hydrodynamic diameter of the L ‐modified nanoparticles was estimated to be about 13 nm. The nanoparticles show effective longitudinal water proton relaxivity. The relaxivity values obtained for GO‐ L and Eu:GO‐ L were r₁=6.4 and 6.3 s^?1 mM ^?1 with r₂/r₁ ratios close to unity at 1.4 T. Longitudinal proton relaxivities of these nanoparticles are higher than those of positive contrast agents based on gadolinium complexes such as Gd‐DOTA, which are commonly used for clinical magnetic resonance imaging. Moreover, these particles are suitable for cellular imaging and show good biocompatibility.     

Synthesis,Relaxivity and MRI Enhancement of Linear Oligo‐Gd(III) Complexes with Poly (DTPA‐ester) Ligands Derived from Amino Acids

Six linear oligo‐DTPA‐ester Gd(III) complexes being used for potential MRI contrast agents were synthesized from amino adds and characterized. Their longitudinal relaxation rates were measured. One of them, die phenylalanine derivative, with high relaxivity, was chosen for the acute toxicity and T₁,‐weighted imaging test. The results indicated that there was no obvious toxicity for this new oligomeric Gd(III) complex, and it exhibits the highly enhanced MRI signal intensity and the increasing signal duration in the liver tissue compared to Gd‐DTPA.     

Gadolinium containing photochromic micelles as potential magnetic resonance imaging traceable drug carriers

Novel photochromic amphipathic molecules, KMR‐AZn (Gd‐DTPA‐AZCn), composed of hydrophilic Gd‐DTPA and hydrophobic alkylated azobenzene were prepared. In aqueous environment, KMR‐AZn indicated self‐assembly. The resulting aggregates were demonstrated to be able to include a hydrophobic drug substitute (hydrophobic fluorescent dye) into the internal core, and to release the included compound upon photoirradiation within 10 min through the influence of azobenzene photoisomerization. This micellar MRI contrast agent exhibited three‐ to four‐fold higher r₁ relaxivity (r₁ = 14.5–16.5 mm ^?1 s^?1, 0.47 T at 40°C) than the widely applied small molecule contrast agent Gd‐DTPA (Magnevist^®r₁ = 4.1 mm ^?1 s^?1, 0.47 T at 40°C). This dual functionality of encapsulated compound release and increased MR imaging contrast indicates that KMR‐AZn is a potential candidate for application as a lipid‐based MRI‐traceable drug carrier.     

Hexameric MnII Dendrimer as MRI Contrast Agent

A Mn^II chelating dendrimer was prepared as a contrast agent for MRI applications. The dendrimer comprises six tyrosine‐derived [Mn(EDTA)(H₂O)]^2? moieties coupled to a cyclotriphosphazene core. Variable temperature ¹⁷O NMR spectroscopy revealed a single water co‐ligand per Mn^II that undergoes fast water exchange (k_ex=(3.0±0.1)×10⁸ s^?1 at 37 °C). The 37 °C per Mn^II relaxivity ranged from 8.2 to 3.8 mM ^?1 s^?1 from 0.47 to 11.7 T, and is sixfold higher on a per molecule basis. From this field dependence a rotational correlation time was estimated as 0.45(±0.02) ns. The imaging and pharmacokinetic properties of the dendrimer were compared to clinically used [Gd(DTPA)(H₂O)]^2? in mice at 4.7 T. On first pass, the higher per ion relaxivity of the dendrimer resulted in twofold greater blood signal than for [Gd(DTPA)(H₂O)]^2?. Blood clearance was fast and elimination occurred through both the renal and hepatobiliary routes. This Mn^II containing dendrimer represents a potential alternative to Gd‐based contrast agents, especially in patients with chronic kidney disease where the use of current Gd‐based agents may be contraindicated.     

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.     

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     

Multifunctional Uniform Core–Shell Fe3O4@mSiO2 Mesoporous Nanoparticles for Bimodal Imaging and Photothermal Therapy

Multimodal imaging and simultaneous therapy is highly desirable because it can provide complementary information from each imaging modality for accurate diagnosis and, at the same time, afford an imaging‐guided focused tumor therapy. In this study, indocyanine green (ICG), a near‐infrared (NIR) imaging agent and perfect NIR light absorber for laser‐mediated photothermal therapy, was successfully incorporated into superparamagnetic Fe₃O₄@mSiO₂ core–shell nanoparticles to combine the merit of NIR/magnetic resonance (MR) bimodal imaging properties with NIR photothermal therapy. The resultant nanoparticles were homogenously coated with poly(allylamine hydrochloride) (PAH) to make the surface of the composite nanoparticles positively charged, which would enhance cellular uptake driven by electrostatic interactions between the positive surface of the nanoparticles and the negative surface of the cancer cell. A high biocompatibility of the achieved nanoparticles was demonstrated by using a cell cytotoxicity assay. Moreover, confocal laser scanning microscopy (CLSM) observations indicated excellent NIR fluorescent imaging properties of the ICG‐loaded nanoparticles. The relatively high r₂ value (171.6 mM ^?1 s^?1) of the nanoparticles implies its excellent capability as a contrast agent for MRI. More importantly, the ICG‐loaded nanoparticles showed perfect NIR photothermal therapy properties, thus indicating their potential for simultaneous cancer diagnosis as highly effective NIR/MR bimodal imaging probes and for NIR photothermal therapy of cancerous cells.     

Platinum(II)–Gadolinium(III) Complexes as Potential Single‐Molecular Theranostic Agents for Cancer Treatment

Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)–gadolinium(III) complexes with the formula [{Pt(NH₃)₂Cl}₂GdL](NO₃)₂ possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt–Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mM ), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd–DTPA. T₁‐weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt–Gd complexes promising theranostic agents for cancer treatment.     

Block copolymer composition drives function of self‐assembled nanoparticles for delivery of small‐molecule cargo

Nanoparticles are useful for the delivery of small molecule therapeutics, increasing their solubility, in vivo residence time, and stability. Here, we used organocatalytic ring opening polymerization to produce amphiphilic block copolymers for the formation of nanoparticle drug carriers with enhanced stability, cargo encapsulation, and sustained delivery. These polymers comprised blocks of poly(ethylene glycol) (PEG), poly(valerolactone) (PVL), and poly(lactide) (PLA). Four particle chemistries were examined: (a) PEG‐PLA, (b) PEG‐PVL, (c) a physical mixture of PEG–PLA and PEG–PVL, and (d) PEG–PVL–PLA tri‐block copolymers. Nanoparticle stability was assessed at room temperature (20 °C; pH = 7), physiological temperature (37 °C; pH = 7), in acidic media (37 °C; pH = 2), and with a digestive enzyme (lipase; 37 °C; pH = 7.4). PVL‐based nanoparticles demonstrated the highest level of stability at room temperature, 37 °C and acidic conditions, but were rapidly degraded by lipase. Moreover, PVL‐based nanoparticles demonstrated good cargo encapsulation, but rapid release. In contrast, PLA‐based nanoparticles demonstrated poor stability and encapsulation, but sustained release. The PEG–PVL–PLA nanoparticles exhibited the best combination of stability, encapsulation, and release properties. Our results demonstrate the ability to tune nanoparticle properties by modifying the polymeric architecture and composition. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1322–1332     

Serum Albumin Targeted,pH‐Dependent Magnetic Resonance Relaxation Agents

The objective of this work was the synthesis of serum albumin targeted, Gd^III‐based magnetic resonance imaging (MRI) contrast agents exhibiting a strong pH‐dependent relaxivity. Two new complexes ( Gd‐glu and Gd‐bbu ) were synthesized based on the DO3A macrocycle modified with three carboxyalkyl substituents α to the three ring nitrogen atoms, and a biphenylsulfonamide arm. The sulfonamide nitrogen coordinates the Gd in a pH‐dependent fashion, resulting in a decrease in the hydration state, q, as pH is increased and a resultant decrease in relaxivity (r₁). In the absence of human serum albumin (HSA), r₁ increases from 2.0 to 6.0 mM ^?1 s^?1 for Gd‐glu and from 2.4 to 9.0 mM ^?1 s^?1 for Gd‐bbu from pH 5 to 8.5 at 37 °C, 0.47 T, respectively. These complexes (0.2 mM ) are bound (>98.9 %) to HSA (0.69 mM ) over the pH range 5–8.5. Binding to albumin increases the rotational correlation time and results in higher relaxivity. The r₁ increased 120 % (pH 5) and 550 % (pH 8.5) for Gd‐glu and 42 % (pH 5) and 260 % (pH 8.5) for Gd‐bbu . The increases in r₁ at pH 5 were unexpectedly low for a putative slow tumbling q=2 complex. The Gd‐bbu system was investigated further. At pH 5, it binds in a stepwise fashion to HSA with dissociation constants K_d1=0.65, K_d2=18, K_d3=1360 μM . The relaxivity at each binding site was constant. Luminescence lifetime titration experiments with the Eu^III analogue revealed that the inner‐sphere water ligands are displaced when the complex binds to HSA resulting in lower than expected r₁ at pH 5. Variable pH and temperature nuclear magnetic relaxation dispersion (NMRD) studies showed that the increased r₁ of the albumin‐bound q=0 complexes is due to the presence of a nearby water molecule with a long residency time (1–2 ns). The distance between this water molecule and the Gd ion changes with pH resulting in albumin‐bound pH‐dependent relaxivity.     

Perfluorocarbon‐loaded shell crosslinked knedel‐like nanoparticles: Lessons regarding polymer mobility and self‐assembly

Reversible addition‐fragmentation chain transfer polymerization was employed to synthesize a set of copolymers of styrene (PS) and 2,3,4,5,6‐pentafluorostyrene (PPFS), as well as block copolymers with tert‐butyl acrylate (PtBA)‐b‐PS‐co‐PPFS, with control over molecular weight and polydispersity. It was found that the copolymerization of styrene and PFS allowed for the preparation of gradient copolymers with opposite levels of monomer consumption, depending on the feed ratio. Conversion to amphiphilic block copolymers, PAA‐b‐(PS‐co‐PPFS), by removing the protecting groups was followed by fitting with monomethoxy poly(ethylene glycol) chains. Solution‐state assembly and intramicellar crosslinking afforded shell crosslinked knedel‐like (SCK) block copolymer nanoparticles. These fluorinated nanoparticles (ca. 20 nm diameters) were studied as potential magnetic resonance imaging (MRI) contrast agents based on the ¹⁹F‐nuclei; however, it was found that packaging of the hydrophobic fluorinated polymers into the core domain restricted the mobility of the chains and prohibited ¹⁹F NMR spectroscopy when the particles were dispersed in water without an organic cosolvent. Packing of perflouro‐15‐crown‐5‐ether (PFCE) into the polymer micelle was demonstrated with good uptake efficiency; however, it was necessary to swell the core with a good solvent (DMSO) to increase the mobility and observe the ¹⁹F NMR signal of the PFCE. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1023–1037, 2009     

Approaching the Kinetic Inertness of Macrocyclic Gadolinium(III)‐Based MRI Contrast Agents with Highly Rigid Open‐Chain Derivatives

A highly rigid open‐chain octadentate ligand (H₄cddadpa) containing a diaminocylohexane unit to replace the ethylenediamine bridge of 6,6′‐[(ethane‐1,2 diylbis{(carboxymethyl)azanediyl})bis(methylene)]dipicolinic acid (H₄octapa) was synthesized. This structural modification improves the thermodynamic stability of the Gd³⁺ complex slightly (log K_GdL=20.68 vs. 20.23 for [Gd(octapa)]^?) while other MRI‐relevant parameters remain unaffected (one coordinated water molecule; relaxivity r₁=5.73 mm ^?1 s^?1 at 20 MHz and 295 K). Kinetic inertness is improved by the rigidifying effect of the diaminocylohexane unit in the ligand skeleton (half‐life of dissociation for physiological conditions is 6 orders of magnitude higher for [Gd(cddadpa)]^? (t_1/2=1.49×10⁵ h) than for [Gd(octapa)]^?. The kinetic inertness of this novel chelate is superior by 2–3 orders of magnitude compared to non‐macrocyclic MRI contrast agents approved for clinical use.     

Polymeric 1H MRI Probes for Visualizing Tumor In Vivo

Magnetic resonance imaging (MRI) has become a prominent non– or low–invasive imaging technique, providing high–resolution, three–dimensional images as well as physiological information about tissues. Low–molecular–weight Gd–MRI contrast agents (CAs), such as Gd–DTPA (DTPA: diethylenetriaminepentaacetic acid), are commonly used in the clinical diagnosis, while macromolecular Gd–MRI CAs have several advantages over low–molecular–weight Gd–MRI CAs, which help minimize the dose of CAs and the risk of side effects. Accordingly, we developed chiral dendrimer Gd–MRI CAs, which showed high r₁ values. The association constant values (K_a) of S–isomeric dendrimer CAs to bovine serum albumin (BSA) were higher than those of R–isomeric dendrimer CAs. Besides, based on a totally new concept, we developed ¹³C/¹⁵N–enriched multiple–resonance NMR/MRI probes, which realized highly selective observation of the probes and analysis of metabolic reactions of interest. This account summarizes our recent study on developing both chiral dendrimer Gd–MRI CAs, and self–traceable ¹³C/¹⁵N–enriched phosphorylcholine polymer probes for early detection of tumors.     

Tetraphenylporphyrin‐based dual‐functional medical agent for magnetic resonance and fluorescence imaging

A bimodal magnetic resonance imaging contrast agent, TPP‐M‐Gd, was developed by modifying tetraphenylporphyrin (TPP) with a small dendritic molecule as a ligand (M) to chelate gadolinium (Gd) ions. The ligand featured four carboxylate groups, which contributed to good water solubility and a strong combination with metal ions. The longitudinal relaxivity (R₁) of the resulting agent was calculated to be 12.45 mM^?1 s^?1, which is much higher than that of DTPA‐Gd (4.49 mM^?1 s^?1). The magnetic resonance imaging experiments showed that the newly synthesized contrast agent could enhance T₁‐weighted magnetic resonance imaging quality both in vitro and in vivo. In addition, TPP‐M‐Gd exhibited good fluorescent property as shown in cell imaging experiments. The cytotoxicity of TPP‐M‐Gd was even better than that of clinically approved DTPA‐Gd, which makes it a promising dual‐functional medical imaging agent to provide more detailed information about biological and disease‐related events.     

Synthesis and Characterization of a Hypoxia‐Sensitive MRI Probe

Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium(III) complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with a 2‐nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia‐sensitive MRI agent. A control complex, Gd(DO3A‐monobutylamide), was also prepared in order to test whether the nitroimidazole side‐chain alters either the water proton T₁ relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)^? as expected for mono‐amide derivatives. The water proton T₁ relaxivity (r₁), bound water residence lifetime (τ_M) and rotational correlation time (τ_R) of both complexes was determined by relaxivity measurements, variable temperature ¹⁷O NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r₁=6.38 mM ^?1 s^?1 at 20 MHz , τ_M=0.71 μs, τ_R=141 ps) determined for the nitroimidazole derivative closely parallel to those of other Gd(DO3A‐monoamide) complexes of similar molecular size. In vitro MR imaging experiments with 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative was trapped in cells maintained under N₂ as evidenced by an approximately twofold decrease in T₁ measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative might serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.     

Comparative study of paclitaxel physically encapsulated in and chemically conjugated with PEG‐PLA

Paclitaxel‐loaded poly(ethylene glycol)‐b‐poly(l ‐lactide (LA)) (PEG‐PLA) micelles were prepared by two methods. One is physical encapsulation of paclitaxel in micelles composed of a PEG‐PLA block copolymer and the other is based on a PEG‐PLA–paclitaxel conjugate, abbreviated as “conjugate micelles”. Their physicochemical characteristics, e.g. critical micelle concentration (CMC), morphology, and micelle size distribution were then evaluated by means of fluorescence spectroscopy, scanning electron microscopy (SEM), and dynamic light scattering (DLS). The results show that the CMC of PEG‐PLA–paclitaxel and PEG‐PLA are 6.31 × 10^?4 and 1.78 × 10^?3 g L^?1, respectively. Both micelles assume a spherical shape with comparable diameters and have unimodal size distribution. Moreover, invitro drug delivery behavior was studied by high performance liquid chromatography (HPLC). The antitumor activity of the paclitaxel‐loaded micelles against human liver cancer H7402 cells was evaluated by 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) method. The conjugate micelles show a lower burst release during the initial stage and higher accumulative release amount of paclitaxel after a period of time while the encapsulated ones behave in the opposite way. Both the paclitaxel‐loaded micelles showed comparable anticancer efficacy with the free drug. Copyright © 2008 John Wiley & Sons, Ltd.     

Structural and Relaxometric Characterization of Peptide Aggregates Containing Gadolinium Complexes as Potential Selective Contrast Agents in MRI

The structural and relaxometric characterization of a novel class of supramolecular aggregates, as potential tumor‐specific contrast agents in magnetic resonance imaging (MRI), is reported. The aggregates are based on a new monomer with an upsilon shape (MonY) that contains, in the same molecule, all three fundamental tasks that are required: 1) a hydrophobic moiety that allows the formation of supramolecular aggregates; 2) the bioactive CCK8 peptide for target recognition; and 3) a chelating agent able to give stable gadolinium complexes. As indicated by dynamic light scattering and small‐angle neutron scattering (SANS) measurements, MonY and its gadolinium complex MonY(Gd) aggregate in aqueous solution to give ellipsoidal micelles with a ratio between the micellar axes of ≈1.7 and an aggregation number N_agg of ≈30. There are no differences in the aggregation behavior of MonY and MonY(Gd), which indicates that the presence of metal ions, and therefore the reduction of the net charge, does not influence the aggregation behavior. When MonY or MonY(Gd) are blended with dioleoyl phosphatidylcholine (DOPC), the aggregation behavior is dictated by the tendency of DOPC to give liposomes. Only when the amount of MonY or MonY(Gd) is higher than 20 % is the coexistence of liposomes and micelles observed. The thickness d of the bilayer is estimated by SANS to be ≈35–40 Å, whereas cryogenic transmission electron microscopy images show that the diameter of the liposomes ranges from ≈50 to 150 nm. Self‐assembling micelles of MonY(Gd) present high relaxivity values (r_1p=15.03 mM ^?1 s^?1) for each gadolinium complex in the aggregate. Liposomes containing MonY(Gd) inserted in the DOPC bilayer at a molar ratio of 20:80 present slightly lower relaxivity values (r_1p=12.7 mM ^?1 s^?1), independently of their internal or external position in the liposome.     

The Role of Equilibrium and Kinetic Properties in the Dissociation of Gd[DTPA‐bis(methylamide)] (Omniscan) at near to Physiological Conditions

[Gd(DTPA‐BMA)] is the principal constituent of Omniscan, a magnetic resonance imaging (MRI) contrast agent. In body fluids, endogenous ions (Zn²⁺, Cu²⁺, and Ca²⁺) may displace the Gd³⁺. To assess the extent of displacement at equilibrium, the stability constants of DTPA‐BMA^3? complexes of Gd³⁺, Ca²⁺, Zn²⁺, and Cu²⁺ have been determined at 37 °C in 0.15 M NaCl. The order of these stability constants is as follows: GdL≈CuL>ZnL?CaL. Applying a simplified blood plasma model, the extent of dissociation of Omniscan (0.35 mM [Gd(DTPA‐BMA)]) was found to be 17 % by the formation of Gd(PO₄), [Zn(DTPA‐BMA)]^? (2.4 %), [Cu(DTPA‐BMA)]^? (0.2 %), and [Ca(DTPA‐BMA)]^? (17.7 %). By capillary electrophoresis, the formation of [Ca(DTPA‐BMA)]^? has been detected in human serum spiked with [Gd(DTPA‐BMA)] (2.0 mM ) at pH 7.4. Transmetallation reactions between [Gd(DTPA‐BMA)] and Cu²⁺ at 37 °C in the presence of citrate, phosphate, and bicarbonate ions occur by dissociation of the complex assisted by the endogenous ligands. At physiological concentrations of citrate, phosphate, and bicarbonate ions, the half‐life of dissociation of [Gd(DTPA‐BMA)] was calculated to be 9.3 h at pH 7.4. Considering the rates of distribution and dissociation of [Gd(DTPA‐BMA)] in the extracellular space of the body, an open two‐compartment model has been developed, which allows prediction of the extent of dissociation of the Gd^III complex in body fluids depending on the rate of elimination of the contrast agent.