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Pol Besenius,
Kelly P van den Hout,
Harald M H G Albers,
Tom F A de Greef,
Luuk L C Olijve,
Thomas M Hermans,
Bas F M de Waal,
Paul H H Bomans,
Nico A J M Sommerdijk,
Giuseppe Portale,
Anja R A Palmans, Marcel H P van Genderen,
Jef A J M Vekemans,
E W Meijer
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ABSTRACT: The supramolecular oligomerization of three water-soluble C(3)-symmetrical discotic molecules is reported. The compounds all possess benzene-1,3,5-tricarboxamide cores and peripheral Gd(III)-DTPA (diethylene triamine pentaacetic acid) moieties, but differ in their linker units and thus in their propensity to undergo secondary interactions in H(2)O. The self-assembly behavior of these molecules was studied in solution using circular dichroism, UV/Vis spectroscopy, nuclear magnetic resonance, and cryogenic transmission electron microscopy. The aggregation concentration of these molecules depends on the number of secondary interactions and on the solvophobic character of the polymerizing moieties. Hydrophobic shielding of the hydrogen-bonding motif in the core of the discotic is of paramount importance for yielding stable, helical aggregates that are designed to be restricted in size through anti-cooperative, electrostatic, repulsive interactions.
Chemistry 03/2011; 17(18):5193-203. · 5.93 Impact Factor
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ABSTRACT: Details of the forces between nanoparticles determine the ways in which the nanoparticles can self-assemble into larger structures. The use of directed interactions has led to new concepts in self-assembly such as asymmetric dendrons, Janus particles, patchy colloids and colloidal molecules. Recent models that include attractive regions or 'patches' on the surface of the nanoparticles predict a wealth of intricate modes of assembly. Interactions between such particles are also important in a range of phenomena including protein aggregation and crystallization, re-entrant phase transitions, assembly of nanoemulsions and the organization of nanoparticles into nanowires. Here, we report the synthesis of 6-nm nanoparticles with dynamic hydrophobic patches and show that they can form reversible self-assembled structures in aqueous solution that become topologically more connected upon dilution. The organization is based on guest-host supramolecular chemistry with the nanoparticles composed of a hydrophobic dendrimer host molecule and water-soluble hydrophilic guest molecules. The work demonstrates that subtle changes in hierarchal composition and/or concentration can dramatically change mesoscopic ordering.
Nature Nanotechnology 11/2009; 4(11):721-6. · 27.27 Impact Factor
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Thomas M Hermans,
Maarten A C Broeren,
Nikos Gomopoulos,
A F Smeijers,
Brahim Mezari,
Ellen N M Van Leeuwen,
Matthijn R J Vos,
Pieter C M M Magusin,
Peter A J Hilbers, Marcel H P Van Genderen,
Nico A J M Sommerdijk,
George Fytas,
E W Meijer
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ABSTRACT: We provide detailed insight into complex supramolecular assembly processes by fully characterizing a multicomponent model system using dynamic light scattering, cryogenic transmission electron microscopy, atomic force microscopy, and various NMR techniques. First, a preassembly of a host molecule (the fifth-generation urea-adamantyl poly(propylene imine) dendrimer) and 32 guest molecules (a water- and chloroform-soluble ureidoacetic acid guest) was made in chloroform. The association constant in chloroform is concealed by guest self-association and is therefore higher than 10(3) M(-1). Via the neat state the single-host complex was transferred to water, where larger dendrimer-based assemblies were formed. The core of these assemblies, consisting of multiple host molecules (on average three), is kinetically trapped upon dissolution in water, and its size is constant irrespective of the concentration. The guest molecules forming the corona of the assemblies, however, stay dynamic since they are still in rapid exchange on the NMR time scale, as they were in chloroform. A stepwise noncovalent synthesis provides a means to obtain metastable dynamic supramolecular assemblies in water, structures that cannot be formed in one step.
Journal of the American Chemical Society 01/2008; 129(50):15631-8. · 9.91 Impact Factor
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03/2007: pages 47 - 88; , ISBN: 9780470511497
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ABSTRACT: Different generations of Gd(III)DTPA-terminated poly(propylene imine) dendrimers {G1 [n = 4 Gd(III) ions per molecule], G3 (n = 16) and G5 (n = 64)} and reference Gd(III)DTPA complex [G0 (n = 1)] were characterized in terms of (i) longitudinal (r1) and transverse (r2) relaxivities in mouse blood plasma, (ii) concentration detection limits in vitro and (iii) in vivo contrast-enhanced MR imaging (CE-MRI) in mice at 1.5 T. Serial and dynamic CE-MRI were performed to monitor the distribution of MRI contrast agent in the heart, arteries, renal system, liver, spleen, bladder and tumor periphery. The relaxivities increased non-linearly with molecular weight (for G0 ionic r1 = 8.1 mM(-1) s(-1) and ionic r2 = 8.6 mM(-1) s(-1) to G5 19.3 and 25.0, respectively). The minimal detectable dendrimer concentration was more than two orders of magnitude lower for G5 (8.1 x 10(-8) M) than for G0 (3.1 x 10(-5) M). Sub-millimeter-sized blood vessels were well visualized with serial CE-MRI with each contrast agent. Dynamic CE-MRI showed timely renal clearance for all contrast agents, but a stronger and a prolonged blood signal enhancement for the higher generations of the dendritic contrast agent. Moreover, G0 and G1 showed a rapid tumor wash-in and wash-out, whereas G3 and G5 displayed a more gradual and prolonged tumor wash-in. In conclusion, both G0 and dendritic contrast agents G1, G3 and G5 are well suited for non-tissue-specific MRI of sub-millimeter-sized blood vessels and evaluating tumor microcirculatory characteristics in mice. Higher generations of dendritic contrast agents display lower concentration detection limits, which suggests their future use for molecular imaging.
NMR in Biomedicine 03/2006; 19(1):133-41. · 3.21 Impact Factor
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Journal of Polymer Science Part A Polymer Chemistry 10/2005; 43(24):6431 - 6437. · 3.92 Impact Factor
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ABSTRACT: Host-guest interactions between the periphery of adamantylurea-functionalized dendrimers (host) and ureido acetic acid derivatives (guest) were shown to be specific, strong and spatially well-defined. The binding becomes stronger when using phosphonic or sulfonic acid derivatives. In the present work we have quantified the binding constants for the host-guest interactions between two different host motifs and six different guest molecules. The host molecules, which resemble the periphery of a poly(propylene imine) dendrimer, have been fitted with an anthracene-based fluorescent probe. The two host motifs differ in terms of the length of the spacer between a tertiary amine and two ureido functionalities. The guest molecules all contain an acidic moiety (either a carboxylic acid, a phosphonic acid, or a sulfonic acid) and three of them also contain an ureido moiety capable of forming multiple hydrogen bonds to the hosts. The binding constants for all 12 host-guest complexes have been determined by using fluorescence titrations by monitoring the increase in fluorescence of the host upon protonation by the addition of the guest. The binding constants could be tuned by changing the design of the acidic part of the guest. The formation of hydrogen bonds gives, in all cases, higher association constants, demonstrating that the host is more than a proton sensor. The host with the longer spacer (propyl) shows higher association constants than the host with the shorter spacer (ethyl). The gain in association constants are higher when the urea function is added to the guests for the host with the longer spacer, indicating a better fit. Collision-induced dissociation mass spectrometry (CID-MS) is used to study the stability of the six motifs using the corresponding third generation dendrimer. A similar trend is found when the six different guests are compared.
Chemistry 09/2005; 11(17):5126-35. · 5.93 Impact Factor
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ABSTRACT: A new way to analyze supramolecular dendritic architectures is reported by making use of (13)C NMR and (31)P NMR. Two ethylene glycol guest molecules have been synthesized containing a (13)C labeled carboxylic acid headgroup (2) and a phosphonic acid headgroup (3). The binding of these guests to urea-adamantyl modified poly(propylene imine) dendrimers has been investigated with (13)C NMR and (31)P NMR next to 1D and 2D (1)H NMR techniques. Different amounts of guest 2 have been added to fifth generation dendrimer 1e, and the observed chemical shift values in (13)C NMR were fitted to a model that assumes 1:1 binding between guest and binding site. An association constant of 400 +/- 95 M(-)(1) is obtained for guest 2 with 41 binding sites per dendrimer. When different amounts of phosphonic acid guest 3 are added to dendrimer 1e, two different signals are observed in (31)P NMR. Deconvolution gives the fractions of free and bound guest, resulting in an association constant of (4 +/- 3) x 10(4) M(-)(1) and 61 +/- 1 binding sites. A statistical analysis shows that guest 2 forms a "polydisperse supramolecular aggregate", while guest 3 is able to form a "monodisperse supramolecular aggregate" when the amount of guest is high enough. The NMR results are compared with dynamic light scattering experiments, and a remarkable agreement is found. Phosphonic acid guest 3 is able to exchange with guest 2, which is in agreement with the obtained association constants, and shows that these techniques can be used to analyze multicomponent dendritic aggregates.
Journal of the American Chemical Society 08/2005; 127(29):10334-43. · 9.91 Impact Factor
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ABSTRACT: The synthesis of a cyclic peptide-Gd(III)DTPA molecule equipped with biotin is presented, yielding a well-defined multivalent MRI contrast agent after its coupling to avidin.
Chemical Communications 07/2005; · 6.17 Impact Factor
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Annalen der Chemie und Pharmacie 06/2005; 2005(12):2534 - 2538. · 3.10 Impact Factor
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ABSTRACT: To evaluate the relationship between dynamic contrast agent-enhanced magnetic resonance (MR) imaging-derived kinetic parameters and contrast agents of equal chemical composition and configuration but with different molecular weights in a tumor angiogenesis model.
This study was approved by the ethical review committee. Maintenance and care of animals was in compliance with guidelines set by the institutional animal care committee. Dynamic contrast-enhanced MR imaging was performed with dendritic contrast agents in 16 mice with tumor xenografts; mice were placed in groups of four for each molecular weight of the contrast agent. The magnitude and spatial distribution of kinetic parameters (transfer coefficient [K(PS)] and plasma fraction [f(PV)]) were compared with molecular weight of the contrast agent by determining the Spearman correlation coefficient (r) and the quantitative relationship between the endothelial K(PS) and molecular weight.
Inverse relationships between molecular weight of contrast agent and K(PS) and f(PV) of tumor rim (r = -0.8, P < .001 and r = -0.5, P = .04, respectively) and core (r = -0.7, P = .004 and r = -0.6, P = .01, respectively) were observed. The quantitative relationship between K(PS) and molecular weight (MW) was K(PS) = 0.4/MW(0.44). A decreasing stepwise pattern in f(PV) was noted between contrast agents with low (0.7- and 3.0-kDa) molecular weight and those with high (12- and 51-kDa) molecular weight.
Macromolecular permeability is best measured with high-molecular-weight contrast agents; endothelial K(PS) values measured with low-molecular-weight contrast agents incorporate tissue perfusion and permeability and demonstrate heterogeneous microcirculatory flow.
Radiology 05/2005; 235(1):65-72. · 5.73 Impact Factor
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ABSTRACT: Boc-protected L-phenylalanine has been connected to a spacer-armed ureido-acetic acid derivative, which can form multiple supramolecular complexes with urea-adamantyl modified poly(propylene imine) dendrimers in chloroform. Complexes of this guest with several generations of urea-adamantyl dendrimers were prepared. The dendrimer-guest complexes were characterized in detail by (1)H-NMR, (1)H-(1)H-NOESY spectroscopy and mass spectrometry to prove their formation. Optical rotation experiments performed on different generations of dendrimer-guest complexes showed a constant positive value. These observations indicate that, though guest molecules decrease the flexibility at the periphery of the dendrimer upon binding, the amino acid at the terminus of the guest molecule retains its high local conformational freedom. This is in agreement with values found for covalently modified spacer-armed dendrimers.
Organic & Biomolecular Chemistry 02/2005; 3(2):281-5. · 3.70 Impact Factor
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ABSTRACT: [structure: see text] A bimodal target-specific contrast agent based on a cyclic peptide containing the target-specific NGR sequence, gadolinium(III) diethylenetriaminepentaacetic acid (Gd(III)DTPA), and Oregon Green 488 (OG488) suitable for both MR imaging and optical imaging of angiogenesis is developed. The synthetic strategy for this target-specific contrast agent exploits the use of highly efficient, chemoselective reactions, such as native chemical ligation, and gives a straightforward approach for double labeling of peptides in general.
Organic Letters 01/2005; 6(26):4857-60. · 5.86 Impact Factor
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ABSTRACT: The supramolecular chemistry of the third generation poly(propyleneimine) dendrimers (1) having adamantylurea end groups was investigated using multidimensional NMR on a 750 MHz spectrometer. A stable complex (3) is formed when 1 is combined with cyanobiphenyl guest molecules (2) having glycinylurea type end groups. Proton connectivities were obtained from 2D 1H−1H TOCSY experiment. The 13C and 1H resonances were correlated from the 2D 1H−13C gHSQC experiment. Spatial proximity of the host−guest molecules was determined from a 2D 1H−1H NOESY experiment. Evidence of the specific binding interactions responsible for the stable complex of 1 with 2 was obtained from 1H−1H interactions determined from the NOESY spectrum.
10/2004;
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Angewandte Chemie International Edition 08/2004; 43(27):3557-62. · 13.45 Impact Factor
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ABSTRACT: A biotinylated Gd-DTPA complex is designed to study the biotin-avidin complexation using the longitudinal relaxivity of this new MRI label, which illustrates the use of MRI contrast agents to probe the formation of supramolecular assemblies in water.
Organic & Biomolecular Chemistry 06/2004; 2(9):1271-3. · 3.70 Impact Factor
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ABSTRACT: 15N-Labeled ureido-4[1H]-pyrimidinones 4a and 5a were synthesized in order to investigate hydrogen bonding in the strongly hydrogen-bonded dimers in solution with intermolecular (2h)J(NN) coupling. Both direct-detection (15)N NMR and one-dimensional (15)N INADEQUATE (for smaller scalar coupling constants) were employed to determine the coupling constants. For dimers of 4 in CDCl(3), a temperature-dependent (2h)J(NN) was observed ranging from 2 Hz at +10 degrees C to 5.1 Hz at -20 degrees C. In dimers of more slowly exchanging bifunctional derivative 5, the coupling constants could be determined at room temperature from an inverse-gated (1)H-decoupled (15)N NMR experiment. Coupling constants in different isomers of the dimer of 5a (4.96, 5.13, 4.37, and 5.27 Hz) were used to test the relationship between (2h)J(NN) values and N-N distances as proposed by Del Bene et al. The N-N distances calculated with the aid of this relationship show excellent agreement with the distances observed in the X-ray crystal structures of 5b, particularly when the nonlinearity of the hydrogen bonds is taken into account.
The Journal of Organic Chemistry 12/2003; 68(23):9070-5. · 4.45 Impact Factor
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ABSTRACT: Redistribution of poly(2,6-dimethyl-1,4-phenylene ether) (PPE) with a phenolic compound yields a depolymerized polymer having the phenolic compound incorporated as the tail end. The molecular weight of the product is adjusted by use of the ratio of phenol over PPE repeating units. PPE oligomers and telechelics with a large variety of end groups, including reactive end groups, can be prepared in this way. Furthermore, block copolymers can be prepared by reacting a phenol terminated polymer in a redistribution with PPE. This is illustrated by the reaction of phenol terminated polystyrene with PPE, leading to polystyrene−PPE diblock copolymers. TMDPQ or copper/amine catalysts can be used as catalyst depending on the reacting phenolic compound, desired reaction time, and product purity. For a fast PPE redistribution with ortho-unsubstituted phenols, without any oxidation of the methyl substituents of the PPE chain, the use of TMDPQ is preferred. For the preparation of pure oligomers and block copolymers, a slow redistribution using copper catalysts in the absence of oxygen is preferred.
10/1997;
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ABSTRACT: A convenient methodology has been developed for the synthesis of gadolinium-diethylene-triaminepentaacetic acid (Gd-DTPA)-terminated poly(propylene imine) dendrimers as contrast agents for magnetic resonance imaging (MRI). In our strategy, isocyanate-activated, tert-butyl-protected DTPA analogues were coupled to different generations of poly(propylene imine) dendrimers. Deprotection of the tert-butyl esters with trifluoroacetic acid in dichloromethane and extensive dialysis afforded gadolinium-chelating poly(propylene imine) dendrimers. The corresponding Gd-DTPA-based dendritic contrast agents were prepared from GdCl 3 in either water or citrate buffer. Atomic force microscopy and cryogenic transmission electron microscopy experiments of the fifth-generation Gd-DTPA based dendritic contrast agent in citrate buffer demonstrated the presence of well-defined spherical particles with nanoscopic dimensions (5-6 nm), and no self-aggregation of dendrimers was observed. The efficiencies of these dendritic contrast agents in MRI, expressed in terms of longitudinal (r 1) and transverse (r2) relaxivities, were determined at 1.5 T at 20 °C. The r1 and r2 values increase considerably with increasing generation of Gd-DTPA-terminated dendrimer. The fifth-generation dendritic contrast agent displays the highest ionic relaxivities (per gadolinium), r1) 19.7 mM -1 s -1 and r2) 27.8 mM -1 s -1 , which are substantially higher than the ionic relaxivities of parent Gd-DTPA. Moreover, a series of combined gadolinium and yttrium complexes of the fifth-generation dendrimer are prepared, resulting in well-defined dendritic contrast agents with tunable molecular relaxivities.
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ABSTRACT: Signal enhancement in heteronuclear correlation spectra as well as signal selection in 1H experiments can be achieved through inverse, i.e., 1H, detection in the solid state under fast MAS conditions. Using recoupled polarization transfer (REPT), a heteronuclear 1H–15N single-quantum correlation (HSQC) experiment is presented whose symmetrical design allows the frequency dimensions to be easily interchanged. By observing the 15N dimension indirectly and detecting on 1H, the sensitivity is experimentally found to be increased by factors between 5 and 10 relative to conventional 15N detection. In addition, the inverse 1H–15N REPT-HSQC scheme can be readily used as a filter for the 1H signal. As an example, we present the combination of such a heteronuclear filter with a subsequent 1H–1H DQ experiment, yielding two-dimensional 15N-edited 1H–1H DQ MAS spectra. In this way, specific selection or suppression of 1H resonances is possible in solid-state MAS experiments, by use of which the resolution can be improved and information can be unravelled in 1H spectra.
Journal of Magnetic Resonance.
