Lectin Conjugates as Biospecific Contrast Agents for MRI. Coupling of Lycopersicon esculentum Agglutinin to Linear Water-Soluble DTPA-Loaded Oligomers (original) (raw)
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Journal of Inorganic Biochemistry, 2011
With the purpose to develop macromolecular magnetic resonance imaging contrast agents, we herein report three different synthetic approaches to the covalent attachment of bifunctional chelating agents to human serum albumin followed by coordination to contrast enhancing gadolinium(III). Applied methods cover active ester-mediated conjugation, linkage through glutaryl spacer, as well as the connection by the employment of glutaraldehyde. The content of gadolinium(III) was evaluated by inductively-coupled-plasma massspectrometry (ICP-MS) measurements and indicated reproducible amounts of conjugated contrast enhancing material. Small angle X-ray scattering (SAXS) experiments provided the size and altered shape of the gadolinium loaded proteins in comparison to unmodified albumin. Finally, the magnetic resonance properties of the protein conjugates were evaluated. The results indicated suitability of the gadolinium(III) loaded protein conjugates for use as macromolecular contrast agents in magnetic resonance imaging (MRI).
Bioconjugate Chemistry, 1990
The synthesis and characterization of polysaccharides esterified with gadolinium diethylenetriaminepentaacetic acid (GdDTPA) are described. The results of several synthetic methods are presented for esterification of dextrans and inulin with DTPA. One method results in highly conjugated products labeled with an average of 0.4 mol of GdDTPA/mol of glucopyranose unit in dextrans of up to 70 800 average molecular weight and 0.5 mol of GdDTPA/mol of fructofuranose unit in inulin. Chromatographic and potentiometric evidence supporting the absence of significant chelate cross-linking of the conjugated polysaccharides is presented. The thermodynamic stability constant, log K (Gd3+ + L4-GdL-), of the complexes was 18.0 f 0.2 based on an independent chelate model. In vitro ester hydrolysis of the GdDTPA-dextran 70 800 (at 37 "C, pH = 7.4 phosphate buffer) occurs with a half-life of 21 h. The agents exhibit TI relaxivities ranging from 1.5 to 2.3 times that of GdDTPA at 100 MHz, and decreasing in vitro relaxivity with increasing molecular weight of the dextran carrier was observed. Phantom MRI studies indicate that the T I and T2 effects of the complexes differ from those of GdDTPA, with the polysaccharide-bound complexes exhibiting a considerably faster drop in relative signal intensity with increased concentration in T I and T2 weighted pulse sequences. Magnetic resonance imaging (MRI) has rapidly become the method of choice for the initial screening of patients suspected of a variety of physiological disorders including certain types of cancer (1-3). The gadolinium(II1) complex of diethylenetriaminepentaacetic acid (GdDTPA) (4-8) and other paramagnetic compounds (9-11) have been used successfully to enhance the imaging of several types of carcinomas, particularly those of the brain. GdDTPA undergoes rapid renal excretion following extracellular biodistribution with a blood-concentration half-life of 20 min (12). The short persistence and rapid extravascular distribution of GdDTPA make t h e contrast agent * Author to whom correspondence should be addressed.
Mechanistic Investigation of β-Galactosidase-Activated MR Contrast Agents
Inorganic Chemistry, 2008
We report a mechanistic investigation of an isomeric series of -galactosidase-activated magnetic resonance contrast agents. Our strategy focuses on the synthesis of macrocyclic caged-complexes that coordinatively saturate a chelated lanthanide. Enzyme cleavage of the complex results in an open coordination site available for water that creates a detectable MR contrast agent. The complexes consist of a DO3A Gd(III) chelator modified with a galactopyranose at the N-10 position of the macrocycle. We observed significant differences in relaxometric properties and coordination geometry that can be correlated to subtle variations of the linker between the macrocycle and the galactopyranose. After synthesis and purification of the R, S, and racemic mixtures of complexes 1 and 3 and measurement of the hydration number, water residence lifetime, and longitudinal relaxation rates, we propose mechanisms for water exclusion from the lanthanide in the precleavage state. While the stereochemistry of the linker does not influence the agents' properties, the mechanism of water exclusion for each isomer is significantly influenced by the position of modification. Data for one series with a methyl group substituted on the sugar-macrocycle linker at the R-position suggests a steric mechanism where the galactopyranose sugar blocks water from the Gd(III) center. In contrast, our observations for a second series with methyl substitution at the position of the sugar-macrocycle linker are consistent with a mechanism in which a bidentate anion occupies two available coordination sites of Gd(III) in the precleavage state.
… -A European Journal, 2004
The synthesis and characterization of a new class of DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10tetraazacyclododecane) monoamide-linked glycoconjugates (glucose, lactose and galactose) of different valencies (mono, di and tetra) and their Sm III , Eu III and Gd III complexes are reported. The 1 H NMR spectrum of Eu III -DOTALac 2 shows the predominance of a single structural isomer of square antiprismatic geometry of the DOTA chelating moiety and fast rotation about the amide bond connecting to the targeting glycodendrimer.
Bovine serum albumin (BSA) (Mn= 66.5 kD, size = 14 × 4 × 4 nm) is an attractive biological molecule forbiomedical applications because of its water-solubility and bio-compatibility. It can also bind manyultrasmall nanoparticles (NPs) as confirmed in this study. We synthesized polyethylene glycol diacid(PEGD) coated ultrasmall Gd2O3nanoparticles (PEGD-GNPs, the core davg= 2.0 nm), which were then con-jugated to BSA and cleaved-BSA (C-BSA) (i.e. BSA-PEGD-GNPs and C-BSA-PEGD-GNPs) through amidebonding. Large relaxivities were observed in both aqueous sample solutions (r1= 6.0 s−1mM−1andr2= 28.0 s−1mM−1for BSA-PEGD-GNPs and r1= 7.6 s−1mM−1and r2= 22.0 s−1mM−1for C-BSA-PEGD-GNPs). Three tesla T2magnetic resonance imaging (MRI) in a mouse after the injection of an aqueoussample solution of BSA-PEGD-GNPs into a mouse tail vein revealed significant negative contrast enhance-ments. Large relaxivities and in vivo MR images prove that BSA-PEGD-GNPs and C-BSA-PEGD-GNPs arepotential MRI contrast agents.
Development of novel oligomer-based intravascular contrast agents for MRI using gadolinium chelates
First of all, I wish to express my deepest and sincere gratitude to my supervisor, Asst. Prof. Roderick W. Bates for his supervision, meaningful guidance, invaluable suggestions, kindness and encouragement throughout my study. This accomplishment would not be possible without his help. I also would like to express my gratitude to Dr Yang Chang-Tong for his collaboration in bioactivities testing and excellent comments. My appreciation is also extended to the staff of the Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, particularly Miss Goh Ee-Ling, Miss Yeo Siew-Ping, and Ms Zhu Wen-Wei for their guidance about recording spectral data and also Dr. Li Yongxin for X-ray crystal structure analysis. I would like to thank all of my friends and colleagues, especially in the Bates group for their warm relationship and kind cooperation. I am grateful to Nanyang Technological University and A*Star (Agency for Science, Technology and Research) through SBIC for financial support. Finally, I am deeply grateful to my parents, my sister and brothers for their invaluable love, encouragement and long-term support. To all of them, I would like to give my gratitude and thanks again.
Lectin–Gd-Loaded Chitosan Hydrogel Nanoparticles: A New Biospecific Contrast Agent for MRI
Molecular Imaging and Biology, 2011
Purpose: Non-specific extracellular contrast agents have been on the market for more than 15 years. Here, we report on the synthesis of new selective lectin-gadolinium (Gd)-loaded chitosan nanoparticles with a prolonged clearance time and a much higher relaxivity in comparison to other preparations. Procedures: Chitosan nanoparticles were prepared from 85% deacetylated chitin by glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in a mixture of n-hexane using sodium bis(ethylhexyl)sulfosuccinate as a surfactant. Results: Several crucial parameters, namely, the Gd and protein content of the nanoparticles, their size and dispersity were determined. Magnetic resonance measurements were carried out by intravenous perfusion of mono-disperse suspensions of the nanoparticles into mice. Conclusions: Chitosan nanoparticles can be used as contrast agents in magnetic resonance imaging (MRI). They are excellent candidates for controlled delivery of bioactive compounds to molecular targets and as biospecific diagnostic tools in MRI.