Effect of size and charge on pharmacokinetics and in vivo MRI contrast enhancement of biodegradable polydisulfide Gd(III) complexes

Zong, Yuda; Guo, Junyu; Ke, Tianyi; Mohs, Aaron M.; Parker, Dennis L.; Lü, Zheng Rong

doi:10.1016/j.jconrel.2006.03.006

Cited by 38 publications

(48 citation statements)

References 20 publications

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“…After reaction with endogenous thiols, the released chelates are excreted through the kidneys. Similar observations have been made by these authors with DTPA-cystine copolymers (7). The reactivity of the disulfide bond with thiols has recently been exploited by Raghunand et al (8) in a study of the association between human serum albumin (HSA) and a DOTA derivative featuring an amide arm substituted with a propyl or hexylthiol group.…”

Section: Introductionsupporting

confidence: 58%

“…On the contrary, covalent bonding proved to have a detrimental effect on the clearance of the metal complexes and it was thus suggested to create reversible covalent bonds with macromolecules that are cleaved by endogenous biomolecules or after administration of exogenous substances following the imaging examination. The disulfide bond appears particularly interesting in this respect as it is easily cleaved by thiols present in the body (3,7,8). The latter are found in relatively low concentrations in the circulation [about 15 mM (3)] and the residence times in the body of thiolated contrast agents should thus remain sufficiently long to allow imaging.…”

Section: Introductionmentioning

confidence: 99%

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A gadolinium triacetic monoamide DOTA derivative with a methanethiosulfonate anchor group. Relaxivity properties and conjugation with albumin and thiolated particles

Thonon

Jacques

Desreux

2007

Contrast Media & Molecular

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The gadolinium(III) complex with a new DOTA-based ligand bearing a methanethiosulfonate group (MTS) was synthesized and its relaxivity properties were investigated. MTS-ADO3A is a triacid DOTA derivative with an amide arm substituted by an ethylmethanethiosulfonate function. This ligand was obtained in two steps: tri-tert-butyl 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate was reacted with S-(2-aminoethyl)methanesulfonothioate and the tert-butyl groups were removed with trifluoroacetic acid. The Gd(III) MTS-ADO3A complex readily formed disulfide bonds with albumin (BSA) in its native and reduced forms and with thiolated silica particles. Four- to five-fold relaxivity increases at 20 MHz were measured on the isolated adducts. The EuMTS-ADO3A chelate was found to be monohydrated by fluorescence and the relaxivity parameters of the Gd(III) complex were obtained by (17)O NMR and by measuring the nuclear magnetic relaxation dispersion between 0.01 and 80 MHz. The water exchange time tau(m) is increased upon forming disulfide bonds with macromolecules and particles and the relaxivity gains of all the complexes are limited by the tau(m) factor. Forming covalent or hydrophobic/electrostatic bonds with BSA seems to bring about similar relaxivity changes but the covalent BSA adducts can be isolated and their properties can be directly studied. The addition of dithiothreitol or glutathione leads to the removal of the metal chelates from the macromolecules, as indicated by the relaxation times reverting to their values before binding. It is thus expected that the chelate will stay in the body long enough for imaging but will still be excreted through the kidneys.

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Section: Introductionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

A gadolinium triacetic monoamide DOTA derivative with a methanethiosulfonate anchor group. Relaxivity properties and conjugation with albumin and thiolated particles

Thonon

Jacques

Desreux

2007

Contrast Media & Molecular

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“…These low molecular weight contrast agents have been incorporated into biomedical polymers to modify their pharmacokinetics, thus improving the image contrast enhancement. [2,5,7,8].…”

Section: Polymer Gd(iii) Chelate Conjugates With a Disulfide Spacer Amentioning

confidence: 99%

“…The incorporation of imaging agents into biocompatible polymers prolongs their retention in the tissues of interest with increased concentrations, which allows more accurate disease detection and characterization [5,6]. For example, the incorporation of a magnetic resonance imaging (MRI) contrast agent into a macromolecule would increase its blood circulation time for effective contrast enhanced cardiovascular imaging and tumor imaging [7,8].…”

Section: Introductionmentioning

confidence: 99%

Polymer platforms for drug delivery and biomedical imaging

Lü

Vaidya

2007

Journal of Controlled Release

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Biocompatible synthetic polymers have demonstrated advantageous pharmacokinetic properties as compared to small molecular agents. Incorporation of low molecular weight therapeutics and imaging agents into biocompatible polymers can optimize their pharmacokinetic properties with improved efficacy of therapy and diagnostic imaging, respectively. We have applied the concept of drug delivery to design safe and effective contrast agents for magnetic resonance imaging (MRI) and used biomedical imaging in non-invasive evaluation of drug delivery and image-guided therapy. We summarize here the recent progress in our research on biodegradable macromolecular MRI contrast agents, non-invasive visualization of in vivo drug delivery of polymeric conjugates with contrast enhanced MRI, and contrast enhanced MRI guided photodynamic therapy. The preliminary results have shown that biocompatible polymers can be used as an effective platform for drug delivery and biomedical imaging. Safe and effective imaging agents can be designed by using the concept of polymeric drug delivery. Biomedical imaging can be used as a non-invasive method for the evaluation of in vivo drug delivery of polymeric drug delivery systems. The combination of drug delivery and biomedical imaging can result in image-guided therapies, which include tumor detection, therapy and non-invasive evaluation of therapeutic responses.Biocompatible and water-soluble polymers have demonstrated unique pharmacokinetic properties, including prolonged blood circulation and tissue retention, and preferential accumulation in lesions with blood vessel hyperpermeability, because of their large sizes. Biocompatible synthetic polymers have been used as a platform for the modification of pharmacokinetics of small molecular therapeutics and imaging agents to improve their efficacy in drug delivery and molecular imaging [1,2]. The conjugation of therapeutics to biocompatible polymers prolongs in vivo drug retention time, increases drug bioavailability, reduces systemic toxicity and enhances therapeutic efficacy [3,4]. The incorporation of imaging agents into biocompatible polymers prolongs their retention in the tissues of interest with increased concentrations, which allows more accurate disease detection and characterization [5,6]. For example, the incorporation of a magnetic resonance imaging (MRI) contrast agent into a macromolecule would increase its blood circulation time for effective contrast enhanced cardiovascular imaging and tumor imaging [7,8].Both drug delivery and molecular imaging can benefit from the large sizes and unique pharmacokinetic properties of biomedical polymers. However, the applications of biomedical polymers in these areas are not mutually exclusive. In fact, the concept of drug delivery can be applied in molecular imaging to design and develop effective and specific imaging agents Correspondence to: Dr. Zheng-Rong Lu, 421 Wakara Way, Suite 318, Salt Lake City, UT 84108, Phone: 801 587-9450, Fax: 801 585-3614, Email: E-mail: zhengrong.lu@utah.edu....

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“…Although Gd(III) has some serious and toxic side effects, after chelation with DTPA (diethylenetriamine pentaacetic acid), the complexed ions have only a minor impact on in vivo metabolism of certain enzymes, thereby reducing toxicity. [11,12] For reduce toxicity, increase biocompatibility and half-life, and prevent the nanoparticle aggregations, contrast agents in MRI are coated with various materials. Some of them are polymers which don't have fixed sizes and molecular weights.…”

Section: Ifmbe Proceedings Vol 51mentioning

confidence: 99%

Gadolinium Labeled Glycosylated Nanomagnetic Particles as Metabolic Contrast Agents in Molecular Magnetic Resonance Imaging

Heydarnezhadi

Alam

Haghoo³

et al. 2015

IFMBE Proceedings

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Abstract-Difficulties in the use, preparation, and cost of radioactively-labeled glycosylated compounds led us to this research and development study of a new gadolinium-labeled glucose compounds that do not have a radioactive half-life or difficulties in its synthesis and utilization. Despite its good resolution, Magnetic Resonance Imaging (MRI) has low sensitivity, therefor, using MRI contrast agents, such as GD-DTPA (Magnevist) will improve tissue discrimination in MRI images.The purpose of this study is the synthesis and physicochemical characterization of glycosylated gadolinium as metabolic contrast agent for molecular MRI (mMRI). In-vitro T1 relaxivity measurement and signal intensity of the glycosylated compounds has been also performed in comparison with magnevist ( GD-DTPA).Based on the structure of the 2-fluoro-2-deoxy-D-glucose molecule (FDG), first compound consisting of D-glucose conjugated to a well-known chelator, diethylenetriamine pentaacetic acid (DTPA), was syntheside , labeled with Gd to achieve Gd-DTPA-DG, another comound consisting of gadolinium oxide-based nanoparticle coating of diethyleneglycol conjugated with D-glucose via N,N-carbonyldiimidazole (CDI) mediate reaction, to achieve Gd-DEG-DG, and characterized by various analytical technique, utilizes dynamic light scattering (DLS) to determine the size distribution. The nanoparticle size and morphology were using high resolution transmission electron microscopy (HTEM). In our study, the Gd-DTPA-DG were well defined nanoparticle with size 40 nm in diameter TEM images. While Gd-DEG-DG were 10 nm . The mean hydrodynamic diameter of nanoparticles, as measured by DLS, were 300 nm and 70 nm for GD-DTPA-DG and GD-DEG-DG, respectively.The synthesized GD-DTPA-DG and GD-DEG-DG were shown higher relaxometery rates in vitro relative to magnevist. GD-DEG-DG and GD-DTPA-DG demonstrated shorter T1 than GD-DTPA at the same conectration.

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Effect of size and charge on pharmacokinetics and in vivo MRI contrast enhancement of biodegradable polydisulfide Gd(III) complexes

Cited by 38 publications

References 20 publications

A gadolinium triacetic monoamide DOTA derivative with a methanethiosulfonate anchor group. Relaxivity properties and conjugation with albumin and thiolated particles

A gadolinium triacetic monoamide DOTA derivative with a methanethiosulfonate anchor group. Relaxivity properties and conjugation with albumin and thiolated particles

Polymer platforms for drug delivery and biomedical imaging

Gadolinium Labeled Glycosylated Nanomagnetic Particles as Metabolic Contrast Agents in Molecular Magnetic Resonance Imaging

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