Preparation, characterization and in vivo assessment of Gd-albumin and Gd-dendrimer conjugates as intravascular contrast-enhancing agents for MRI

Nwe, Kido; Milenic, Diane E.; Bryant, L. Henry; Regino, Celeste A.S.; Brechbiel, Martin W.

doi:10.1016/j.jinorgbio.2011.01.017

Cited by 31 publications

(37 citation statements)

References 55 publications

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“…Furthermore, AuNPs in a variety of instances, including encapsulation within dendrimers, have also been shown to possess heightened biocompatibility and stability [15, 20, 21]. With regard to MRI, Gadolinium (Gd) chelated into 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is a long recognized contrast agent because of its unique soft tissue resolving capabilities [22, 23]. When DOTA-Gd was conjugated to dendrimers, the relaxivity and retention time of the contrast agent was increased [24].…”

Section: Introductionmentioning

confidence: 99%

Dendrimer antibody conjugate to target and image HER-2 overexpressing cancer cells

et al. 2016

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Although many breast and lung cancers overexpress human epidermal growth factor receptor-2 (HER-2), no methods currently exist for effective and early detection of HER-2-positive cancers. To address this issue, we designed and synthesized dendrimer-based novel nano-imaging agents that contain gold nanoparticles (AuNPs) and gadolinium (Gd), conjugated with the humanized anti-HER-2 antibody (Herceptin). Generation 5 (G5) polyamidoamine (PAMAM) dendrimers were selected as the backbone for the nano-imaging agents due to their unique size, high ratio of surface functional groups and bio-functionality. We modified G5 PAMAM dendrimer surface with PEG and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to encapsulate AuNPs and complex Gd. These dendrimer entrapped AuNPs were further conjugated with Herceptin through copper-catalyzed azide- alkyne click reaction to construct the nano-imaging agent Au-G5-Gd-Herceptin. The targeted nano-imaging agent bound selectively to HER-2 overexpressing cell lines, with subsequent internalization into the cells. More importantly, non-targeted nano-imaging agent neither bound nor internalized into cells overexpressing HER-2. These results suggest that our approach could provide a platform to develop nano-diagnostic agents or nano-therapeutic agents for early detection and treatment of HER-2-positive cancers.

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Section: Introductionmentioning

confidence: 99%

Dendrimer antibody conjugate to target and image HER-2 overexpressing cancer cells

et al. 2016

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“…26-27, 32-33 Herein, the approach was extended to the preparation of antibody based agents with the ultimate goal of utilizing them for target-specific imaging agents. The presence of a cleavable disulfide bond in a cystamine core dendrimer provides a unique orthogonal building block site to assemble an antibody-dendrimer conjugate.…”

Section: Resultsmentioning

confidence: 99%

“…This behavior is similar to previously reported measurement using dendrimer- and albumin-based agents. 26, 32, 36-37 …”

Section: Resultsmentioning

confidence: 99%

“…32 The anionic carboxylate moieties or other functional groups might coordinate to the metal ion and replace or block bound water molecules, or the bulky antibody might hinder the water path and reduce availability of second sphere water molecules. This is contrary to what was observed for dendrimer conjugates where higher molecular weight compounds have a higher impact on the proton relaxation enhancement.…”

Section: Resultsmentioning

confidence: 99%

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Preparation of Cystamine Core Dendrimer and Antibody–Dendrimer Conjugates for MRI Angiography

et al. 2011

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We herein report the preparation along with the in vivo and in vitro MRI characterization of two generation four and five cystamine core dendrimers loaded with thirty and fifty-eight derivatized Gd-DOTA (G4SS30, G5SS58) respectively. Likewise the development and characterization of two half-dendrimers conjugated to the F(ab’)2 fragment of the monoclonal antibody (mAb) panitumumab functionalized with a maleimide conjugation functional group site (Ab-(G4S15)4, Ab-(G5S29)4) are also described. The in vitro molar relaxivity of the Ab-(G4S15)4 conjugate, measured at pH 7.4, 22°C, and 3T showed a moderate increase in relaxivity as compared to Magnevist (6.7 vs. 4.0 mM-1s-1) while the Ab-(G5S29)4 conjugate was two-fold higher (9.1 vs. 4.0 mM-1s-1). The data showed that only a high injection dose (0.050 mmol Gd3+/kg) produced a detectable contrast enhanced contrast for the Ab-(G4S15)4 conjugate while a lower dose (0.035 mmol Gd3+/kg) was sufficient for the Ab-(G5S29)4 conjugate. The antibody-SMCC conjugate was purified by a Sephadex G-100 column and the antibody-dendrimer-based agents were purified by spin filtration using a Centricon filter (50,000 MCO). The protein assay coupled with Cysteine and Ellman's assay indicated an antibody to dendrimer ratio of 1:4. The in vivo blood clearance half-lives of the four agents measured at the jugular vein were ~12-22 min.

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“…35 In both cases, the delivery components were cross-linked on the target cell surface, which significantly enhanced internalization. This system can be applied for the delivery of MRI contrast agents (Figure 7) since, a) albumin is a biocompatible rigid platform to load Gd-based contrast agents with appropriate pharmacokinetics and delivery profile in vivo 36–39 , b) high loading capacity of albumin allows for conjugation of multiple Gd groups to increase sensitivity; and c) in situ generation of nanoclusters enhanced the internalization of target-specific nanoclusters at the tumor site efficiently amplifies the signal and increases MRI contrast. 40 …”

Section: Future Directionsmentioning

confidence: 99%

Click Chemistry in the Development of Contrast Agents for Magnetic Resonance Imaging

Hapuarachchige

Artemov

2016

Topics in Magnetic Resonance Imaging

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Click chemistry provides fast, convenient, versatile and reliable chemical reactions that take place between pairs of functional groups of small molecules that can be purified without chromatographic methods. Due to the fast kinetics and low or no elimination of byproducts, click chemistry is a promising approach that is rapidly gaining acceptance in drug discovery, radiochemistry, bioconjugation, and nanoscience applications. Increasing use of click chemistry in synthetic procedures or as a bioconjugation technique in diagnostic imaging is occurring because click reactions are fast, provide a quantitative yield, and produce minimal amount of nontoxic byproducts. This review summarizes the recent application of click chemistry in magnetic resonance imaging and discusses the directions for applying novel click reactions and strategies for further improving MRI performance.

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Preparation, characterization and in vivo assessment of Gd-albumin and Gd-dendrimer conjugates as intravascular contrast-enhancing agents for MRI

Cited by 31 publications

References 55 publications

Dendrimer antibody conjugate to target and image HER-2 overexpressing cancer cells

Dendrimer antibody conjugate to target and image HER-2 overexpressing cancer cells

Preparation of Cystamine Core Dendrimer and Antibody–Dendrimer Conjugates for MRI Angiography

Click Chemistry in the Development of Contrast Agents for Magnetic Resonance Imaging

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