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An intein-mediated site-specific click conjugation strategy for improved tumor targeting of nanoparticle systems.

ABSTRACT: The ability to modify and directly target nanoparticulate carriers has greatly increased their applicability in diagnostic and therapeutic studies. Generally essential to the targeting of nanoparticles is the bioconjugation of targeting ligands to the agent's surface. While bioconjugation techniques have steadily improved in recent years, the field is still plagued with inefficient conjugations reactions and/or the lack of site-specific coupling. To overcome these limitations, click chemistry and expressed protein ligation (EPL) are combined to produce a highly efficient, site-specific reaction. This new EPL-click conjugation strategy is applied to create superparamagnetic iron oxide nanoparticles (SPIO) labeled with HER2/neu affibodies. These HER2-SPIO nanoparticles prove to be highly potent and receptor-specific in both in vitro cell studies and murine tumor models. Moreover, when EPL-click-derived HER2-SPIO are compared with SPIO that had been labeled with HER2 affibodies using other popular bioconjugation methods, they produce a statistically significant improvement in contrast enhancement upon cell binding. The EPL-click system is also successfully extended to other nanoparticle platforms (i.e., liposomes and dendrimers) highlighting the versatility of the approach.

SUBMITTER: Elias DR

PROVIDER: S-EPMC3019098 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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An intein-mediated site-specific click conjugation strategy for improved tumor targeting of nanoparticle systems.

Elias Drew R DR Cheng Zhiliang Z Tsourkas Andrew A

Small (Weinheim an der Bergstrasse, Germany) 20101101 21

The ability to modify and directly target nanoparticulate carriers has greatly increased their applicability in diagnostic and therapeutic studies. Generally essential to the targeting of nanoparticles is the bioconjugation of targeting ligands to the agent's surface. While bioconjugation techniques have steadily improved in recent years, the field is still plagued with inefficient conjugations reactions and/or the lack of site-specific coupling. To overcome these limitations, click chemistry an ...[more]

PMID: 20925038

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Project description:Antibody pretargeting is a promising strategy for improving molecular imaging, wherein the separation in time of antibody targeting and radiolabeling can lead to rapid attainment of high contrast, potentially increased sensitivity, and reduced patient radiation exposure. The inverse electron demand Diels-Alder 'click' reaction between trans-cyclooctene (TCO) conjugated antibodies and radiolabeled tetrazines presents an ideal platform for pretargeted imaging due to rapid reaction kinetics, bioorthogonality, and potential for optimization of both slow and fast clearing components. Herein, we evaluated a series of anti-human epidermal growth factor receptor 2 (HER2) pretargeting antibodies containing distinct molar ratios of site-specifically incorporated TCO. The effect of stoichiometry on tissue distribution was assessed for pretargeting TCO-modified antibodies (monitored by 125I) and subsequent accumulation of an 111In-labeled tetrazine in a therapeutically relevant HER2+tumor-bearing mouse model. Single photon emission computed tomography (SPECT) imaging was also employed to assess tumor imaging at various TCO-to-monoclonal antibody (mAb) ratios. Increasing TCO-to-mAb molar ratios correlated with increased in vivo click reaction efficiency evident by increased tumor distribution and systemic exposure of 111In-labeled tetrazines. The pharmacokinetics of TCO-modified antibodies did not vary with stoichiometry. Pretargeted SPECT imaging of HER2-expressing tumors using 111In-labeled tetrazine demonstrated robust click reaction with circulating antibody at ~2 hours and good tumor delineation for both the 2 and 6 TCO-to-mAb ratio variants at 24 hours, consistent with a limited cell-surface pool of pretargeted antibody and benefit from further distribution and internalization. To our knowledge, this represents the first reported systematic analysis of how pretargeted imaging is affected solely by variation in click reaction stoichiometry through site-specific conjugation chemistry.

Dataset Information

An intein-mediated site-specific click conjugation strategy for improved tumor targeting of nanoparticle systems.

Publications

An intein-mediated site-specific click conjugation strategy for improved tumor targeting of nanoparticle systems.

Similar Datasets

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