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Research Paper
Controlled Internalization of Her-2/neu Receptors by Cross-linking for Targeted Delivery
Wenlian Zhu, Baasil Okollie and Dmitri Artemov
volume 6 | issue 12
December 2007Pages: 1960 - 1966
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Receptor mediated internalization is a crucial step for targeted intracellular delivery of therapeutic and imaging agents. It was recently demonstrated that trastuzumab, an FDA approved humanized monoclonal antibody against Her-2/neu tyrosine kinase receptor, did not induce endocytosis of the internalization resistant Her-2/neu receptor. Here we report that accelerated internalization of trastuzumab can be induced by cross-linking the cell membrane bound antibody-receptor complex with an avidin/streptavidin-biotin system. We demonstrated that internalization was achieved both in vitro and in vivo in Her-2/neu expressing human breast cancer cell lines (BT-474, SK-BR-3, and AU-565) and that repetitive labeling cycles further amplified the loading of cargo molecules within the targeted cells. No trastuzumab binding and internalization was observed in Her-2/neu negative MDA-MB-231 cells, whereas weak membrane binding and negligible internalization were detected in MCF-7 cells with low expression level of Her-2/neu receptor. The method was used to noninvasively image Her-2/neu receptors in isolated cells and in a preclinical breast cancer model with MRI. The controlled internalization of Her-2/neu receptors can potentially enhance intracellular delivery of drugs and imaging probes, and improve imaging sensitivity and selectivity as well as therapeutic efficacy, through antibody-directed binding and internalization using a pretargeting approach.
Authors
Wenlian Zhu
Johns Hopkins University School of Medicine, Baltimore, MD
Baasil Okollie
The Johns Hopkins University School of Medicine, Baltimore, MD USA
Dmitri Artemov
Johns Hopkins University, School of Medicine; Baltimore MD USA