Hild, Wolfgang and Pollinger, Klaus and Caporale, Andrea and Cabrele, Chiara and Keller, Max and Pluym, Nicola and Buschauer, Armin and Rachel, Reinhard and Tessmar, Joerg and Breunig, Miriam and Goepferich, Achim (2010) G protein-coupled receptors function as logic gates for nanoparticle binding and cell uptake. Proceedings of the National Academy of Sciences USA: PNAS 107 (23), pp. 10667-10672.
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More selective interactions of nanoparticles with cells would substantially increase their potential for diagnostic and therapeutic applications. Thus, it would not only be highly desirable that nanoparticles can be addressed to any cell with high target specificity and affinity, but that we could unequivocally define whether they rest immobilized on the cell surface as a diagnostic tag, or if they are internalized to serve as a delivery vehicle for drugs. To date no class of targets is known that would allow direction of nanoparticle interactions with cells alternatively into one of these mutually exclusive events. Using MCF-7 breast cancer cells expressing the human Y1-receptor, we demonstrate that G protein-coupled receptors provide us with this option. We show that quantum dots carrying a surface-immobilized antagonist remain with nanomolar affinity on the cell surface, and particles carrying an agonist are internalized upon receptor binding. The receptor functions like a logic “and-gate” that grants cell access only to those particles that carry a receptor ligand “and” where the ligand is an agonist. We found that agonist- and antagonist-modified nanoparticles bind to several receptor molecules at a time. This multiligand binding leads to five orders of magnitude increased-receptor affinities, compared with free ligand, in displacement studies. More than 800 G protein-coupled receptors in humans provide us with the paramount advantage that targeting of a plethora of cells is possible, and that switching from cell recognition to cell uptake is simply a matter of nanoparticle surface modification with the appropriate choice of ligand type.
|Institutions:|| Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Technology (Prof. Göpferich) |
Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer)
|Projects:||GRK 760, Graduiertenkolleg Medizinische Chemie|
|Subjects:||500 Science > 500 Natural sciences & mathematics|
600 Technology > 615 Pharmacy
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Deposited On:||22 Oct 2010 10:56|
|Last Modified:||07 Jul 2012 09:38|
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