title: G protein-coupled receptors function as logic gates for nanoparticle binding and cell uptake.
abstract: 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 Y(1)-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.
authors.affiliation: Department of Pharmaceutical Technology, Center for Electron Microscopy at the Institute for Anatomy, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hild
authors.forename: Klaus
authors.initials: K
authors.lastname: Pollinger
authors.forename: Andrea
authors.initials: A
authors.lastname: Caporale
authors.forename: Chiara
authors.initials: C
authors.lastname: Cabrele
authors.forename: Max
authors.initials: M
authors.lastname: Keller
authors.forename: Nicola
authors.initials: N
authors.lastname: Pluym
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Rachel
authors.forename: Joerg
authors.initials: J
authors.lastname: Tessmar
authors.forename: Miriam
authors.initials: M
authors.lastname: Breunig
authors.forename: Achim
authors.initials: A
authors.lastname: Goepferich
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry*; D045663:Quantum Dots; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013552:Swine
chemical_list: D008024:Ligands; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor