title: How Carrier Size and Valency Modulate Receptor-Mediated Signaling: Understanding the Link between Binding and Endocytosis of ICAM-1-Targeted Carriers.
abstract: Targeting of drug carriers to endocytic cell receptors facilitates intracellular drug delivery. Carrier size and number of targeting moieties (valency) influence cell binding and uptake. However, how these parameters influence receptor-mediated cell signaling (the link between binding and uptake) remains uncharacterized. We studied this using polymer carriers of different sizes and valencies, targeted to endothelial intercellular adhesion molecule-1 (ICAM-1), a marker overexpressed in many pathologies. Unexpectedly, induction of cell signals (ceramide and protein kinase C (PKC) enrichment and activation) and uptake, were independent of carrier avidity, total number of carriers bound per cell, cumulative cell surface area occupied by carriers, number of targeting antibodies at the carrier-cell contact, and cumulative receptor engagement by all bound carriers. Instead, "valency density" (number of antibodies per carrier surface area) ruled signaling, and carrier size independently influenced uptake. These results are key to understanding the interplay between carrier design parameters and receptor-mediated signaling conducive to endocytosis, paramount for intracellular drug delivery.
authors: Department of Cell Biology and Molecular Genetics, ‡Fischell Department of Bioengineering, and §Institute for Bioscience and Biotechnology Research, University of Maryland , College Park, Maryland 20742-4450, United States.
authors: Daniel
authors: D
authors: Serrano
authors: Department of Cell Biology and Molecular Genetics, ‡Fischell Department of Bioengineering, and §Institute for Bioscience and Biotechnology Research, University of Maryland , College Park, Maryland 20742-4450, United States.
authors: Rachel L
authors: RL
authors: Manthe
authors: Department of Cell Biology and Molecular Genetics, ‡Fischell Department of Bioengineering, and §Institute for Bioscience and Biotechnology Research, University of Maryland , College Park, Maryland 20742-4450, United States.
authors: Eden
authors: E
authors: Paul
authors: Department of Cell Biology and Molecular Genetics, ‡Fischell Department of Bioengineering, and §Institute for Bioscience and Biotechnology Research, University of Maryland , College Park, Maryland 20742-4450, United States.
authors: Rishi
authors: R
authors: Chadha
authors: Department of Cell Biology and Molecular Genetics, ‡Fischell Department of Bioengineering, and §Institute for Bioscience and Biotechnology Research, University of Maryland , College Park, Maryland 20742-4450, United States.
authors: Silvia
authors: S
authors: Muro
mesh_terms: D002518:Ceramides / Q000096:biosynthesis; D004337:Drug Carriers / Q000737:chemistry* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry* / Q000627:therapeutic use; D011108:Polymers / Q000737:chemistry* / Q000627:therapeutic use; D011485:Protein Binding; D011493:Protein Kinase C / Q000096:biosynthesis
chemical_list: D002518:Ceramides; D004337:Drug Carriers; D011108:Polymers; D018799:Intercellular Adhesion Molecule-1; D011493:Protein Kinase C