How Carrier Size and Valency Modulate Receptor-Mediated Signaling: Understanding the Link between Binding and Endocytosis of ICAM-1-Targeted Carriers

Biomacromolecules. 2016 Oct 10;17(10):3127-3137. doi: 10.1021/acs.biomac.6b00493. Epub 2016 Sep 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Ceramides / biosynthesis
  • Drug Carriers / chemistry*
  • Drug Carriers / therapeutic use
  • Drug Delivery Systems*
  • Endocytosis / drug effects
  • Gene Expression Regulation / drug effects
  • Humans
  • Intercellular Adhesion Molecule-1 / chemistry*
  • Intercellular Adhesion Molecule-1 / therapeutic use
  • Polymers / chemistry*
  • Polymers / therapeutic use
  • Protein Binding
  • Protein Kinase C / biosynthesis


  • Ceramides
  • Drug Carriers
  • Polymers
  • Intercellular Adhesion Molecule-1
  • Protein Kinase C