Effects of linker length and flexibility on multivalent targeting

Thomas A. Shewmake, Francisco Solis, Robert J. Gillies, Michael Caplan

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Increasing valence can enhance the ability of molecular targeting constructs to bind specifically to targeted cells for drug delivery. Here, we mathematically model the length and flexibility of a linker used to conjoin two peptide ligands of a divalent targeting construct and investigate the influence both on binding avidity and specificity. Four different models are used to approximate varying degrees of linker flexibility (random coil, rigid rod, jointed rods, and combined rod-random coil) and for each linker a binding enhancenzent factor (VR) is derived that quantifies the increased rate of each construct's second binding event over the first. Results indicate that the moderately flexible models can best reproduce experimentally measured avidities. Also, the magnitude of VR, in conjunction with receptor density and ligand concentration, significantly influences the achievable specificity. Thus, the model elucidates important considerations in designing multivalent targeting constructs for use in delivery of targeted therapy or imaging.

Original languageEnglish (US)
Pages (from-to)3057-3064
Number of pages8
JournalBiomacromolecules
Volume9
Issue number11
DOIs
StatePublished - Nov 2008

ASJC Scopus subject areas

  • Bioengineering
  • Biomaterials
  • Polymers and Plastics
  • Materials Chemistry

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