Effects of linker length and flexibility on multivalent targeting.
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 enhancement 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.
Shewmake
Thomas A
TA
Harrington Department of Bioengineering and Center for Interventional Biomaterials, Arizona State University, Tempe, Arizona 85287, USA.
Solis
Francisco J
FJ
Gillies
Robert J
RJ
Caplan
Michael R
MR
D003432:Cross-Linking Reagents / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D008024:Ligands; D008962:Models, Theoretical; D010455:Peptides; D018583:Pliability
D003432:Cross-Linking Reagents; D008024:Ligands; D010455:Peptides