Influence of Targeting Ligand Flexibility on Receptor Binding of Particulate Drug Delivery Systems

• Published in: Bioconjugate chemistry 2003-11, Vol.14 (6), p.1203-1208
• Main Authors: Olivier, Verena, Meisen, Iris, Meckelein, Barbara, Hirst, Timothy R, Peter-Katalinic, Jasna, Schmidt, M. Alexander, Frey, Andreas
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Biotinylation; Cholera Toxin - genetics; Cholera Toxin - metabolism; Drug Delivery Systems; Fibroblasts - metabolism; Fluorescent Dyes; G(M1) Ganglioside - metabolism; ganglioside GM1; Ligands; Mice; Mice, Inbred BALB C; Microspheres; Receptors, Cell Surface - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Spectrometry, Mass, Electrospray Ionization - methods
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc034077z

Receptor-mediated drug targeting via nanoengineered particulate delivery systems is an emerging field. However, little is known about how such magic bullets should be assembled to yield optimal targeting efficiency. Here we investigated the influence of targeting ligand flexibility on binding of ligand-coated microparticles to cell surface receptors. Using the ganglioside GM1-binding B subunit of cholera toxin as ligand and fluorescent microparticles as a model delivery system, conjugates with different numbers of linkages between ligand and particle were prepared and tested for their efficiency to bind to live fibroblast monolayers. Our results show that multiple bonds between ligand and particle reduce the targeting rate by up to 50% compared to constructs where ligands are attached via single aliphatic chains. Thus, for maximum performance, targeted particulate drug delivery systems should be assembled such that ligands are attached via single σ bonds only, allowing the ligand molecules to adopt an optimal binding conformation.