1. Cross-linker-Modulated Nanogel Flexibility Correlates with Tunable Targeting to a Sterically Impeded Endothelial Marker
- Author
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Vladimir V. Shuvaev, Kelsey G. DeFrates, Olivia M. McPherson, Vladimir R. Muzykantov, Jenna H Towslee, David M. Eckmann, Russell J. Composto, Bruce Braender, Jacob W. Myerson, and Oscar A. Marcos-Contreras
- Subjects
Steric effects ,Surface Properties ,Nanogels ,General Physics and Astronomy ,02 engineering and technology ,Conjugated system ,Caveolae ,Microscopy, Atomic Force ,010402 general chemistry ,01 natural sciences ,Article ,chemistry.chemical_compound ,Elastic Modulus ,Animals ,Humans ,General Materials Science ,Ethylenedioxy ,General Engineering ,Membrane Proteins ,Adhesion ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,chemistry ,Targeted drug delivery ,Biophysics ,Nanoparticles ,Polystyrene ,Nanocarriers ,0210 nano-technology ,Nanogel - Abstract
Deformability of injectable nanocarriers impacts rheological behavior, drug loading, and affinity target adhesion. Here, we present atomic force microscopy (AFM) and spectroscopy measurements of nanocarrier Young's moduli, tune the moduli of deformable nanocarriers with cross-linkers, and demonstrate vascular targeting behavior that correlates with Young's modulus. Homobifunctional cross-linkers were introduced into lysozyme-dextran nanogels (NGs). Single particle-scale AFM measurements determined NG moduli varying from ∼50-150 kPa for unmodified NGs or NGs with a short hydrophilic cross-linker (2,2'-(ethylenedioxy)bis(ethylamine), EOD) to ∼350 kPa for NGs modified with a longer hydrophilic cross-linker (4,9-dioxa-1,12-dodecanediamine, DODD) to ∼10 MPa for NGs modified with a longer hydrophobic cross-linker (1,12-diaminododecane, DAD). Cross-linked NGs were conjugated to antibodies for plasmalemma vesicle associated protein (PLVAP), a caveolar endothelial marker that cannot be accessed by rigid particles larger than ∼100 nm. In previous work, 150 nm NGs effectively targeted PLVAP, where rigid particles of similar diameter did not. EOD-modified NGs targeted PLVAP less effectively than unmodified NGs, but more effectively than DODD or DAD modified NGs, which both yielded low levels of targeting, resembling results previously obtained with polystyrene particles. Cross-linked NGs were also conjugated to antibodies against intracellular adhesion molecule-1 (ICAM-1), an endothelial marker accessible to large rigid particles. Cross-linked NGs and unmodified NGs targeted uniformly to ICAM-1. We thus demonstrate cross-linker modification of NGs, AFM determination of NG mechanical properties varying with cross-linker, and tuning of specific sterically constrained vascular targeting behavior in correlation with cross-linker-modified NG mechanical properties.
- Published
- 2019