Cross-linker-Modulated Nanogel Flexibility Correlates with Tunable Targeting to a Sterically Impeded Endothelial...

Area of Science:

• Biomaterials Science
• Nanotechnology
• Rheology

Background:

• Injectable nanocarrier deformability influences rheological properties, drug loading, and target adhesion.
• Nanocarrier mechanical properties are critical for effective vascular targeting, especially for sterically hindered targets.

Purpose of the Study:

• To measure nanocarrier Young's moduli using atomic force microscopy (AFM).
• To tune nanocarrier deformability with cross-linkers.
• To correlate nanocarrier mechanical properties with vascular targeting behavior.

Main Methods:

• Homobifunctional cross-linkers were introduced into lysozyme-dextran nanogels (NGs).
• Single-particle AFM measurements determined NG Young's moduli, ranging from ~50-150 kPa to ~10 MPa based on cross-linker type (EOD, DODD, DAD).
• Cross-linked NGs were conjugated with antibodies against PLVAP (caveolar endothelial marker) and ICAM-1 (endothelial marker) for targeting studies.

Main Results:

• NG Young's modulus varied significantly with cross-linker type: unmodified/EOD NGs (~50-150 kPa), DODD NGs (~350 kPa), and DAD NGs (~10 MPa).
• NGs modified with shorter/hydrophilic cross-linkers (unmodified, EOD) showed better PLVAP targeting than those with longer/hydrophobic cross-linkers (DODD, DAD), which exhibited low targeting similar to rigid particles.
• All cross-linked NGs, regardless of stiffness, uniformly targeted ICAM-1, an accessible endothelial marker.

Conclusions:

• Cross-linker modification effectively tunes the mechanical properties (Young's modulus) of nanogels.
• Nanocarrier deformability is a key factor in achieving specific vascular targeting, particularly for sterically constrained targets like PLVAP.
• This study demonstrates a method to control nanocarrier targeting by adjusting their mechanical properties through cross-linker modification.