Flexible Nanoparticles Reach Sterically Obscured Endothelial Targets Inaccessible to Rigid Nanoparticles

• Published in: Advanced materials (Weinheim) 2018-08, Vol.30 (32), p.e1802373-n/a
• Main Authors: Myerson, Jacob W., Braender, Bruce, Mcpherson, Olivia, Glassman, Patrick M., Kiseleva, Raisa Y., Shuvaev, Vladimir V., Marcos‐Contreras, Oscar, Grady, Martha E., Lee, Hyun‐Su, Greineder, Colin F., Stan, Radu V., Composto, Russell J., Eckmann, David M., Muzykantov, Vladimir R.
• Format: Article
• Language: English
• Subjects: Animals; Atomic force microscopy; cell biology; Cell membranes; Deformation; Drug Carriers; Drug Delivery Systems; Extrusion; Fluid filters; Formability; functional nanoparticles; Lungs; Lysozyme; Materials science; Mice; Microbalances; nanogels; nanomechanics; nanomedicine; Nanoparticles; Polyethylene Glycols; Polyethyleneimine; Polystyrene resins; Proteins
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.201802373

Molecular targeting of nanoparticle drug carriers promises maximized therapeutic impact to sites of disease or injury with minimized systemic effects. Precise targeting demands addressing to subcellular features. Caveolae, invaginations in cell membranes implicated in transcytosis and inflammatory signaling, are appealing subcellular targets. Caveolar geometry has been reported to impose a ≈50 nm size cutoff on nanocarrier access to plasmalemma vesicle associated protein (PLVAP), a marker found in caveolae in the lungs. The use of deformable nanocarriers to overcome that size cutoff is explored in this study. Lysozyme‐dextran nanogels (NGs) are synthesized with ≈150 or ≈300 nm mean diameter. Atomic force microscopy indicates the NGs deform on complementary surfaces. Quartz crystal microbalance data indicate that NGs form softer monolayers (≈60 kPa) than polystyrene particles (≈8 MPa). NGs deform during flow through microfluidic channels, and modeling of NG extrusion through porous filters yields sieving diameters less than 25 nm for NGs with 150 and 300 nm hydrodynamic diameters. NGs of 150 and 300 nm diameter target PLVAP in mouse lungs while counterpart rigid polystyrene particles do not. The data in this study indicate a role for mechanical deformability in targeting large high‐payload drug‐delivery vehicles to sterically obscured targets like PLVAP. Nanoparticles can be addressed to specific molecular signatures in the body, but some molecules are sequestered in a manner that sterically impedes access by nanoparticles. Rigid nanoparticles with diameter greater than 100 nm cannot access plasmalemma vesicle associated protein (PLVAP), but highly deformable polymeric nanoparticles of 150 nm or 300 nm diameter successfully target to PLVAP in this study.