Flexible Nanoparticles Reach Sterically Obscured Endothelial Targets Inaccessible to Rigid Nanoparticles

Abstract

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.

Intracellular Fate of Hydrophobic Nanocrystal Self‐Assemblies in Tumor Cells

“…nanocarriers such as viruses. [5,6] However, the fate of nanoparticles once inside the cell is poorly controlled and understood. [7,8] This is unfortunate since the intracellular localization of nanoparticles will directly shape their biological effects.…”

Spatially controlled assembly of affinity ligand and enzyme cargo enables targeting ferritin nanocarriers to caveolae

“…Our previous in vivo studies revealed that caveolae-targeted rigid spherical particles larger than 70–90 nm do not accumulate in the lungs [18]. In contrast, elastic parameters of the carriers seem even more important than size: flexible nanogels with mean diameter 300 nm do get internalized via caveolar pathway(s) and accumulate effectively in the lungs [60]. However, the nanocarriers used in the present study are smaller than the caveolar aperture, and, therefore, the key parameter controlling targeting in this case is particle avidity.…”

Supramolecular Organization Predicts Protein Nanoparticle Delivery to Neutrophils for Acute Lung Inflammation Diagnosis and Treatment

“…Lysozyme-dextran nanogels (LDNGs, NGs) and poly(ethylene)glycol (PEG)crosslinked albumin NPs have been characterized as targeted drug delivery agents in previous work. [36][37][38] Here, LDNGs (136.4±3.6 nm diameter, 0.10±0.02 PDI, Supplementary Figure 1A) and PEG-crosslinked human albumin NPs (317.8±3.6 nm diameter, 0.14±0.05 PDI, Supplementary Figure 1B) were administered in naïve and IV-LPS-injured mice. Neither NP was functionalized with antibodies or other affinity tags.…”

“…Lysozyme-dextran nanogels (LDNGs) were synthesized as previously described. 37,42 70 kDa rhodamine-dextran or FITC-dextran (Sigma) and lysozyme from hen egg white (Sigma) were dissolved in deionized and filtered water at a 1:1 or 2:1 mol:mol ratio, and pH was adjusted to 7.1 before lyophilizing the solution. For Maillard reaction between lysozyme and dextran, the lyophilized product was heated for 18 hours at 60°C, with 80% humidity maintained via saturated KBr solution in the heating vessel.…”