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

• Published in: Biomaterials 2018-12, Vol.185, p.348-359
• Main Authors: Shuvaev, Vladimir V., Khoshnejad, Makan, Pulsipher, Katherine W., Kiseleva, Raisa Yu, Arguiri, Evguenia, Cheung-Lau, Jasmina C., LeFort, Kathleen M., Christofidou-Solomidou, Melpo, Stan, Radu V., Dmochowski, Ivan J., Muzykantov, Vladimir R.
• Format: Article
• Language: English
• Subjects: animal models; Animals; anti-inflammatory activity; Archaeal Proteins - metabolism; Archaeoglobus fulgidus - metabolism; Caveolae - metabolism; Cell Line; cytokines; dissociation; Drug Carriers - metabolism; Drug Delivery Systems; endosomes; endothelial cells; Endothelial targeting; ferritin; Ferritin nanocage; Ferritins - metabolism; Immunoconjugates - metabolism; Inflammation; ligands; lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; nanocarriers; nanomedicine; Nanoparticles - metabolism; physiological transport; Protein nanoparticle; Superoxide dismutase; Superoxide Dismutase - administration & dosage; Superoxide Dismutase - pharmacokinetics
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2018.09.015

One of the goals of nanomedicine is targeted delivery of therapeutic enzymes to the sub-cellular compartments where their action is needed. Endothelial caveolae-derived endosomes represent an important yet challenging destination for targeting, in part due to smaller size of the entry aperture of caveolae (ca. 30–50 nm). Here, we designed modular, multi-molecular, ferritin-based nanocarriers with uniform size (20 nm diameter) for easy drug-loading and targeted delivery of enzymatic cargo to these specific vesicles. These nanocarriers targeted to caveolar Plasmalemmal Vesicle-Associated Protein (Plvap) deliver superoxide dismutase (SOD) into endosomes in endothelial cells, the specific site of influx of superoxide mediating by such pro-inflammatory signaling as some cytokines and lipopolysaccharide (LPS). Cell studies showed efficient internalization of Plvap-targeted SOD-loaded nanocarriers followed by dissociation from caveolin-containing vesicles and intracellular transport to endosomes. The nanocarriers had a profound protective anti-inflammatory effect in an animal model of LPS-induced inflammation, in agreement with the characteristics of their endothelial uptake and intracellular transport, indicating that these novel, targeted nanocarriers provide an advantageous platform for caveolae-dependent delivery of biotherapeutics.