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

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 ca...

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Bibliographic Details
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:
Animals
Archaeal Proteins - metabolism
Archaeoglobus fulgidus - metabolism
Caveolae - metabolism
Cell Line
Drug Carriers - metabolism
Drug Delivery Systems
Endothelial targeting
Ferritin nanocage
Ferritins - metabolism
Immunoconjugates - metabolism
Inflammation
Male
Mice
Mice, Inbred C57BL
Nanoparticles - metabolism
Protein nanoparticle
Superoxide dismutase
Superoxide Dismutase - administration & dosage
Superoxide Dismutase - pharmacokinetics
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Summary: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.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2018.09.015