1. Spatially controlled assembly of affinity ligand and enzyme cargo enables targeting ferritin nanocarriers to caveolae.
- Author
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Shuvaev VV, Khoshnejad M, Pulsipher KW, Kiseleva RY, Arguiri E, Cheung-Lau JC, LeFort KM, Christofidou-Solomidou M, Stan RV, Dmochowski IJ, and Muzykantov VR
- Subjects
- Animals, Archaeal Proteins metabolism, Archaeoglobus fulgidus metabolism, Cell Line, Drug Delivery Systems, Immunoconjugates metabolism, Male, Mice, Mice, Inbred C57BL, Superoxide Dismutase pharmacokinetics, Caveolae metabolism, Drug Carriers metabolism, Ferritins metabolism, Nanoparticles metabolism, Superoxide Dismutase administration & dosage
- Abstract
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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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