Targeting Mast Cells and Basophils with Anti-FcεRIα Fab-Conjugated Celastrol-Loaded Micelles Suppresses Allergic Inflammation.
Mast cells and basophils are effector cells in the pathophysiology of allergic diseases. Targeted elimination of these cells may be a promising strategy for the treatment of allergic disorders. Our present study aims at targeted delivery of anti-FcεRIα Fab-conjugated celastrol-loaded micelles toward FcεRIα receptors expressed on mast cells and basophils to have enhanced anti-allergic effect. To achieve this aim, we prepared celastrol-loaded (PEO-block-PPO-block-PEO, Pluronic) polymeric nanomicelles using thin-film hydration method. The anti-FcεRIα Fab Fragment was then conjugated to carboxyl groups on drug-loaded micelles via EDC amidation reaction. The anti-FcεRIα Fab-conjugated celastrol-loaded micelles revealed uniform particle size (93.43 ± 12.93 nm) with high loading percentage (21.2 ± 1.5% w/w). The image of micelles showed oval and rod like. The anti-FcεRIα Fab-conjugated micelles demonstrated enhanced cellular uptake and cytotoxity toward target KU812 cells than non-conjugated micelles in vitro. Furthermore, diffusion of the drug into the cells allowed an efficient induction of cell apoptosis. In mouse model of allergic asthma, treatment with anti-FcεRIα Fab-conjugated micelles increased lung accumulation of micelles, and significantly reduced OVA-sIgE, histamine and Th2 cytokines (IL-4, IL-5, TNF-α) levels, eosinophils infiltration and mucus production. In addition, in mouse model of passive cutaneous anaphylaxis, anti-FcεRIα Fab-conjugated celastrol-loaded micelles treatment significantly decreased extravasated evan's in the ear. These results indicate that anti-FcεRIα Fab-conjugated celastrol-loaded micelles can target and selectively kill mast cells and basophils which express FcεRIα, and may be efficient reagents for the treatment of allergic disorders and mast cell related diseases.
Xia
X
Peng
Juan
J
Wang
Xianyang
X
Li
Lihui
L
Lin
Guogang
G
Xie
Zelin
Z
Cui
Jia
J
Li
Yuping
Y
Wang
Li
L
Li
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001249:Asthma / Q000150:complications; D001491:Basophils / Q000276:immunology*; D001692:Biological Transport; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D065546:Drug Liberation; D006967:Hypersensitivity / Q000150:complications / Q000276:immunology* / Q000628:therapy; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008823:Micelles; D010047:Ovalbumin / Q000276:immunology; D010316:Particle Size; D010323:Passive Cutaneous Anaphylaxis / Q000276:immunology; D053978:Pentacyclic Triterpenes; D017455:Receptors, IgE / Q000276:immunology*; D014018:Tissue Distribution; D014315:Triterpenes / Q000737:chemistry*
D004337:Drug Carriers; C543355:FcepsilonRI alpha-chain, human; D007140:Immunoglobulin Fab Fragments; D008823:Micelles; D053978:Pentacyclic Triterpenes; D017455:Receptors, IgE; D014315:Triterpenes; D010047:Ovalbumin; C050414:celastrol