FcRn-targeting and ROS-responsive Fedratinib-incorporated Nanoparticles
Alleviate Asthma by Inducing Eosinophil Apoptosis
Abstract
Background: Reducing the number of airway eosinophils is
critical for treating eosinophilic asthma. The JAK2-STATs pathway is
essential for myelopoiesis of eosinophils and production of type I and
II cytokines, and therefore can be a novel target for intervention of
eosinophilic asthma. Here, we aimed to demonstrate the
apoptosis-inducing potential of Fedratinib (FDTN), a JAK2-specific
inhibitor, and test the efficacy of the ROS-responsive, FcRn-targeting
and FDTN-caged nanoparticles on eosinophilic asthma alleviation.
Methods: The apoptosis-inducing potential of FDTN in
eosinophils from asthma patients was assessed by flow cytometry, and
light and electron microscopy. FDTN-caged nanoparticles (NPs-FDTN) were
designed to ROS responsive and modified with Fc portion of IgG through
the avidin-biotin interaction. The biological availability of NPs-FDTN
was assembled via biochemical and immunological analysis, and the
therapeutic effects were investigated in eosinophilic asthma model mice
by comparing free FDTN and budesonide treatment. Results: FDTN
blocked the JAK2/STAT5 pathway and activated the intrinsic pathway of
apoptosis in eosinophils in a concentration-dependent manner. NPs-FDTN
crossed the epithelial barrier via the Fc/FcRn-mediated transcytosis,
bypassed the lysosome and entered the inflammatory microenvironment.
Caged FDTN was released from the nanoparticles in the presence of ROS.
Compared to free FDTN, the residence time of FDTN in the lung parenchyma
was prolonged and the therapeutic effects were improved when delivered
in nanoparticles. Conclusion: Ros-responsive, FcRn-targeting
and FDTN-caged nanoparticles overcame the airway epithelial barrier and
improved the bioavailability on eosinophil apoptosis. This study
provides a fancy and safe therapeutic strategy for treatment of
eosinophilic asthma.