Triphenylphosphine bromide enhances the effect of nano-micellar drug delivery system loaded with ROS inhibitor TEMPO on acute lung injury.

Abstract

BACKGROUND: Sepsis acute lung injury (ALI) is one of the common complications in sepsis. The molecular mechanism and treatment methods of acute lung injury in sepsis are unknown. AIM: The aim of this study was to prepare triphenylphosphine bromide (TPP)-polyethylene glycol-b-polycaprolactone (PEG-PCL) nano-micelles for the delivery of ROS inhibitor (TEMPO) [TEMPO@PP-PEG-PCL] in the treatment of acute lung injury (ALI). METHODS: TEMPO@TPP-PEG-PCL were prepared. The particle size, zeta potential and morphology of the TEMPO@TPP-PEG-PCL were determined. The stability, in vitro release, pharmacokinetics and critical micelle concentration of the TEMPO@TPP-PEG-PCL were determined. Lipopolysaccharide (LPS) was used to establish the models of ALI. in vivo and in vitro. Immunohistochemistry, western blot and immunofluorescence were used to evaluate the effects of TEMPO@TPP-PEG-PCL on mtDNA-cGAS-STING signal pathway in ALI. RESULTS: The particle size of TEMPO@TPP-PEG-PCL was (22.7 ± 0.3) nm and the zeta potential was (24.3 ± 0.4) mV. The transmission electron microscope showed that TEMPO@TPP-PEG-PCL were regular spheres. The results of fluorescence showed that TEMPO@TPP-PEG-PCL promoted the cellular uptake of drugs. Compared with TEMPO, TEMPO@TPP-PEG-PCL significantly decreased the level of intracellular ROS (P < 0.01) and mtDNA (P < 0.01) and the protein expressions of cGAS-STING-IRF3/NF-κB signal pathway(P < 0.01). CONCLUSIONS: Our results demonstrated that TEMPO@TPP-PEG-PCL were successfully prepared to deliver TEMPO for treatment of ALI. The mechanism was related to the regulation of cGAS-STING-IRF3/NF-κB signaling pathway.