Synthesis of benzoic acid-modified poly(L-lysine) star polymer as a potential anti-inflammatory agent in Lipopolysaccharide-induced sepsis

Abstract

Sepsis is a systemic inflammatory response caused by bacteria infection It is known that star-shaped structure polypeptides efficiently interact with the outer membranes of bacteria and enhance antimicrobial activity However there were few studies reported their ability on LPS-induced sepsis For this linear and star polypeptides were synthesized by ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs) with benzoic acid modified as functional group In this study these synthetic polypeptides show highly affinity to the endotoxin LPS by electrostatic force and may reduce the toxicity of LPS through forming a compounded aggregation Furthermore we found that star polypeptide with modification inhibited the expression of pro-inflammatory mediators and cytokines such as inflammatory nitric oxide TNF-? and IL-6 from the LPS-stimulated RAW264 7 macrophages and exhibited significant anti-inflammatory properties as well compared to linear modified polypeptide and non-modified star polypeptide Mechanism studies revealed that the inhibitory effects of modified star polypeptide was mainly mediated by the inhibition of phosphorylated PI3K/Akt pathway partial MAPK pathway and the down-regulated nuclear translocation of p65 expression which is the main transcription factor to regulate the inflammation Furthermore modified star polypeptide decreased the production of TNF-? IL-6 in the LPS-induced sepsis mice model without causing tissue damage These results support that this simply synthesized star polypeptide with additional functionality is a promising therapeutic agent for bacteria induced diseases

Date of Award	2018 Sept 1
Original language	English
Supervisor	Ming-Long Yeh (Supervisor)