Star-Block Copolymer-Based Drug And Insulin Carriers And Their PH-responsive Releasing Properties

The research mainly aimed to design and synthesize a series of poly(L-lysine)-based star-block copolymers PEI-PLL-b-PEG, to investigate their encapsulation towards model proteins and model anionic drugs as well as the pH-responsive releasing properties. The synthesized core-shell star-block copolymer PEI-PLL-b-PEG consisted of a low-molecular-weight hyperbranched polyethyleneimine (PEI) core, a biodegradable poly(L-lysine) (PLL) inner shell, and a water-soluble and biocompatible poly(ethylene glycol)(PEG) outer shell.ε-Benzoxycarbonyl-L-lysine-N-carboxylanhydrides (ZLL-NCA) was synthesized by phosgenation ofε-benzoxycarbonyl-L-lysine in ethyl acetate, and its polymerization was initiated by the amine groups in the periphery of PEI to prepare star poly(ε-benzoxycarbonyl-L-lysine) (PEI-PZLL). The peripheral amines of PEI-PZLL were conjugated with PEG 4-nitrophenyl carbonate (PEG-NPC) to obtain the star-block copolymer PEI-PZLL-b-PEG. The final product PEI-PLL-b-PEG was obtained after the deprotection procedures by removing the benzoxycarbonyl groups in the presence of anisole and methanesulfonic acid.The synthesized star-block copolymer PEI-PLL-b-PEG showed efficient and stable encapsulation towards model protein insulin and model anionic drugs under physiological pH, as a result of electrostatic interactions. Model protein insulin, or model anionic compounds methyl orange (MO) or diclofenac sodium (DS) was mixed with star-block copolymer PEI-PLL-b-PEG and then dialyzed thoroughly against water. The concentration of insulin entrapped in PEI-PLL-b-PEG can be determined by RP-HPLC while the concentration of MO or DS could be detected by UV-Vis spectrophotometer, and subsequently, the loading capacities of insulin and anionic compouds were calculated accordingly. The model compounds encapsulated in PEI-PLL-b-PEG demonstrated pH-responsive releasing properties. The insulin or anionic model compounds-loaded star-block copolymer solution was dialyzed against buffers with different pH at room temperature. The releasing rate of polymer-encapsulated insulin increased remarkably when the pH was decreased from 7.4 to 4.5, furthermore, the released insulin from the star-block copolymer showed retained chemical integrity and bioactivity. Meanwhile, an accelerated releasing rate of MO was also observed when the pH was increased from 7.4 to 11.0, or decreased from 7.4 to 2.0, indicating a dual pH-responsive property.In conclusion, the synthesized star-block copolymer PEI-PLL-b-PEG demonstrated efficient encapsulation towards model protein insulin and model anionic compounds under physiological pH, together with pH-responsive releasing property. Therefore, these core-shell copolymers could be potentially used as novel carriers for proteins and anionic hydrophilic drugs.