Stable, Bioresponsive, and Macrophage-Evading Polyurethane Micelles Containing an Anionic Tripeptide Chain Extender

Abstract

Polymeric nanocarriers have been extensively used in medicinal applications for drug delivery. However, intravenous nanocarriers circulating in the blood will be rapidly cleared from the mononuclear macrophage system. The surface physicochemical characterizations of nanocarriers are the primary factors to determine their fate in vivo, such as evading the reticuloendothelial system, exhibiting long blood circulation times, and accumulating in the targeted site. In this work, we develop a series of polyurethane micelles containing segments of an anionic tripeptide, hydrophilic mPEG, and disulfide bonds. It is found that the long hydrophilic mPEG can shield the micellar surface and have a synergistic effect with the negatively charged tripeptide to minimize macrophage phagocytosis. Meanwhile, the disulfide bond can rapidly respond to the intracellular reduction environment, leading to the acceleration of drug release and improvement of the therapeutic effect. Our results verify that these anionic polyurethane micelles hold great potential in the development of the stealth immune system and controllable intracellular drug transporters.

Effects of oppositely charged moieties on the self-assembly and biophysicochemical properties of polyurethane micelles

“…According to our previous reports, single cationic GQA or anionic TPT polyurethane micelles with short mPEG chains still have good self-assembly ability. 33,37 The influence of the short hydrophilic mPEG chain on the instability of G25T25mE0 and G25T25mE500 can be excluded. These results indicate that the oppositely charged moieties in one polymer chain can impair the action of the GQA surfactant and severely hinder its self-assembly ability and stabilization due to the interchain electrostatic attraction.…”

“…32 In our previous report, we demonstrated that polyurethane micelles bearing an anionic tripeptide could minimize the phagocytosis by macrophages and elimination from the reticuloendothelial system. 33 Meanwhile, cationic gemini quaternary ammonium (GQA), which exhibits superior physicochemical properties attributed to its unique structure with a hydrophilic head group and hydrophobic alkyl chain, usually acts as a surfactant with a low critical micelle concentration (CMC) and improved micellization ability. 34 We also found that the GQA surfactant efficiently improved the cellular uptake and permeability of the cell membrane.…”