A Paradigm Change: Efficient Transfection of Human Leukemia Cells by Stimuli-Responsive Multicompartment Micelles

The controlled nonviral delivery of genetic material using cationic polymers into cells has been of interest during the past three decades, yet the ideal delivery agent featuring utmost transfection efficiency and low cytotoxicity still has to be developed. Here, we demonstrate that multicompartment micelles from stimuli-responsive triblock terpolymers, polybutadiene-<i>block</i>-poly(methacrylic acid)-<i>block</i>-poly(2-(dimethylamino)ethyl methacrylate) (BMAAD), are promising candidates. The structures exhibit a patchy shell, consisting of amphiphilic (interpolyelectrolyte complexes, MAA and D) and cationic patches (excess D), generating a surface reminiscent to those of certain viruses and capable of undergoing pH-dependent changes in charge stoichiometry. After polyplex formation with plasmid DNA, superior transfection efficiencies can be reached for both adherent cells and human leukemia cells. Compared to the gold standard PEI, remarkable improvements and a number of advantages were identified for this system, including increased cellular uptake and an improved release of the genetic material, accompanied by fast and efficient endosomal escape. Furthermore, high sedimentation rates might be beneficial regarding <i>in vitro</i> applications

Small but Powerful: Co-Assembly of Polyether-Based Triblock Terpolymers into Sub-30 nm Micelles and Synergistic Effects on Cellular Interactions

We introduce a versatile ABC triblock terpoly- mer platform based on poly­(ethylene oxide)-<i>block</i>-poly­(allyl glycidyl ether)-<i>block</i>-poly­(<i>tert</i>-butyl glycidyl ether) (PEO-<i>b</i>-PAGE-<i>b</i>-P<i>t</i>BGE) and subsequent functionalization of the PAGE segment with thiogalactose (hydroxyl), cysteamine (amino), and 2-mercaptopropionic acid (carboxy) by thiol–ene chemistry. These materials are used to prepare core-shell-corona micelles with a P<i>t</i>BGE core, a PAGE shell, and a PEO corona and sizes below 30 nm in aqueous media. We investigate the influence of different functional groups on micelle formation and cellular uptake. Moreover, co-assembly of differently functionalized materials allows to create micelles with a mixed shell and adjustable charge and, in that way, important characteristics such as cell uptake or cytotoxicity can be controlled. Furthermore, we demonstrate that even the uptake mechanism depends on the substitution pattern of the underlying triblock terpolymer