Hydrolytically Stable Cationic Bis-MPA Dendrimers as Efficient Transfectants for Glioblastoma Cells and Primary...

We report the biological evaluation of bis-MPA dendrimers terminated with either cysteamine (CYS) or 2-(dimethylamino)ethanethiol (DA) groups for siRNA transfection. The results show that aggregation phenomena are critical to the biological performance of these constructs. Confocal and 2D microscopy demonstrated that only the G3-CYS dendrimer transported siRNA into cells. Accordingly, G3-CYS-mediated siRNA transfection reduced intracellular levels of the target proteins─p42-MAPK, Rheb, and MGMT─to 15-25% of control levels in a human glioblastoma cell line and mouse astrocytes. G3-CYS transfection efficiency was similar to that of commercial transfectants. However, its self-degradable bis-MPA backbone and tunable peripheral groups render it markedly superior, making it a promising transfection agent and emphasize the critical balance between structural design, biological efficacy, and safety. Despite its efficacy, G3-CYS displayed a narrow therapeutic window with pronounced cytotoxicity above 1 μM. In vivo studies further confirmed dose-dependent systemic toxicity, likely associated with enhanced blood coagulation.