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

## TL;DR

This study evaluates a new type of dendrimer for delivering siRNA into brain cancer and astrocyte cells, showing high efficiency but also significant toxicity.

## Contribution

The development of hydrolytically stable cationic bis-MPA dendrimers with tunable groups for efficient and safe siRNA transfection.

## Key findings

- G3-CYS dendrimer effectively delivered siRNA into glioblastoma and astrocyte cells, reducing target protein levels by 75–85%.
- G3-CYS showed transfection efficiency comparable to commercial agents but with a self-degradable backbone.
- G3-CYS exhibited dose-dependent toxicity in vivo, likely due to enhanced blood coagulation.

## Abstract

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.