The development of nonviral synthetic vectors for clinical application of gene
therapy using siRNA transfection technology is of particular importance for
treatment of human diseases, which is yet an unsolved challenge. By employing
a rational design approach, we have synthesized a set of well-defined, low-
molecular-weight dendritic polyglycerol-based amphiphiles, which are decorated
peripherally with the DAPMA (N,N-di-(3-aminopropyl)-N-(methyl)amine) moiety.
The main differences that were introduced in the structural motif relate to
dendron generation and the type of linker between the hydrophilic and
hydrophobic segment. The synthesized amphiphiles were then characterized for
their aggregation behaviour and further evaluated with respect to their siRNA
transfection potential by comparing their physico-chemical and biological
features. Our findings demonstrated that all four synthesized amphiphiles
yielded high gene binding affinities. Furthermore, the ester-linked compounds
(G1-Ester-DAPMA, G2-Ester-DAPMA) revealed noticeable gene silencing in vitro
without affecting the cell viability in the tumor cell line 786-O. Remarkably,
neither G1-Ester-DAPMA nor G2-Ester-DAPMA induced inflammatory side effects
after systemic administration in vivo, which is noteworthy because such highly
positively charged compounds are typically associated with toxicity concerns
which in turn supports their prospective application for in vivo purposes.
Therefore, we believe that these structures may serve as new promising
alternatives for nonviral siRNA delivery systems and have great potential for
further synthetic modifications
