Glioblastoma multiforme (GBM) are aggressive primary neoplasms of the brain that exhibit notable refractivity to standard treatment regimens. Recent large-scale molecular profiling has revealed deregulated molecular networks as potential targets for therapeutic development. MicroRNAs (miRNAs) are noncoding RNA molecules which act as post-transcriptional regulators of specific messenger RNA transcripts. miRNAs play major roles in normal developmental processes, and their deregulation significantly contributes to various aspects of carcinogenesis.
Nevertheless,in vivodelivery of small interfering RNA (siRNA) and miRNA remains a crucial challenge for their therapeutic success. siRNAs and miRNAs on their own are not taken-up by most mammalian cells in a way that preserves their activity. In order to circumvent these limitations, we developed a cationic carrier system, which can strongly improve its stability, intracellular trafficking and silencing efficacy. Polyglycerol (PG)-Amine, a water-soluble polyglycerol-based hyperbranched polymer accumulates in the tumor microenvironment due to the enhanced permeability and retention (EPR) effect, and therefore, represents an ideal delivery vehicle for antitumor biological agents.
Using our novel nanocarrier, we have studied the expression targets and functional effects of anticancer miRNAs in several human glioblastoma cell lines. The miRNAs levels inversely correlated to their target gene levels measured in the same cell lines. Transient transfection of the anticancer miRNA-PGNH2polyplex into glioblastoma cells strongly inhibited cell proliferation, cell cycle progression, and cell migration.Consequently we performed an in vivo experiment and achieved a significant tumor growth inhibition effect following treatment with the anticancer miRNA-PGNH2polyplex in a human glioblastoma mouse model.
We further characterized the synergistic effect of combining the miRNA polyplex with chemotherapy and achieved promising results. Together, our findings show that PG-Amine is able to deliver anticancer miRNAs to glioblastoma cells and to suppress brain tumor growth. These results suggest that our polyplex could serve as a potential nanomedicine for glioblastoma.
