Multi-Modal Nanomedicine for Glioblastoma

Glioblastoma multiforme (GBM) is an aggressive primary neoplasm 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) play major roles in normal developmental processes, and their deregulation significantly contributes to various aspects of carcinogenesis. Nevertheless, in vivo delivery of small interfering RNA (siRNA) and miRNA remains a crucial challenge for their therapeutic success.

We have recently 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 nanocarrier for antitumor oligonucleotides.

Using our novel nanocarrier, we have studied the expression targets and functional effects of miR-34a in several human glioblastoma cell lines and human tissue samples. miR-34a levels inversely correlated to their target gene levels measured in the same cell lines or tissue. Transient transfection of PG-NH₂-miR-34a polyplex 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 following treatment with PG-NH₂-miR-34a polyplex in a human glioblastoma mouse model. We further characterized the synergistic effect of combining PG-NH₂-miR-34a polyplex with chemotherapy and achieved promising results.

Together, our findings show that PG-NH₂ efficiently delivers anticancer miRNAs to glioblastoma cells and their microenvironment and suppresses brain tumor growth. These results suggest that our polyplex could serve as a potential nanomedicine for glioblastoma.