Despite potential for clinical efficacy, therapeutic delivery of microRNAs (miRNA) remains a major translational barrier. Here, we explore a strategy for miRNA delivery in the treatment of glioblastoma, the most common form of adult brain cancer, that involves complexation of miRNA with polyethylenimine (PEI) and encapsulation in targeted liposomes. miRNA 603 (miR-603) is a master regulatory miRNA that suppresses glioblastoma radiation resistance through down-regulation of insulin-like growth factor 1 (IGF1) signaling. miR-603 was complexed with PEI, a cationic polymer, and encapsulated into liposomes decorated with polyethylene glycol (PEG) and PR_b, a fibronectin-mimetic peptide that specifically targets the α5β1 integrin that is overexpressed in glioblastomas. Cultured patient-derived glioblastoma cells internalized PR_b-functionalized liposomes but not the non-targeted liposomes. The integrin targeting and complexation of the miRNA with PEI were associated with a 22-fold increase in intracellular miR-603 levels, and corresponding decreases in IGF1 and IGF1 receptor (IGF1R) mRNA expression. Moreover, treatment of glioblastoma cells with the PR_b liposomes encapsulating miR-603/PEI sensitized the cells to ionizing radiation (IR), a standard of care treatment for glioblastomas. These results suggest that PR_b-functionalized PEGylated liposomes encapsulating miR-603/PEI complexes hold promise as a therapeutic platform for glioblastomas.
|Original language||English (US)|
|State||Published - Aug 2021|
Bibliographical noteFunding Information:
Funding: This research was funded by the Whiting School of Engineering of the Johns Hopkins University.
Acknowledgments: We thank Michael Bevan for giving us access to his Zetasizer. We would also like to thank the Johns Hopkins University Integrated Imaging Center, which is supported by the Whiting School of Engineering and the Krieger School of Arts & Sciences.
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- Glioblastoma stem-cell state
- MicroRNA delivery
- Radiation therapy
- Stealth liposomes
- Targeting integrin α5β1