Abstract
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.
Highlights
MicroRNAs play key roles in modulating therapeutic resistance of glioblastomas, the most common form of brain cancer in adults, and one of the deadliest of human cancers [1]
We previously demonstrated that complexation of small interfering RNA (siRNA)/PEI in the liposomes was advantageous [8], as PEI facilitates escape from endosomes and lysosomes into the cytoplasm, resulting in increased targeted gene suppression. miRNA 603 (miR-603) has been previously encapsulated in liposomes [9,10]
Anionic miR-603 was complexed with the cationic branched PEI at different nitrogen to phosphate (N:P) ratios
Summary
MicroRNAs (miRNAs) play key roles in modulating therapeutic resistance of glioblastomas, the most common form of brain cancer in adults, and one of the deadliest of human cancers [1]. By binding to the 30 untranslated regions of target mRNAs, these short (19–24 base pairs), noncoding RNAs dampen gene expression [2]. RNA extracted from glioblastomas of patients pre- and post-treatment with standard-of-care therapy (ionizing radiation (IR)/temozolomide), showed that miR603, miR-181d, and miR-124_3-p, were lower in the post-treatment specimens, with miR603 demonstrating the greatest decrease [4]. This increase, in turn, promotes cancer stem-cell state and acquired radiation resistance in glioblastomas [4]. Exogenous expression or transfection of miR-603 suppresses ionizing radiation resistance [4], and represents an attractive therapeutic strategy, especially in light of recent approval of the first small interfering RNA (siRNA)-based therapy [5]. Nanoparticles that can provide solutions to these barriers by protecting and targeting miRNAs to specific cells, are needed
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