Anti-seed PNAs targeting multiple oncomiRs for brain tumor therapy

Glioblastoma (GBM) is one of the most lethal malignancies in the United States with poor survival and high recurrence rates, suggesting the need for approaches targeting the most important molecular drivers of tumor growth. Here, we aimed to simultaneously target oncomiRs 10b and 21, which have been reported to drive the aggressive growth and invasiveness of GBM. We designed short (8-mer bases) gamma-(g)-modified peptide nucleic acids (sPNAs), which target the seed region of oncomiRs 10b and 21 with high affinity. We entrapped these anti-miR sgPNAs in nanoparticles (NPs) formed from a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). The surfaces of the NPs were functionalized with aldehydes to produce bioadhesive NPs: we have previously shown that these bioadhesive NPs (BNPs) produce superior transfection efficiency, with a tropism for tumor cells. The sgPNA BNPs showed superior anti-miR efficacy in comparison to the regular full length PNA BNPs in vitro. When combined with temozolomide, sgPNA?BNPs administered via convection-enhanced delivery (CED) inhibited the growth of intracranial tumors and significantly improved the survival of animals (>120 days). RNA sequencing analysis revealed the downregulation of multiple genes associated with PI3-Akt, focal adhesion, and hypoxia inducible factor 1 (HIF-1) pathway to inhibit GBM progression after simultaneous inhibition of oncomiRs 10b and 21. Hence, we established that BNPs loaded with anti-seed sgPNAs?targeting multiple oncomiRs is a promising approach to improve the treatment of GBM, with a potential to personalize treatment based on tumor specific oncomiRs. Overall design: Human glioma cells (U87) were used in this study. Nucleic acid mediated kockdown of miR-21 and miR-10b was achieved. mRNA profiles in U87 cells after konckdown of miR-10b or miR-21 or miR-10b+21 was compared against the untreated U87 cells.