Paper Title
Delivery of Nanoparticle Loaded with MIRNAS to Inhibit GBM Stem Cells
Abstract
Multiple complementary genomic and epigenomic abnormalities are responsible for cancer that deregulate pathways which control cell proliferation and tissue homeostasis. Epigenetic modifications, involving deregulation of non-coding RNAs, are emerging as critical determinants of gene expression and essential drivers of neoplastic phenotypes.Our knowledge of how these complex epigenetic mechanisms operate in the context of cancer cell phenotype regulation remains limited. Non-coding RNAs, in particular miRNAs (micro-RNAs), are emerging as critical epigenetic regulators of cell fate and oncogenesis. MiRNAs act by selectively inhibiting gene expression primarily by targeting mRNA for degradation usually via complementary 3’-UTR seed sequences. MiRNAs have been found to regulate tumorigenesis and cancer cell stemness by virtue of their capacity to target tumor-suppressing or tumor promoting transcripts. We showed that combined effect of Oct4 and Sox2 to induce a tumor-propagating stem-like state in GBM(Glioblastoma) cells through a mechanism that changes the induction of DNMTs (DNA methyl transferase) and down-regulation of a network of miRNAs through promoter DNA methylation. Two of the miRNAs repressed by Oct4/Sox2, miR-148a and miR-296-5p, efficiently inhibit the tumor propagating capacity of GBM stem-like cells, making them excellent candidates for therapeutic intervention. Current therapeutic options for treating high-grade brain tumors remain limited. Recent advancements in nanomedicine (nanoparticles loaded with therapeutic) provide new and exciting opportunities to treat and manage brain tumors. Cationic polymers are a class of biomaterials with great promise for targeted molecular therapeutics. We combined this cutting-edge technology with our newly discovered stem cell inhibiting miRNAs to develop nano/miR (nanoparticle/microRNA) conjugates to treat gliomas. We show these nano/miR distribute throughout an established tumor in vivo, and more importantly, delivering these tumor-suppressing miRNAs using Poly(beta-amino esters) (PBAE) polymers inhibits the growth of established GBM tumor and extends survival in mouse models. Our findings demonstrate that identifying and validating stem cell-inhibitory miRNAs in combination with current advances in nanomedicine will undoubtedly impact the development of novel therapies for targeting the CSC population and treating GBM.
Keywords - GBM, DNMTs, miRNA, nanomedicine, CSC.