Functionalized nanogels carrying an anticancer microRNA for glioblastoma therapy

JOURNAL OF CONTROLLED RELEASE

卷:239

Article

Shatsberg, Zohar¹  Zhang, Xuejiao^2,3  Ofek, Paula¹  Malhotra, Shashwat²  Krivitsky, Adva¹  Scomparin, Anna¹  Tiram, Galia¹  Calderon, Marcelo²  Haag, Rainer²  Satchi-Fainaro, Ronit¹ 

[1] Tel Aviv Univ, Sackler Sch Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel

[2] Free Univ Berlin, Inst Chem & Biochem, Takustr 3, D-14195 Berlin, Germany

[3] Chinese Acad Sci, Inst Appl Ecol, Key Lab Pollut Ecol & Environm Engn, Shenyang 110016, Peoples R China

关键词: Polymer therapeutics;    Nanogels;    Polyplex;    Polycations;    Polyglycerol;    microRNAs;    miR-34a;    Glioblastoma;    Nanomedicine;   

DOI  :  10.1016/j.jconrel.2016.08.029

来源: Elsevier

【 摘 要 】

Glioblastoma Multiforme (GBM) is one of the most aggressive forms of all cancers. The median survival with current standard-of-care radiation and chemotherapy is about 14 months. GBM is difficult to treat due to heterogeneity in cancer cell population. MicroRNA-based drugs have rapidly become a vast and burgeoning field due to the ability of a microRNA (miRNA) to target many genes involved in key cellular pathways. However, in vivo delivery of miRNA remains a crucial challenge for its therapeutic success. To bypass this shortcoming, we designed polymeric nanogels (NGs), which are based on a polyglycerol-scaffold, as a new strategy of miRNA delivery for GBM therapy. We focused on miR-34a, which is known for its key role in important oncogenic pathways and its tumor suppression ability in GBM and other cancers. We evaluated the capability of six NG derivatives to complex with miR-34a, neutralize its negative charge and deliver active miRNA to the cell cytoplasm. Human U-87 MG GBM cells treated with our NG-miR-34a nano-polyplexes showed remarkable downregulation of miR-34a target genes, which play key roles in the regulation of apoptosis and cell cycle arrest, and induce inhibition of cells proliferation and migration. Administration of NG-miR-34a nano-polyplexes to human U-87MG GBM-bearing SCID mice significantly inhibited tumor growth as opposed to treatment with NG-negative control miR polyplex or saline. The comparison between different polyplexes highlighted the key features for the rational design of polymeric delivery systems for oligonucleotides. Taken together, we expect that this new therapeutic approach will pave the way for safe and efficient therapies for GBM. (C) 2016 Elsevier B.V. All rights reserved.

【 授权许可】

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