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Nanoparticle-mediated intratumoral inhibition of miR-21 for improved survival in glioblastoma

Author:
Seo, Young-Eun, Suh, Hee-Won, Bahal, Raman, Josowitz, Alexander, Zhang, Junwei, Song, Eric, Cui, Jiajia, Noorbakhsh, Seth, Jackson, Christopher, Bu, Tom, Piotrowski-Daspit, Alexandra, Bindra, Ranjit, Saltzman, W. Mark
Source:
Biomaterials 2019 v.201 pp. 87-98
ISSN:
0142-9612
Subject:
adjuvants, apoptosis, blood-brain barrier, brain, brain neoplasms, chemosensitization, composite polymers, convection, drug therapy, drugs, glioblastoma, humans, microRNA, nanoparticles, peptides, polylactic acid, toxicity, United States
Abstract:
Glioblastoma (GBM) is the most common and deadly form of malignant brain tumor in the United States, and current therapies fail to provide significant improvement in survival. Local delivery of nanoparticles is a promising therapeutic strategy that bypasses the blood-brain barrier, minimizes systemic toxicity, and enhances intracranial drug distribution and retention. Here, we developed nanoparticles loaded with agents that inhibit miR-21, an oncogenic microRNA (miRNA) that is strongly overexpressed in GBM compared to normal brain tissue. We synthesized, engineered, and characterized two different delivery systems. One was designed around an anti-miR-21 composed of RNA and employed a cationic poly(amine-co-ester) (PACE). The other was designed around an anti-miR-21 composed of peptide nucleic acid (PNA) and employed a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). We show that both nanoparticle products facilitate efficient intracellular delivery and miR-21 suppression that leads to PTEN upregulation and apoptosis of human GBM cells. Further, when administered by convection-enhanced delivery (CED) to animals with intracranial gliomas, they both induced significant miR-21 knockdown and provided chemosensitization, resulting in improved survival when combined with chemotherapy. The challenges involved in optimizing the two delivery systems differed, and despite offering distinct advantages and limitations, results showed significant therapeutic efficacy with both methods of treatment. This study demonstrates the feasibility and promise of local administration of miR-21 inhibiting nanoparticles as an adjuvant therapy for GBM.
Agid:
6345902