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

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 convectionenhanced 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.

Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

“…Among those miRNAs previously described to have a role in the regulation of molecular mechanisms of oxidative stress, some of them have been suggested as therapeutic targets. For example, miR-21-conjugated NPs has been assessed in glioblastoma treatment [154,155]. Specifically, Seo and colleagues demonstrated that both RNA-based anti-miR-21 conjugated with a cationic Poly(Amine-Co-Ester) (PACE) and Peptide Nucleic Acid (PNA) anti-miR-21 conjugated with a copolymer of Poly(Lactic Acid) and Hyperbranched Polyglycerol (PLA-HPG), provided an efficient intracellular delivery system to inhibit miR-21 expression, leading to PTEN upregulation and apoptosis of human GBM (Glyoblastoma Multiforme) cancer cells.…”

Peptide nucleic acid-based targeting of microRNAs: possible therapeutic applications for glioblastoma

“…More recently, high levels of apoptosis on glioma cell lines were obtained following co-treatment with two PNAs, one targeting miR-221-3p, the other targeting miR-222-3p. In addition, Seo et al [113] showed the use of a PNA targeting miR-21 as in vivo inhibitor of glioma U87 cells.…”

“…As far as delivered PNAs in vivo to experimental models of GBM, local delivery of nanoparticles should be considered a promising therapeutic strategy that bypasses the blood-brain barrier, minimizes systemic toxicity, and enhances intracranial drug distribution and retention. In this respect, Seo et al [113] developed nanoparticles loaded with PNAs inhibiting miR-21, a microRNA overexpressed in GBM and retaining oncogenic features. These authors employed a block copolymer of poly(lactic acid) and hyperbranched polyglycerol to deliver an anti-miR-21 PNA, showing that efficient intracellular delivery was facilitated, leading to miR-21 suppression and PTEN upregulation and apoptosis of human GBM cells.…”

“…These authors employed a block copolymer of poly(lactic acid) and hyperbranched polyglycerol to deliver an anti-miR-21 PNA, showing that efficient intracellular delivery was facilitated, leading to miR-21 suppression and PTEN upregulation and apoptosis of human GBM cells. This anti-miR-21 PNA was also administered by convection-enhanced delivery to animals with intracranial gliomas, inducing significant miR-21 knockdown and chemosensitization, resulting in improved survival when combined with chemotherapy [113] . This study demonstrates the feasibility and promise of local administration Modified from Gasparello et al .…”

Systemic Brain Tumor Delivery of Synthetic Protein Nanoparticles for Glioblastoma Therapy

“…However, a positive therapeutic effect was only observed in peripheral tumors, but not in intracranial tumors, pointing towards the inability of CPA-7, like many small molecule therapeutics and biomolecules, to cross the protective BBB and enter the brain tumor compartment. 6 A wide range of nanoparticles have been developed to deliver chemotherapeutic drugs, such as docetaxel, [11][12][13] paclitaxel, [14][15][16] doxorubicin 17 or other small molecule chemotherapeutics; [18][19][20][21][22] or, to leverage antibodies, 23,24 RNA, [25][26][27][28] or peptides 29 in an attempt to enhance GBM therapy.…”