Exth-61. Targeted Nanoparticle Delivery of Therapeutic Antimir-21 and Antimir-10b Presensitizes Glioblastoma to Lower Effective Doses of Temozolomide in Cells and Xenografts
Year: 2017
Type: conference-abstract
Abstract: MiR-21 and miR-10b are oncomiRs overexpressed in glioblastoma (GBM). Therapeutic antisense microRNAs (antimiRs) can effectively initiate cellular apoptosis. We hypothesized that encapsulating antimiR-21 and antimiR-10b into c-RGD peptide surface tagged PLGA nanoparticles (NPs) would lead to enhanced GBM cell uptake of NPs, efficient in vivo antimiR delivery, and greater chemosensitization to concurrent temozolomide (TMZ). We developed and characterized c-RGD-targeted and non-targeted NPs. We first treated U-87MG and Ln229 cells with NPs, with and without different doses of TMZ to determine cellular uptake, toxicity, anti-proliferation, and apoptosis by qRT-PCR and an immunoassay for key target genes of miR-21 and miR-10b. We then treated mouse U-87MG xenografts to measure changes in tumor volumes. In culture, we found higher (p<0.001) cellular uptake of targeted versus non-targeted NPs, and increased chemosensitivity (p<0.01) towards TMZ at lower concentrations (62.75 µM). There was increased cell cycle arrest at G2/M phase, especially for targeted NPs plus TMZ. We observed an increase in U-87MG cell expression of miR-21 key target genes: PTEN, PDCD4, Caspase 3, and p53, when treated with NPs. In mice there was significant (p<0.01) reduction in tumor volumes after Day 6 of TMZ treatment (25 mg/kg) for NPs irrespective of surface modifications. However, in a dose escalation study of TMZ following delivery of targeted NPs, we found a reduction (p<0.01) in tumor volumes starting at 6.25 mg/kg TMZ. Tagging NPs with c-RGD enhances their targeting to GBM cells in culture. Although passive tumor targeting of NPs in vivo may be a key mechanism for NP tumor localization, chemosensitization of cancer cells with antimiRs leads to a reduction in tumor volumes at lower TMZ dosages. Thus, NP-assisted silencing of miR-21 and miR-10b prior to TMZ treatment is an effective molecular theranostic strategy that may lead to improved treatment options for GBM.
Source: Neuro-Oncology
Institutions: Stanford Medicine, Stanford University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2767464985