Abstract 2668: The exosomes derived from BM-hMSCs home to glioma and deliver synthetic microRNA mimics after systemic administration

Glioblastoma is the most malignant type of glioma (World Health Organization grade 4) and has a median survival time of only 14.6 months even after the standard treatment of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide administration. Although some novel and promising anti-glioma agents have been developed, therapeutic advancement has remained disappointing due to the lack of efficient delivery tools. Here we focused on exosomes derived from mesenchymal stem cells (MSCs) as carriers to deliver biological therapeutic agents for the treatment of gliomas. These exosomes are expected to cross the blood-brain barrier and selectively home to the glioma tissue, similar to the parental cells (MSCs). Additionally, MSCs could produce sufficient amounts of exosomes on a clinically applicable scale. Thus, MSC exosomes present a potentially ideal cell-free delivery vehicle for glioma therapy. We hypothesized that exosomes derived from human bone marrow-derived MSCs (BM-hMSCs) can target gliomas and can be used as delivery vehicles following systemic administration. In this study, we employed microRNA (miR-128) as the therapeutic cargo, and exosomes were isolated from a cultured media of BM-hMSCs using ultracentrifugation. At first, exosomes labeled with fluorescent dye were incubated with glioma cells, and exosomes taken up by glioma cells were evaluated by confocal fluorescence microscopy and flow cytometry. Labeled exosomes were also systemically injected into a glioma xenograft model and the ability to home to glioma tissue was evaluated by an in vivo imaging system and histological study. The results showed that MSC exosomes can be taken up by glioma cells and can home to glioma tissues. Next, we cultured miR-128-enriched MSC exosomes with glioma cells. To check the function of miR-128 delivered to glioma cells by MSC exosomes, the down-regulation of the BMI-1 target gene of miR128 was evaluated using real-time polymerase chain reaction and western blot analyses. We also systemically injected these exosomes into glioma xenograft models and evaluated the function of miR-128 by analyzing the downregulation of BMI-1 at the tumor site and the animal survival time in vivo. We confirmed that miR-128 delivered by MSC exosomes could function at the target site both in vitro and in vivo. These results indicate that MSC exosomes may be an ideal delivery vehicle for the treatment of gliomas, especially for microRNA replacement therapy. Citation Format: Shinji Yamashita, Tal Shahar, Anwar Hossain, Brittany Parker Kerrigan, Joy Gumin, Shoudong Li, Feng Gao, Kouji Yamasaki, Yuzaburo Shimizu, Frederick F. Lang. The exosomes derived from BM-hMSCs home to glioma and deliver synthetic microRNA mimics after systemic administration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2668.