Targeted Exosomes for Drug Delivery: Biomanufacturing, Surface Tagging, and Validation.

Abstract

Exosomes hold great potential to deliver therapeutic reagents for cancer treatment due to its inherent low antigenicity. However, several technical barriers, such as low productivity and ineffective cancer targeting, need to be overcome before wide clinical applications. The present study aims at creating a new biomanufacturing platform of cancer-targeted exosomes for drug delivery. Specifically, a scalable, robust, high-yield, cell line based exosome production process is created in a stirred-tank bioreactor, and an efficient surface tagging technique is developed to generate monoclonal antibody (mAb)-exosomes. The in vitro characterization using transmission electron microscopy, NanoSight, and western blotting confirm the high quality of exosomes. Flow cytometry and confocal laser scanning microscopy demonstrate that mAb-exosomes have strong surface binding to cancer cells. Furthermore, to validate the targeted drug delivery efficiency, romidepsin, a histone deacetylase inhibitor, is loaded into mAb-exosomes. The in vitro anti-cancer toxicity study shows high cytotoxicity of mAb-exosome-romidepsin to cancer cells. Finally, the in vivo study using tumor xenograft animal model validates the cancer targeting specificity, anti-cancer efficacy, and drug delivery capability of the targeted exosomes. In summary, new techniques enabling targeted exosomes for drug delivery are developed to support large-scale animal studies and to facilitate the translation from research to clinics.