April 30, 2021 — Science Advances
Abstract
RNA-based therapies offer unique advantages for treating brain tumors. However, tumor penetrance and uptake are hampered by RNA therapeutic size, charge, and need to be “packaged” in large carriers to improve bioavailability. Here, we have examined delivery of siRNA, packaged in 50-nm cationic lipid-polymer hybrid nanoparticles (LPHs:siRNA), combined with microbubble-enhanced focused ultrasound (MB-FUS) in pediatric and adult preclinical brain tumor models. Using single-cell image analysis, we show that MB-FUS in combination with LPHs:siRNA leads to more than 10-fold improvement in siRNA delivery into brain tumor microenvironments of the two models. MB-FUS delivery of Smoothened (SMO) targeting siRNAs reduces SMO protein production and markedly increases tumor cell death in the SMO-activated medulloblastoma model. Moreover, our analysis reveals that MB-FUS and nanoparticle properties can be optimized to maximize delivery in the brain tumor microenvironment, thereby serving as a platform for developing next-generation tunable delivery systems for RNA-based therapy in brain tumors.
Authors: Yutong Guo1, Hohyun Lee1, Zhou Fang2, Anastasia Velalopoulou1, Jinhwan Kim1, Midhun Ben Thomas3, Jingbo Liu4, Ryan G. Abramowitz1, YongTae Kim1,2, Ahmet F. Coskun2, Daniel Pomeranz Krummel5, Soma Sengupta5, Tobey J. MacDonald4, Costas Arvanitis1,2,
1Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA.; 2Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA; 3Department of Neurology, Emory University School of Medicine, Atlanta, GA; 4Department of Pediatrics, Aflac Cancer and Blood, Emory University School of Medicine, Atlanta, GA; 5Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
Read full text at: https://advances.sciencemag.org/content/7/18/eabf7390
Science Advances – Vol. 7, no. 18, eabf7390; DOI: 10.1126/sciadv.abf7390
