Towards controlled drug delivery in brain tumors with microbubble-enhanced focused ultrasound

• Type of Material: Article
• Authors: Scott Schoen, Georgia Institute of Technology; Sait Kilinc, School of Electrical and Computer Engineering; Hohyun Lee, The George W. Woodruff School of Mechanical Engineering; Yutong Guo, The George W. Woodruff School of Mechanical Engineering; Levent F Degertekin, The George W. Woodruff School of Mechanical Engineering; Graeme F Woodworth, University of Maryland School of Medicine; Costas Arvanitis, The George W. Woodruff School of Mechanical Engineering
• Language: English
• Date: 2022-01-01
• Publisher: Elsevier BV
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.addr.2021.114043
• Title of Journal or Parent Work: Advanced Drug Delivery Reviews
• Volume: 180
• Start Page: 114043
• End Page: 114043
• Keywords: Blood brain barrier; Brain Neoplasms; Drug delivery; Animals; Sonication; Brain cancer; Micro-bubbles; Focused ultrasound; Tumor Microenvironment; Drug Delivery Systems; Glioma; Microbubbles; Antineoplastic Agents; Blood tumor barrier; Humans; Ultrasound Immunomodulation

Abstract

Brain tumors are particularly challenging malignancies, due to their location in a structurally and functionally distinct part of the human body – the central nervous system (CNS). The CNS is separated and protected by a unique system of brain and blood vessel cells which together prevent most bloodborne therapeutics from entering the brain tumor microenvironment (TME). Recently, great strides have been made through microbubble (MB) ultrasound contrast agents in conjunction with ultrasound energy to locally increase the permeability of brain vessels and modulate the brain TME. As we elaborate in this review, this physical method can effectively deliver a wide range of anticancer agents, including chemotherapeutics, antibodies, and nanoparticle drug conjugates across a range of preclinical brain tumors, including high grade glioma (glioblastoma), diffuse intrinsic pontine gliomas, and brain metastasis. Moreover, recent evidence suggests that this technology can promote the effective delivery of novel immunotherapeutic agents, including immune check-point inhibitors and chimeric antigen receptor T cells, among others. With early clinical studies demonstrating safety, and several Phase I/II trials testing the preclinical findings underway, this technology is making firm steps towards shaping the future treatments of primary and metastatic brain cancer. By elaborating on its key components, including ultrasound systems and MB technology, along with methods for closed-loop spatial and temporal control of MB activity, we highlight how this technology can be tuned to enable new, personalized treatment strategies for primary brain malignancies and brain metastases.