Unlocking the mysteries of the brain and finding effective treatments for conditions like brain tumors and Alzheimer’s disease has long been a challenge due to the blood-brain barrier (BBB), a natural defense mechanism that regulates what substances can enter the brain. Despite its protective role, the BBB also poses a significant challenge in the field of neurology and oncology, limiting the delivery of potentially life-saving medications to affected brain regions. In the face of these challenges,, recent advancements in medical science have led to exciting breakthroughs in bypassing this barrier and delivering drugs directly to where they’re needed the most, which means that there is a possibility to improve treatment outcomes for patients with brain tumors and Alzheimer’s disease.
Under the guidance of Dr. Stephen Wong and Dr. Hong Zhao, a team from Houston Methodist Hospital and Texas A&M University, with the addition of Gefei Song,Pierce Plumlee, and Ju Young Ahn evaluated contemporary clinical methods for managing brain tumors and Alzheimer’s disease. This comprehensive review has been published in the respected journal, Biomedicine & Pharmacotherapy, representing a significant step forward in the quest to improve therapeutic approaches for these challenging neurological conditions.
The methods examined included focused ultrasound (FUS), which encompasses high-intensity focused ultrasound (HIFU) and low-intensity focused ultrasound (LIFU); mannitol-facilitated delivery of anti-neoplastic drugs; receptor-mediated transcytosis of antibody-drug conjugates (ADCs); and viral vectors for gene therapy. Ongoing clinical trials utilizing FUS techniques can be classified into three categories: implanted ultrasound devices, MR-guided FUS devices (MRgFUS), and neuronavigation-guided devices.
The researchers also delved into the complex molecular dynamics of the BBB, which can undergo alterations in response to disease. By employing systems biology approaches and investigating the interactions among genes, proteins, cells, and signaling pathways, researchers are gaining valuable insights into the mechanisms associated with these changes. This enhanced understanding increases the potential to identify novel strategies for effectively delivering drugs across both the blood-brain barrier and the blood-brain tumor barrier.
While the number of clinical trials utilizing these methods has decreased, trials that combine FUS with drug delivery have demonstrated promising effectiveness. “Most of these clinical trials have small patient cohorts and thus lack the statistical power to conclude, indicating the ongoing need to investigate these strategies,” the researchers conclude, highlighting the need for further investigation. Remaining challenges include establishing safety profiles, determining optimal parameters, minimizing off-target effects, coordinating the timing of drug administration in relation to FUS treatment, and creating a standardized approach for individual patients.
Systems biology approaches have offered fresh insights into the regulation of the BBB and have identified potential new targets and pathways for drug delivery. By integrating molecular profiling, network analysis, and computational modeling, researchers can better understand BBB complexity and identify alternative treatment strategies. These findings hold promise for enhancing selectivity and minimizing off-target effects in drug delivery strategies. “To achieve this goal, it is essential to continue exploring and expanding our understanding of the intricate molecular mechanisms involved in the BBB crossing and targeted drug delivery to the brain,” the researchers debate. It seems that continued research into BBB crossing mechanisms is essential for developing effective therapies for central nervous system diseases.
The review by the team led by Dr. Stephen Wong and Dr. Hong Zhao illuminates the diverse strategies for circumventing the blood-brain barrier (BBB) to treat brain diseases effectively, focusing on the promising integration of focused ultrasound (FUS) with drug delivery, mannitol’s role in facilitating drug permeability, and the potential of receptor-mediated transcytosis (RMT) and gene therapy approaches. Particularly, the integration of FUS with the concurrent administration of circulating microbubbles has, over many years of rigorous experimentation, demonstrated increasingly promising efficacy in the latest clinical trials, underscoring its potential as a non-invasive method to enhance drug delivery to specific brain regions. Additionally, the research highlights the importance of emerging systems biology approaches in understanding the BBB’s complex molecular dynamics. These approaches, including molecular profiling, network analysis, and computational modeling, are critical for identifying new drug delivery targets and strategies, aiming to improve treatment outcomes for brain tumors and Alzheimer’s disease. The paper also stresses the necessity of further investigations to refine these techniques, establish safety profiles, and develop standardized treatment protocols tailored to individual patient needs, marking a significant step forward in the quest for effective treatments for central nervous system diseases. Overall, the findings of the researchers’ review highlight the advancements in developing innovative treatment approaches for central nervous system (CNS) diseases. As we stand on the brink of a new era in neurotherapeutic interventions, the possibility of significantly improving treatment outcomes for those affected by brain tumors and Alzheimer’s disease is not just a distant dream but an impending reality. However, they also stress the ongoing necessity for further research and refinement of current methods. Continued exploration of the molecular mechanisms associated with blood-brain barrier (BBB) penetration and targeted drug delivery remains crucial for the development of novel and efficacious therapies for CNS disorders.
JOURNAL REFERENCE
Song G, Plumlee P, Ahn JY, Wong ST, Zhao H. Translational strategies and systems biology insights for blood-brain barrier opening and delivery in brain tumors and Alzheimer’s disease. Biomed Pharmacother. 2023 Nov;167:115450. DOI: https://doi.org/10.1016/j.biopha.2023.115450.
ABOUT THE AUTHORS
Gefei (Sylvia) Song, B.S., formerly a research assistant at the Systems Medicine and Bioengineering (SMAB) Department of Houston Methodist Near Cancer Center, holds dual bachelor’s degrees in Biology and Statistics from the University of Wisconsin-Madison. She is currently pursuing a Master’s degree in Biostatistics at the University of California, Berkeley. Her research is focused on understanding cancer mechanisms, disease modeling, and computational biology.
Having interned at Houston Methodist Near Cancer Center’s SMAB Department under the funding support of NCI’s Cancer Systems Biology Consortium, Pierce Plumlee is advancing towards his B.S. in Biomedical Engineering from the University of Alabama at Birmingham. His research delves into cancer biology, osteogenesis, and cardiomyopathy.
Ju Young Ahn, B.Sc., a Johns Hopkins-educated Biomedical Engineer, is currently a graduate research assistant at SMAB, Houston Methodist and pursuing an M.D./Ph.D. at Texas A&M University. His dissertation, conducted in the Wong lab, explores the tumor microenvironment, Alzheimer’s disease, computational biology, and machine learning.
Hong Zhao, M.D., Ph.D., serving as an Associate Professor of Molecular Medicine at Houston Methodist Academic Institute and Weill Cornell Medicine, and as the co-Director of the Houston Methodist Advanced Tissue and Cellular Microscope Core Facility. Her research is supported by multiple NIH grants, all within the realm of cancer systems biology. She published over 100 scientific publications with more than 1,700 citations and two U.S. patents.
Stephen T. Wong, Ph.D., holds the John S. Dunn Presidential Distinguished Chair and leads both SMAB and Shared Resources at Houston Methodist Near Cancer Center. He also directs the T.T. & W.F. Chao Center for BRAIN and the Translational Biophotonics Laboratory. With professorships at Cornell University, Dr. Wong’s pioneering research in bioengineering intersects cancer and neurological diseases. His contributions have garnered recognition through fellowships and accolades across multiple organizations, such as IEEE, AIMBE, IAMBE, Optica, ACMI, AMIA, and AAIA.
