Abstract
The blood-brain barrier (BBB) prevents effective delivery of most therapeutic agents to the brain. Intra-arterial (IA) infusion of hyperosmotic mannitol has been widely used to open the BBB and improve parenchymal targeting, but the extent of BBB disruption has varied widely with therapeutic outcomes often being unpredictable. In this work, we show that real-time MRI can enable fine-tuning of the infusion rate to adjust and predict effective and local brain perfusion in mice, and thereby can be allowed for achieving the targeted and localized BBB opening (BBBO). Both the reproducibility and safety are validated by MRI and histology. The reliable and reproducible BBBO we developed in mice will allow cost-effective studies on the biology of the BBB and drug delivery to the brain. In addition, the IA route for BBBO also permits subsequent IA delivery of a specific drug during the same procedure and obtains high targeting efficiency of the therapeutic agent in the targeted tissue, which has great potential for future clinical translation in neuro-oncology, regenerative medicine and other neurological applications.
Highlights
The treatment efficacy for many central nervous system (CNS) diseases is hindered by limited access to therapeutic agents
The overall goal of BBB opening (BBBO) is to maximize CNS targeting of the therapeutic agent while minimizing systemic toxicity
Osmotic BBBO has been an established method for decades, the parameters for inducing BBBO are highly variable and inconsistent
Summary
The treatment efficacy for many central nervous system (CNS) diseases is hindered by limited access to therapeutic agents. The poor drug penetration is mainly caused by the blood-brain barrier (BBB), which sequesters the CNS from the systemic circulation. Strategies are needed that will safely and efficiently disrupt the BBB. Intra-arterial (IA) mannitol followed by the infusion of therapeutic agents, including chemotherapeutics, gene vectors, and stem cells, has been the primary method by which therapeutics have been delivered across a disrupted BBB for several decades, both in preclinical models and in clinical studies [4,5,6,7,8]. Osmotic BBB opening (BBBO) proved highly variable and inconsistent [9], as it is affected by multiple factors, including the mannitol dose, injection speed, vascular anatomy, and cerebral
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