Abstract
Drug delivery in the CNS is limited by endothelial tight junctions forming the impermeable blood-brain barrier. The development of new treatment paradigms has previously been hampered by the restrictiveness of the blood-brain barrier to systemically administered therapeutics. With recent advances in stereotactic localization and noninvasive imaging, we have honed the ability to modulate, ablate, and rewire millimetric brain structures to precisely permeate the impregnable barrier. The wide range of focused radiations offers endless possibilities to disrupt endothelial permeability with different patterns and intensity following 3-dimensional coordinates offering a new world of possibilities to access the CNS, as well as to target therapies. We propose a review of the current state of knowledge in targeted drug delivery using noninvasive image-guided approaches. To this end, we focus on strategies currently used in clinics or in clinical trials such as targeted radiotherapy and magnetic resonance guided focused ultrasound, but also on more experimental approaches such as magnetically heated nanoparticles, electric fields, and lasers, techniques which demonstrated remarkable results both in vitro and in vivo. We envision that biodistribution and efficacy of systemically administered drugs will be enhanced with further developments of these promising strategies. Besides therapeutic applications, stereotactic platforms can be highly valuable in clinical applications for interventional strategies that can improve the targetability and efficacy of drugs and macromolecules. It is our hope that by showcasing and reviewing the current state of this field, we can lay the groundwork to guide future research in this realm.
Highlights
Advanced stereotactic systems, focused ultrasound and proton therapy, have received tremendous attention recently
Since peptide and protein therapeutics are generally excluded from the blood-brain transport, owing to the negligible permeability of the brain –capillary endothelial wall to these drugs, endothelial cells represent the major obstacle to the use of many potential
Even with the breakdown of the blood-brain barrier (BBB) in neuro-oncological disease, the fact remains that the tissue accumulation of chemotherapeutics for CNS metastases is 85% less intracranially compared with penetration and biodistribution for extracranial neoplasms.[9]
Summary
A rapidly developing field of study within stereotactic modulation involves the use of high-intensity focused ultrasound, most notably magnetic resonance guided focused ultrasound (MRgFUS). There have been several recent studies investigating MRI-independent targeted BBB opening by monitoring the acoustic emissions from MBs through the use of a passive cavitation detector for realtime monitoring and treatment efficiency verification.[44,45] The protocol uses a stereotactic targeting procedure, which has initially been shown to be accurate and reliable, with observed targeting error relatively small in rhesus monkeys (2.5+1.2 mm laterally, 1.5+1.3 mm along depth-axis, 3.1+1.3 mm total).[45,46] Another challenge to translating this technology into clinical use is the real-time safety monitoring. Much of the current data focus on animal studies conducted in healthy brains, and there are several key differences between the BBB and environment within cancerous tissue, as well as key differences between animal tissue and human tissue, that must be accounted for
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