Revisiting intra-arterial drug delivery for treating brain diseases or is it “déjà-vu, all over again”?

Abstract

For over six decades intra-arterial (IA) drugs have been sporadically used for the treatment of lethal brain diseases. In recent years considerable advance has been made in the IA treatment of retinoblastomas, liver and locally invasive breast cancers, but relatively little progress has been made in the treatment of brain cancers. High resting blood flow and the presence of the blood-brain barrier (BBB), makes IA delivery to the brain tissue far more challenging, compared to other organs. The lack of advance in the field is also partly due to the inability to understand the complex pharmacokinetics of IA drugs as it is difficult to track drug concentrations in sub-second time frame by conventional chemical methods. The advances in optical imaging now provide unprecedented insights into the pharmacokinetics of IA drug and optical tracer delivery. Novel delivery methods, improved IA drug formulations, and optical pharmacokinetics, present us with untested paradigms in pharmacology that could lead to new therapeutic interventions for brain cancers and stroke. The object of this review is to bring into focus the current practice, problems, and the potential of IA drug delivery for treating brain diseases. A concerted effort is needed at basic sciences (pharmacology and drug imaging), and translational (drug delivery techniques and protocol development) levels by the interventional neuroradiology community to advance the field.

Neurovascular Interventions for Neurotrauma: From Treatment of Injured Vessels to Treatment of the Injured Brain?

“…Importantly, IA delivery can restrict the initial volume of distribution to specific arterial territories. 9 For instance, one cerebral hemisphere could be targeted if perilesional edema or a contusion is limited to one side. This also allows a relatively high initial arterial concentration at low total doses, thereby decreasing systemic toxicity and increasing the therapeutic index.…”

“…Recent advancements in endovascular neurosurgery enable accurate and effective vessel reconstruction/deconstruction techniques, which can contribute to the management of such injuries, 6 and many additional new applications for the treatment of brain-injured patients are being explored. [7][8][9][10][11] A rapidly evolving field, endovascular neurosurgery, is now explored as a route of delivery of treatment for brain tumors, CSF, and movement disorders. 12 Moving beyond treating vessels, future applications of endovascular tools are geared toward treating the brain tissue through the vessels.…”

Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment

“…Uneven distribution of the drug can lead to regions of the brain receiving high concentrations that can lead to the development of neurological deficits. As endovascular techniques advanced, it became possible to control blood flow and inject boluses of drugs that can direct drugs to specific sites [ 21 ]. The ideal drug used in IA delivery for the treatment of brain tumors should be highly extracted during its first pass, have an increased permeability surface area product that can be improved by decreasing polar groups or increasing aliphatic groups, and have a very short half-life so that the drug is metabolized while in the location of the tumor [ 21 ].…”

Imaging the DNA Alkylator Melphalan by CEST MRI: An Advanced Approach to Theranostics

“…Brain tumors are among the most difficult types of cancers to treat. , Standard therapeutic regimens include total resection surgery, followed by radiation therapy and adjuvant chemotherapy . However, in cases where the tumors are considered inoperable, chemotherapy is a major component of the treatment plan. − One of the challenges in delivering chemotherapeutic agents to brain tumors is bypassing the blood–brain/tumor barrier (BBB), which restricts drug penetration into the tumor. − Currently, several interventional procedures are being developed to improve drug delivery across the BBB and into brain tumors. − We recently developed an MRI-guided neurointerventional procedure for targeting selected regions of the brain and transiently opening the BBB in a predictable fashion. , Image-guided, localized BBB opening is an important step toward the more effective treatment of brain tumors; however, the success of targeted drug delivery ultimately is dependent on the drug reaching the tumor. In this context, noninvasive imaging methods that facilitate the direct detection of injected drugs, and subsequently permit the visualization of the drug delivery process, are of utmost importance. − …”