New therapeutic strategies regarding endovascular treatment of glioblastoma, the role of the blood–brain barrier and new ways to bypass it

Abstract

The treatment protocols for glioblastoma multiforme (GBM) involve a combination of surgery, radiotherapy and adjuvant chemotherapy. Despite this multimodal approach, the prognosis of patients with GBM remains poor and there is an urgent need to develop novel strategies to improve quality of life and survival in this population. In an effort to improve outcomes, intra-arterial drug delivery has been used in many recent clinical trials; however, their results have been conflicting. The blood-brain barrier (BBB) is the major obstacle preventing adequate concentrations of chemotherapy agents being reached in tumor tissue, regardless of the method of delivering the drugs. Therapeutic failures have often been attributed to an inability of drugs to cross the BBB. However, during the last decade, a better understanding of BBB physiology along with the development of new technologies has led to innovative methods to circumvent this barrier. This paper focuses on strategies and techniques used to bypass the BBB already tested in clinical trials in humans and also those in their preclinical stage. We also discuss future therapeutic scenarios, including endovascular treatment combined with BBB disruption techniques, for patients with GBM.

Translational gap in ongoing clinical trials for glioma

“…The blood brain barrier (BBB) is a key factor that limits the availability of drugs in the central nervous system and therefore the effectiveness of therapeutics [9, 15]. Hence, to be successful, any anticancer drugs used to treat gliomas should be able to pass the BBB and reach a concentration considerable enough to prevent glioma cell proliferation.…”

Canine Model for Selective and Superselective Cerebral Intra-Arterial Therapy Testing

“…There are currently a number of ongoing cerebral disorder treatments being investigated with IA delivery strategies, most notably cerebral malignancy and ischemic stroke. IA delivery of chemotherapeutic agents may allow for blood brain barrier disruption and delivery of increased therapy concentrations locally, while sparing toxic doses to the systemic circulation [ 22 , 23 ]. A variety of animal models have been utilized in the preclinical testing of IA stem cell infusion after acute ischemic stroke and phase I and phase II trials in humans subjects are ongoing [ 2 , 3 ].…”

Advances in drug delivery to high grade gliomas

“…In particular, IA-delivered drugs have often been found unable to penetrate the BBB and their PK still is poorly understood. These studies may take advantage of a recently developed mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted HGG tumors (30,42). These studies may take advantage of a recently developed mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted HGG tumors (30,42).…”

“…Critical insights into the composition and function of the BBB have been recently reviewed (8). A better understanding of BBB physiology along with the development of new technologies recently allowed for innovative methods to circumvent this barrier (42). The numerous ongoing studies for drug delivery to HGG including convection-enhanced delivery and drug-releasing membranes as well as technologies that may lead to transient BBB disruption thus allowing for more effective drug crossing to the brain will be discussed (4).…”

“…Despite those limits, clinical interest in IA drugs for the treatment of HGG persists, linked to improved drug selections and formulations as well as novel methodologies allowing better definition of the HGG morphology and lower treatment-related neurological injury (29). These studies may take advantage of a recently developed mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted HGG tumors (30,42).…”