Drug Delivery Technology to the CNS in the Treatment of Brain Tumors: The Sherbrooke Experience

Abstract

Drug delivery to the central nervous system (CNS) remains a challenge in neuro-oncology. Despite decades of research in this field, no consensus has emerged as to the best approach to tackle this physiological limitation. Moreover, the relevance of doing so is still sometimes questioned in the community. In this paper, we present our experience with CNS delivery strategies that have been developed in the laboratory and have made their way to the clinic in a continuum of translational research. Using the intra-arterial (IA) route as an avenue to deliver chemotherapeutics in the treatment of brain tumors, complemented by an osmotic breach of the blood-brain barrier (BBB) in specific situations, we have developed over the years a comprehensive research effort on this specialized topic. Looking at pre-clinical work supporting the rationale for this approach, and presenting results discussing the safety of the strategy, as well as results obtained in the treatment of malignant gliomas and primary CNS lymphomas, this paper intends to comprehensively summarize our work in this field.

Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors

“…Several approaches have been used in an effort to circumvent these barriers to improve drug penetration into the brain. For treatment of brain tumors, transient disruption of the tight junctions of the BBB allowing more drug to penetrate have been a successful approach both in preclinical and clinical studies [30,31,32,33]. This can be done through the use of high concentration of osmotic agents (i.e., a high concentration of mannitol) or bradykinin analogues [30,31,32,33], or more recently, through focused, high-intensity ultrasound [34,35,36].…”

Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

“…We perform i.c. chemotherapy infusion on a routine basis in our Sherbrooke hospital center (eight patients/week) in a controlled setting where we monitor the neurological conditions as well as vital signs of the patients, and we successfully treat patients every 4 weeks up to 16 cycles [ 7 , 8 , 54 , 55 ]. The addition of an infusion of a B2R or dual B1R/B2R agonist prior to chemotherapy infusion would represent a minor modification to our procedure.…”

“…These approaches are either highly invasive (e.g., CED), require specialized equipment (e.g., FUS), or necessitate the conjugation of drugs to specific targeting-peptide vectors in limited stoichiometric ratios (e.g., Angiopep-2). For drug delivery to brain cancers, osmotic BBB disruption with mannitol is the only effective method that has successfully made its way into the clinic, with nine International BBB-Consortium Centers operating across the United States, Israel, and Canada, including in our Centre hospitalier universitaire de Sherbrooke (CHUS, Québec, Canada) [ 6 , 7 , 8 ]. However, duly approved, it remains highly invasive, requires general anesthesia, and is accompanied by the nonselective delivery of anticancer drugs to normal brain tissues, and is thus not compatible with chemotherapeutics that are neurotoxic (e.g., taxanes and cisplatin) [ 9 ].…”

Drug Delivery Technology Development in Canada

“…This proof-of-principle study is a novel avenue for drug delivery to the central nervous system. David Fortin [4] in his paper entitled "Drug Delivery Technology to the CNS in the Treatment of Brain Tumors: The Sherbrooke Experience" also addresses challenges regarding drug delivery to the central nervous system and reviews strategies encompassing the path of the drug discovery from laboratory explorations to clinical applications.…”