How to Make Anticancer Drugs Cross the Blood-Brain Barrier to Treat Brain Metastases

Abstract

The incidence of brain metastases has increased in the last 10 years. However, the survival of patients with brain metastases remains poor and challenging in daily practice in medical oncology. One of the mechanisms suggested for the persistence of a high incidence of brain metastases is the failure to cross the blood-brain barrier of most chemotherapeutic agents, including the more recent targeted therapies. Therefore, new pharmacological approaches are needed to optimize the efficacy of anticancer drug protocols. In this article, we present recent findings in molecular data on brain metastases. We then discuss published data from pharmacological studies on the crossing of the blood-brain barrier by anticancer agents. We go on to discuss future developments to facilitate drug penetration across the blood-brain barrier for the treatment of brain metastases among cancer patients, using physical methods or physiological transporters.

Keywords: anticancer drugs; blood–brain barrier; blood–tumor barrier; brain metastases; copy number profiling; mutation; pharmacokinetics.

Figure 1

Neurovascular unit of (a) normal blood–brain barrier (BBB) and (b) blood–tumor barrier (Credits images: © User: Kuebi / Wikimedia Commons / CC-BY-3.0), ↑ means an increase,↓ means a decrease.

Figure 2

Summary of different way to overcome the BBB (except the intranasal). (A) Osmotic disruption, hypertonic mannitol causes a water leakage to the extracellular area and a shrinkage of endothelial cells (blue arrow means an extravasation of H2O from intracellular to extracellular space/ pink arrow means the passage of drugs across the BBB from blood to brain). (B) Ultrasounds combined to microbubbles: when excited by ultrasounds, microbubbles expand and exert a mechanical force on the endothelial cells of the BBB, leading to tight junction disruption. (C) Transcytosis across endothelial cells of the blood–brain barrier. Left side: receptor mediated transport: binding of the ligand to a specific receptor on the apical side, invagination of the membrane containing the complex, transcytosis, fusion, and release of the cargo to the basal side. Middle: inter-endothelial passage of liposomal nanoparticles. Right side: passive diffusion of gold nanoparticles (Credits images: © SMART / CC-BY-3.0).