Overcoming the blood-brain barrier in primary central nervous system lymphoma: a review on new strategies to solve an old problem

Abstract

A great deal of research is being dedicated to the identification of new strategies to improve the transport of medicines across the blood-brain barrier (BBB), which typically hampers the transport of molecules and particles into the brain. Primary DLBCL of the CNS (PCNSL) is a paradigmatic example of this challenge both from a diagnostic and therapeutic point of view. PCNSL is a neoplasm confined to the brain, eyes, meninges, and other structures of the CNS. Histopathologic analyses of tissue sections have demonstrated that tumor cells can be detected not only in the areas highlighted by modern neuroimaging, but also far from these zones. Furthermore, some tumor areas revealed by gadolinium-enhanced MRI are concomitant with histological lesions with only T2-weighted-fluid-attenuated inversion recovery (FLAIR) changes, or with no radiologic abnormalities at all, suggesting the presence of a blood-brain tumor barrier (BBTB) heterogeneously altered in PCNSL, or even intact in some tumor areas. Since the unaltered barrier may impair the homogeneous penetration of low-molecular weight MRI contrast agents and therapeutic compounds in tumors, this issue represents an important diagnostic and therapeutic challenge. Based on these considerations, the induction of BBTB permeabilization to enhance tumor penetration of drugs and molecules could be attractive investigational approaches in this setting. The aim of this review article is to report and critically discuss the strategies recently developed to overcome this obstacle in PCNSL patients, with a special focus on the use of targeted tumor necrosis factor-alpha (TNF) to enhance CNS bioavailability of therapeutic agents.