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Review
. 2016 Jan;18(1):27-36.
doi: 10.1093/neuonc/nov164. Epub 2015 Sep 10.

Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma

Rajneet K Oberoi  1 , Karen E Parrish  1 , Terence T Sio  1 , Rajendar K Mittapalli  1 , William F Elmquist  1 , Jann N Sarkaria  1
Affiliations
Review

Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma

Rajneet K Oberoi et al. Neuro Oncol. 2016 Jan.

Abstract

Glioblastoma (GBM) is a lethal and aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. Molecularly targeted agents hold great promise in treating these genetically heterogeneous tumors, yet have produced disappointing results. One reason for the clinical failure of these novel therapies can be the inability of the drugs to achieve effective concentrations in the invasive regions beyond the bulk tumor. In this review, we describe the influence of the blood-brain barrier on the distribution of anticancer drugs to both the tumor core and infiltrative regions of GBM. We further describe potential strategies to overcome these drug delivery limitations. Understanding the key factors that limit drug delivery into brain tumors will guide future development of approaches for enhanced delivery of effective drugs to GBM.

Keywords: blood-brain barrier; drug delivery; efflux transporters; glioma.

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Figures

Fig. 1.
Fig. 1.
Schematic representation of the neurovascular unit in relation to the blood–brain barrier and the different pathways for drug transport. Abbreviations: P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; MRP, multidrug resistance protein; OATP, organic anion transporting polypeptide; LAT1, large-neutral amino acid transporter 1; GLUT1, glucose transporter 1; OCT, organic cation transporter.
Fig. 2.
Fig. 2.
Representative image from the same patient of (A) 18F-DOPA uptake imaged by PET-CT, (B) regions of contrast accumulation in the same location defined by a T1 postcontrast enhanced MRI, (C) regions of tumor-associated edema as defined by a T2-FLAIR MRI. Contours of these 3 regions were drawn by a neuroradiologist. The figure illustrates that significant tumor burden exists beyond the disrupted BBB defined by the contrast enhancement (CE). (Copyright)
Fig. 3.
Fig. 3.
Schematic representation of the issues for effective delivery of drugs to bulk tumor cells and invasive glioma cells. The presence of intact blood–brain barrier and expression of efflux transporters limit distribution of chemotherapeutics to invasive glioma cells.
See this image and copyright information in PMC

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