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Review
. 2019 Dec;26(1):551-565.
doi: 10.1080/10717544.2019.1616235.

A comprehensive review in improving delivery of small-molecule chemotherapeutic agents overcoming the blood-brain/brain tumor barriers for glioblastoma treatment

Da Wang  1 , Chao Wang  2 , Liang Wang  1 , Yue Chen  1
Affiliations
Review

A comprehensive review in improving delivery of small-molecule chemotherapeutic agents overcoming the blood-brain/brain tumor barriers for glioblastoma treatment

Da Wang et al. Drug Deliv. 2019 Dec.

Abstract

Glioblastoma (GBM) is the most common and lethal primary brain tumor which is highly resistant to conventional radiotherapy and chemotherapy, and cannot be effectively controlled by surgical resection. Due to inevitable recurrence of GBM, it remains essentially incurable with a median overall survival of less than 18 months after diagnosis. A great challenge in current therapies lies in the abrogated delivery of most of the chemotherapeutic agents to the tumor location in the presence of blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). These protective barriers serve as a selectively permeable hurdle reducing the efficacy of anti-tumor drugs in GBM therapy. This work systematically gives a comprehensive review on: (i) the characteristics of the BBB and the BBTB, (ii) the influence of BBB/BBTB on drug delivery and the screening strategy of small-molecule chemotherapeutic agents with promising BBB/BBTB-permeable potential, (iii) the strategies to overcome the BBB/BBTB as well as the techniques which can lead to transient BBB/BBTB opening or disruption allowing for improving BBB/BBTB-penetration of drugs. It is hoped that this review provide practical guidance for the future development of small BBB/BBTB-permeable agents against GBM as well as approaches enhancing drug delivery across the BBB/BBTB to GBM.

Keywords: Small-molecule agents; blood-brain barrier; blood-brain tumor barrier; drug delivery; glioblastoma.

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Figures

Figure 1.
Figure 1.
Schematic representation of (A) neurovascular unit; (B) paracellular transport pathway and transcellular transport pathway of BBB; (C) tight junction (TJ) associated components.
Figure 2.
Figure 2.
Chemical structures and molecular weight of small-molecule chemotherapeutic agents with good BBB/BBTB permeability in treatment of GBM.
Figure 3.
Figure 3.
Chemical structures and molecular weight of small candidate molecules (1–6) with promising anti-GBM activity in vivo.
Figure 4.
Figure 4.
Chemical structures and molecular weight of (A) approved small-molecule drugs (7–10) re-positioned as anti-GBM agents and (B) imidazolium-based candidate molecules (11–16) with promising BBB permeability.
See this image and copyright information in PMC

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Grants and funding

This work was supported by the National Natural Science Foundation of China (NSFC) [Grant No. 81573282 to Y.C.; Grant No. 81703350 to L.W.]; the National Science Fund for Distinguished Young Scholars [Grant No. 81625021] to Y.C.; and the Fundamental Research Funds for the Central Universities and Hundred Young Academic Leaders Program of Nankai University.
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