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

Figures & data

Figure 1. Schematic representation of (A) neurovascular unit; (B) paracellular transport pathway and transcellular transport pathway of BBB; (C) tight junction (TJ) associated components.

Table 1. Summary of approved small-molecule chemotherapeutic agents for the treatment of brain tumors and their substrate status of AETs.

Chemotherapeutic agents	Targeted brain tumor type	Substrate status of AETs (Ref.)
Temozolomide (TMZ)	GBM; primary central nervous system lymphoma^a; refractory anaplastic astrocytoma^a	ABCB1 (Goldwirt et al., 2014)
Lomustine (CCNU)	Grade III glioma; medulloblastoma	No (Dréan et al., 2016)
Carmustine (BCNU)	GBM	No (Hardell et al., 2009)
Procarbazine	Grade III glioma; oligodendrogliomas^a; primary central nervous system lymphoma^a	No (Azad et al., 2015)
Cisplatin	Medulloblastoma	ABCC2, ABCC6 (Gerber et al., 2014)
Carboplatin	GBM	No (Dréan et al., 2016)
Topotecan	GBM	ABCB1 (de Vries et al., 2007), ABCG2 (Huang & Sadée, 2006)
Methotrexate	Central nervous system lymphoma^a	ABCB1 (Agarwal, Sane, et al., 2011), ABCG2 (Staud & Pavek, 2005), ABCC4 (Sane et al., 2014)
Doxorubicin	Neuroblastomas^a	ABCB1, ABCG2 (Oberoi et al., 2016)
Etoposide	GBM; neuroendocrine tumors^a	ABCB1 (Dréan et al., 2016)
Irinotecan	GBM	ABCB1 (Goldwirt et al., 2014), ABCG2 (Oberoi et al., 2016)
Vincristine	Grade III glioma; medulloblastoma	ABCB1 (Azad et al., 2015)

^aAssociated conditions with respect to targeted brain tumor types collected from the public data sources of drugbank (https://www.drugbank.ca/drugs).

Figure 2. Chemical structures and molecular weight of small-molecule chemotherapeutic agents with good BBB/BBTB permeability in treatment of GBM.

Figure 3. Chemical structures and molecular weight of small candidate molecules (1–6) with promising anti-GBM activity in vivo.

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.

Goldwirt L, Beccaria K, Carpentier A, et al. (2014). Irinotecan and temozolomide brain distribution: a focus on ABCB1. Cancer Chemother Pharmacol 74:185–93.

 PubMed Web of Science ®Google Scholar

Dréan A, Goldwirt L, Verreault M, et al. (2016). Blood-brain barrier, cytotoxic chemotherapies and glioblastoma. Expert Rev Neurother 16:1285–300.

 PubMed Web of Science ®Google Scholar

Hardell L, Carlberg M, Hansson Mild K. (2009). Epidemiological evidence for an association between use of wireless phones and tumor diseases. Pathophysiology 16:113–22.

 PubMedGoogle Scholar

Azad TD, Pan J, Connolly ID, et al. (2015). Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurg Focus 38:E9.

 PubMed Web of Science ®Google Scholar

Gerber NU, Mynarek M, von Hoff K, et al. (2014). Recent developments and current concepts in medulloblastoma. Cancer Treat Rev 40:356–65.

 PubMed Web of Science ®Google Scholar

de Vries NA, Zhao J, Kroon E, et al. (2007). P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan. Clin Cancer Res 13:6440–49.

 PubMed Web of Science ®Google Scholar

Huang Y, Sadée W. (2006). Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells. Cancer Lett 239:168–82.

 PubMed Web of Science ®Google Scholar

Agarwal S, Sane R, Oberoi R, et al. (2011). Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain. Expert Rev Mol Med 13:e17.

 PubMed Web of Science ®Google Scholar

Staud F, Pavek P. (2005). Breast cancer resistance protein (BCRP/ABCG2). Int J Biochem Cell Biol 37:720–5.

 PubMed Web of Science ®Google Scholar

Sane R, Wu SP, Zhang R, Gallo JM. (2014). The effect of ABCG2 and ABCC4 on the pharmacokinetics of methotrexate in the brain. Drug Metab Dispos 42:537–40.

 PubMed Web of Science ®Google Scholar

Oberoi RK, Parrish KE, Sio TT, et al. (2016). Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma. Neuro-oncology 18:27–36.

 PubMed Web of Science ®Google Scholar