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Review
.2020 Apr 30:15:2999-3022.
doi: 10.2147/IJN.S231479. eCollection 2020.

Overcoming the Blood-Brain Barrier: Successes and Challenges in Developing Nanoparticle-Mediated Drug Delivery Systems for the Treatment of Brain Tumours

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Review

Overcoming the Blood-Brain Barrier: Successes and Challenges in Developing Nanoparticle-Mediated Drug Delivery Systems for the Treatment of Brain Tumours

Chiara Ferraris et al. Int J Nanomedicine..

Abstract

High-grade gliomas are still characterized by a poor prognosis, despite recent advances in surgical treatment. Chemotherapy is currently practiced after surgery, but its efficacy is limited by aspecific toxicity on healthy cells, tumour cell chemoresistance, poor selectivity, and especially by the blood-brain barrier (BBB). Thus, despite the large number of potential drug candidates, the choice of effective chemotherapeutics is still limited to few compounds. Malignant gliomas are characterized by high infiltration and neovascularization, and leaky BBB (the so-called blood-brain tumour barrier); surgical resection is often incomplete, leaving residual cells that are able to migrate and proliferate. Nanocarriers can favour delivery of chemotherapeutics to brain tumours owing to different strategies, including chemical stabilization of the drug in the bloodstream; passive targeting (because of the leaky vascularization at the tumour site); inhibition of drug efflux mechanisms in endothelial and cancer cells; and active targeting by exploiting carriers and receptors overexpressed at the blood-brain tumour barrier. Within this concern, a suitable nanomedicine-based therapy for gliomas should not be limited to cytotoxic agents, but also target the most important pathogenetic mechanisms, including cell differentiation pathways and angiogenesis. Moreover, the combinatorial approach of cell therapy plus nanomedicine strategies can open new therapeutical opportunities. The major part of attempted preclinical approaches on animal models involves active targeting with protein ligands, but, despite encouraging results, a few number of nanomedicines reached clinical trials, and most of them include drug-loaded nanocarriers free of targeting ligands, also because of safety and scalability concerns.

Keywords: blood–brain barrier; blood–brain tumour barrier; glioma; nanoparticles; targeting.

© 2020 Ferraris et al.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Main mechanisms of experimental drugs used against high-grade gliomas.Abbreviations: avß3/avß5, avß3/avß5 heterodimers; EGFR, epidermal growth factor receptor; EGFRvIII, mutant EGFR; MMP, matrix metalloproteinase; PDGFR, platelet-derived growth factor receptor; PI3K/Akt/mTOR, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin; PKC, protein kinase C; PTEN, phosphatase and tensin homolog; Ras/MAPK, Ras mitogen-activated protein kinase; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
Figure 2
Figure 2
Rationale of employing nanomedicines for glioma treatment.Abbreviations: BBB, blood–brain barrier; BBTB, blood–brain tumour barrier; CMT, carrier-mediated transport; EPR, enhanced permeation and retention; HIF, hypoxia-induced factors; P-gp, P-glycoprotein; RMT, receptor-mediated transport.
Figure 3
Figure 3
Scheme of brain delivery of nanoparticles with focused ultrasound (FUS) technique.Abbreviation: SF6, sulfur hexafluoride.
Figure 4
Figure 4
Scheme of the main mechanism used for active targeting of nanocarriers in glioma therapy. Blue: endogenous ligands; red: exogenous ligands.Abbreviations: avß3/avß5, avß3/avß5 heterodimers; CTX, chlorotoxin; EGFR, epidermal growth factor receptor; GSH, glutathione; HFE, homeostatic iron regulator protein; IL 13, interleukin 13; LDL, low-density lipoprotein; Lf, lactoferrin; MCT-1, monocarboxylic acid transporter 1; MMP, matrix metalloproteinase; Tf, transferrin.
Figure 5
Figure 5
Scheme of nanocarrier mesenchymal stem cells (MSC) combined therapy of gliomas.
Figure 6
Figure 6
Scheme of homotypic targeting of glioma cell membrane-coated nanoparticles.
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