Strategies to disrupt and/or circumvent the BBB (modified from Hendricks et al13); only published clinical trials are reported
| Year—Author | Delivery method | Description | Advantages | Disadvantages | Results |
|---|---|---|---|---|---|
| 2001—Warren et al20 (phase I study) 2006—Warren et al21 (phase II study) | Chemical-mediated BBB disruption (IV) | Transient inflammatory response in endothelial lining, investigated with LTC4, alkylglycerols, IL-2, RMP-7, bradykinin and TNF-α/IFN-γ | Preferential disruption of BTB with kinin agents (RMP-7) | Side effects (of RMP-7): headache, nausea, vomiting, hypertension, and tachycardia | RMP-7+carboplatin proved ineffective in phase I and II clinical trials |
| 2011—Boockvar et al22 2012—Burkhardt et al23 (phase I study) 2010—Guillaume et al24 (phase I study) | Hyperosmotic BBB disruption+IA delivery. SIACI mannitol+bevacizumab 22 23 IA mannitol+IV etoposide/IA melphalan/IA carboplatin 24 | Endothelium dehydration, cell body shriveling and tight junction disruption; mannitol primarily investigated | Widely available | Preferential disruption of healthy BBB causing increased neurotoxicity General anesthesia Phase I studies | Significant radiological tumor reduction and increased PFS |
| 2011—Bogdahn et al25 (phase IIb study) 2006 and 2010—Carpentier et al26 27 (phase I and II studies) 2010—Kunwar34 (phase III study) 2012—White et al35 (phase I study) | Convection-enhanced delivery with surgically implanted intratumoral cathether connected to a subcutaneous port access system | Intratumoral delivery of chemotherapeutics such as TGFβ2 inhibitor,25 oligodeoxynucleotides,27 and cintredekin besudotox34 | Additional surgery Heterogeneous distribution Rapid efflux from injection site Neurotoxicity and/or adverse effects | Marginal efficacy and/or no improvements | |
| 2008 and 2013—da Fonseca et al28 29 (phase I study) | Intranasal delivery | Administration of intranasal POH. BBB circumvention through trigeminal and/or olfactory pathways | Non-invasive delivery method Rare/absent side effects | Stable disease after 4 years of intranasal POH in 19% of patients with malignant glioma (retrospective data29) | |
| 2010—Kunwar et al34 (phase III study) 2008—Attenello et al36 | In situ chemotherapy | Placement of carmustine wafer (Gliadel) in the resection cavity | Cost Modest diffusion potential (few mm) No control of concentration-time exposure | Marginal efficacy and potential increased perioperative complications | |
| 2008—Brown30 (phase I/II study) | Efflux pump inhibitors (IV) | Administration of erlotimib (inhibitor of the EGFR kinase involved in the induction of MDR-1 gene)+TMZ and RxT | Despite good results in vitro, no improvement survival in vivo | ||
| 2013—Drappatz et al31 (phase I study) | Molecular Trojan horse (IV) | Paclitaxel–angiopep-2 peptide–drug conjugate (GRN1005) binds the LRP-1 receptor expressed on the BTB to induce transcytosis. Cohort 1: adjuvant treatment with GRN1005. Cohort 2: neoadjuvant single dose of GNR1005+surgery+adjuvant GNR1005 | GRN1005 was able to cross the BBB. Limited efficacy in terms of survival | ||
| 2015—Fabel et al32 (phase I study) | Liposomal Trojan horse (IV) | Liposomal-loaded doxorubicin crosses the BBB more easily because of its lipophilic nature | Adverse effects | Median OS prolonged in comparison with the OS in other phase II studies | |
| 2000—Rainov33 (phase III study) | Viral-mediated delivery | Intraoperative field administration of murine-derived fibroblasts (VPC) producing a replication-incompetent retroviral agent producing herpes simplex thymidine kinase gene, followed by treatment with ganciclovir | Adverse effects (systemic immunological response) | No significant result in terms of survival |
BBB, blood–brain barrier; BTB, blood–tumor barrier; EGFR, epithelial growth factor receptor; IA, intra-arterial; IFN-γ, interferon γ; IL-2, interleukin 2; IV, intravenous; LRP-1, lipoprotein receptor-related protein-1; LTC4, leukotriene C4; OS, overall survival; MDR, multidrug resistance; PFS, progression-free survival; POH, perillyl alcohol; RMP-7, bradykinin and kinin analog; RxT, radiotherapy; SIACI, superselective intra-arterial cerebral infusion; TGF, transforming growth factor; TMZ, temozolomide; TNF-α, tumor necrosis factor α; VPC, vector-producing cells.