Table 1 |.
Emerging minimally invasive approaches to improve transport across the BBB/BTB
| Method | Route | Compound | Clinical trial | Main findings and comments | Refs |
|---|---|---|---|---|---|
| Molecular | |||||
| Receptor mediated | Transcellular (transcytosis) | LRP1-targeting peptide bound to paclitaxel | Phase II | Similar toxicity to paclitaxel alone, increased delivery and doubled the median survival in patients with breast cancer brain metastasis | 101,102 |
| Lipid soluble | Transcellular (diffusion) | Enzastaurin — a synthetic bisindolylmaleimide that targets/inhibits both the PKC and the PI3K–AKT pathways | Phase III | Well tolerated but did not have superior efficacy compared with chemotherapeutic agent lomustine in patients with recurrent glioblastoma | 226,227 |
| Evade active efflux | Transcellular | None | NA | None | |
| Tight junction pathways | Paracellular (diffusion) | None | NA | None | |
| Biological | |||||
| Cellular | Paracellular and transcellular (diapedesis) | NSCs expressing cytosine deaminase plus 5-fluorocytosine prodrug | Phase I | Therapy was well tolerated in trials against glioblastoma; intracerebral microdialysis revealed that NSCs produced 5-fluoruracil in the brain in a dose-dependent manner | 120 |
| Viral | Paracellular (diffusion) and transcellular (receptor-mediated endocytosis: infect and spread) | Adenovirus-mediated gene therapy | Phase III | Marginal improvement in overall survival in patients with newly diagnosed glioblastoma with more treatment-related adverse events, including hemiparesis and aphasia, as compared with the control group | 228 |
| Physical | |||||
| Focused ultrasound with microbubbles | Paracellular and transcellular (diffusion and convection) | Carboplatin | Phase II | Demonstrated safety and provided preliminary evidence of its efficacy in patients with glioblastoma | 138 |
| Radiation | Paracellular and transcellular | None | NA | Inconsistent results; more rigorous assessment on the direct versus indirect effects (for example, inflammation) of radiation on blood–brain barrier is needed | 154–156 |
| Nanoparticles | Paracellular (diffusion) and transcellular (transcytosis) | Liposomal doxorubicin plus radiotherapy and temozolomide | Phase II | Well tolerated but did not add any significant clinical benefit in patients with glioblastoma | 161–163 |
BBB, blood–brain barrier; BTB, blood–tumour barrier; LRP1, lipoprotein receptor-related protein 1; NA, not available; NSC, neural stem cell; PKC, protein kianse C.