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indications including acute relapses of multiple sclerosis, optic neuritis, neuromyelitis optica and uveitis.
[77]
2B3-201 has completed a Phase I clinical trial in healthy volunteers .

2-BBB is a clear example of industry-driven research aiming at developing innovative passive targeting
technologies to brain and brain metastases. They use triple passive targeting techniques to offer optimal
safety and efficacy profiles, Glutathione passively targeting the cancerous intracellular reductive
[77]
environment, PEGylation and liposomal vesicular carrier system .
Nucleic acid
RNA interference (RNAi) is an endogenous pathway for post-transcriptional silencing of gene expression
that is triggered by double-stranded RNA, including endogenous microRNA (miRNA) and synthetic short
[79]
[80]
[81]
interfering RNA . MicroRNA-122 mediated RNAi brings new prospects . Zhang et al. miRNA-1258 in
BMBC cells inhibited heparanase which regulates many molecules involved in angiogenesis and metastasis
of the tumor.
Advanced physically manipulated systems to disrupt BBB
Another modality of addressing BBB passively is advanced physically manipulated systems that can be
tightly mediated by stimuli to treat diseases specifically and with a controlled dosage of drugs. Physical
manipulation can be achieved based on ultrasound, electricity, magnetism and photonic emission
[82]
[83]
technologies . Davalos et al. applied pulsed electric fields into brain tissue of an animal, to cause
temporary disruption of the BBB in a volume of brain tissue near the source of the pulsed electric fields over
a specified time interval.

The use of focused ultrasound (FUS) combined with circulating microbubbles is a non-invasive method
that increases the permeability of BBTB and improves outcomes of trastuzumab; this technique was used by
[84]
Park et al. to improve outcomes with trastuzumab in a breast cancer brain metastasis model. Similarly,
FUS in combination with microbubbles was able to temporarily disrupt the BBB enhancing the anti-tumor
[85]
efficacy of the two anti-HER2 agents combination therapy . Moreover, reversible disruption of the BBB
by bursts of low frequency MRI-guided ultrasound enhances the brain delivery of monoclonal antibody -
Herceptin (trastuzumab) in mice [86,87] .

Active targeting
[47]
Active targeting was proposed for improved targeting efficacy . These strategies consist in incorporating
affinity molecules or taking advantage of influx transport systems expressed within the BBB/BBTB
depending on specific interactions of ligand-receptor and antibody-antigen [47,88,89] . Also, several ligands have
been studied and utilized to shuttle nanoparticles, antibodies, and drugs across the BBB and into the brain
[90]
cells [Figure 1]. Supplementary Table 2 summarizes recent studies of actively targeted treatments for
BCBM.

Receptor-mediated transcytosis/ligand-based
An overexpression of receptors or antigens in cancer acts as a potential target to achieve efficient drug
[47]
uptake via receptor-mediated endocytosis . Moreover, receptor-mediated transcytosis (RMT) allows for
BBB transport of various macromolecules after initial binding of a targeting ligand to a receptor expressed
[91]
on the brain endothelial cells . Tumor-targeting ligands such as peptides and antibodies may effectively
aid certain cytotoxic agents (either biological or synthetic) to deliver to the tumor cells, thereby improving
[92]
therapeutic efficacy while limiting the exposure of normal tissues to the cytotoxic agents . The transferrin
receptor, the low-density lipoprotein receptor-related protein 1 (LRP-1), the insulin receptor and the
nicotinic acetylcholine receptors are examples of receptor expression on the BBB.