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THE BLOOD-BRAIN BARRIER: THE BRAIN’S next sections of this review.
PROTECTION SYSTEM
Receptor mediated transcytosis
The blood-brain barrier (BBB) represents a diffusion barrier Receptor-mediated transcytosis facilitates trans-BBB transport
system that protects the brain. BBB maintains the brain’s of various macromolecules after initial binding of a targeting
homeostasis by controlling the influx of blood components into ligand to a receptor expressed on the brain endothelial cells. [32,33]
the brain. [15-17] The BBB is mainly formed by brain capillary Transferrin receptor (TfR), insulin receptor, low-density
endothelial cells (BCEC), in addition to other cell types such as lipoprotein receptor (LDLr), acetylcholine receptor, glutathione
pericytes, astrocytes, and neuronal cells that play an important transporter, and diphtheria toxin receptor are examples of
[34]
role in its function. BCEC’s tight junction prevents paracellular receptors of interest. Several ligands have been studied and
[17]
transport of small and large water-soluble compounds from the utilized to shuttle nanoparticles, antibodies, and drugs across
[35]
circulation to the brain, except for some very small or gaseous the BBB and into the brain cells. For instance, the LDL
molecules such as water and carbon dioxide [Figure 2]. [15,17-20] receptor family can be targeted via aprotinin, ApoE3 mimetic,
angiopep-2, and p97 (melanotransferrin). [36-38]
In addition to physical barriers, several functional barriers
contribute to the restrictive nature of BBB, creating major Angiopep-2, a 19-amino-acid peptide, is one of the promising
obstacles to effective drug delivery into the CNS. Besides tight vectors designed to target the LDLr-related protein to mediate
[21]
junctions, a group of efflux transporters [such as P-glycoprotein transcytosis across the BBB. Angiochem Inc., in partnership
[39]
(Pgp), breast cancer resistance protein, and multidrug resistance- with Geron Inc., developed ANG1005 (also known as GRN
associated proteins] are expressed on the brain tissue and 1005), an Angiopep-2-PTX conjugate for treating primary
collectively cause rapid efflux of large groups of lipophilic drugs (glioblastoma) and metastatic brain tumors. ANG1005 showed
from the CNS. [22,23] Also, the presence of numerous degradative promise in many preclinical studies and was well tolerated in
enzymes in the BBB creates another functional barrier. [17,24,25] phase I clinical studies. [32,40] However, phase II clinical trials
utilizing ANG1005 are either terminated or ongoing but not
The functioning and organization of the BBB can be altered actively recruiting participants, and Geron has announced that
under pathological conditions, such as in the case of tumors. it discontinued development of GRN1005 (NCT014880583,
In such a case, the barrier is called the blood-brain tumor NCT01967810, NCT02048059). Other Angiopep drug
[41]
barrier (BBTB). In low-grade gliomas, BBTB resembles conjugates include ANG1007 (angiopep-2-doxorubicin),
[42]
[19]
BBB, while in high-grade gliomas, BBTB becomes disrupted ANG1009 (angiopep-2-dimethylglycine etoposide), and
and “leaky,” characterized by major alterations of the normal ANG4043 (angipep 2-trastuzumab). ANG4043 is a novel brain-
vascular function manifested by contrast-enhanced MRI by penetrant peptide-mAb conjugate that is effective against HER2-
Dhermain et al. [19,26] However, the magnitude of this disruption positive intracranial tumors in mice, an angiopep anti-HER 2
is unlikely sufficient to allow drug penetration in therapeutically mab conjugate. Applications of angiopep as brain targeting
meaningful quantities, and thus BBTB remains a major obstacle moiety are still under intensive research. [43-47]
for brain drug delivery. [27,28]
Pieter Gaillard, in a patent for “to-BBB technologies BV,”
BRAIN DRUG DELIVERY suggested delivery of drugs to cells and across the blood-
brain barrier by targeting them to endogenous internalizing
Although BBB is difficult to bypass, inventions in the area uptake receptors for glutathione on the capillaries of the brain,
of brain delivery in the last five years have shown promising without modifying or disrupting the normal function of the
progress and well-established techniques. There are two general neuroprotective BBB. In another set of patents, Gaillard
[48]
strategies adopted to facilitate crossing the blood-brain barrier: and his to-BBB technologies BV group used diphtheria toxin
invasive techniques and noninvasive techniques. Invasive receptor ligand to control the blood-brain barrier vascular
[29]
techniques rely primarily on disrupting the BBB’s integrity by permeability and deliver lipopolysaccharide-sensitive nucleic
direct intracranial drug delivery through intracerebroventricular, acids and polypeptides across the BBB. [49,50]
intracerebral, or intrathecal administration, use of osmotic
pumps, or biochemical means. All these approaches are Dickerson et al. developed agents that modulate calcitonin-
[29]
[51]
severely limited by poor distribution into brain parenchyma. [30] gene related peptide (CGRP) signaling. This represents a novel
target for cancer, particularly glioma and breast cancer, since
Noninvasive methods include drug modification through CGRP stimulates cell replication and growth. In another patent,
transformation of the drug into lipophilic analogues or Furness et al. invented a method for detecting calcitonin
[52]
prodrugs or through chemical drug delivery, carrier-mediated receptor in brain cells of the subject; this method can be used for
drug delivery, receptor/vector-mediated drug delivery, and therapeutic, diagnostic, and prognostic purposes.
intranasal drug delivery. [29,31] The noninvasive techniques
depend on either pharmacologic strategies (lipid-based Due to the increased expression of the transferrin receptor in
systems), or physiologic-based strategies (nutrient or receptor- brain glioma, it is one of the most extensively studied targets
mediated systems). These techniques will be the focus of the for receptor-mediated transcytosis (RMT). Cedars-Sinai
[53]
[31]
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 15, 2016 ¦