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Page 8 of 14 Kamal et al. J Cancer Metastasis Treat 2019;5:11 I http://dx.doi.org/10.20517/2394-4722.2018.89
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[93]
AngioChem Inc. developed a series of aprotinin polypeptides (Angiopeps) . Angiopep-2, a 19-amino-
acid peptide, is one of the promising vectors designed to target the LRP-1 receptor, to mediate transcytosis
[94]
across the BBB. It is derived from the human Kunitz domain . Angiopep-2 can facilitate brain-targeted
[95]
drug delivery through LRP-1-mediated transcytosis. Regina et al. demonstrated that a conjugate between
angiopep-2 and an anti-HER2 mAb results in a new chemical entity, ANG4043. ANG4043 retains in-vitro
binding affinity for the HER2 receptor and antiproliferative potency against BCBM rat model. This study
showed increased uptake in brain endothelial cells and enhanced BBB permeability compared to poor brain
[96]
penetration of anti-HER2 mAb alone. Similarly, Thomas et al. showed that ANG1005 shows significantly
improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel in mice bearing
BCBM.

[97]
On the other hand, Orthmann et al. formulated rigid and fluid liposomes entrapping Mitoxantrone and
equipped with a 19-mer angiopeptide as a ligand. Angiopeptide bearing fluid liposomes showed in vitro
the highest cellular uptake and transcytosis. They were significantly better than the corresponding ligand-
free fluid liposomes and ligand-bearing rigid vesicles however; the improvement was mainly depending
[98]
on liposomal fluidity while the targeting contributed only to a minor degree. In 2016, Orthmann et al.
encapsulated oxaliplatin (OxP) in liposomes then bound angiopep-2 to the vesicular surface. They
determined that the newly developed OxP liposomes significantly improved the treatment of subcutaneously
and intracerebrally growing breast cancer, but the targeted angiopep-equipped liposomes showed no
superior effect in vivo.

Melanotransferrin (hMTf) is another target to the LRP-1 receptor, which was shown to deliver doxorubicin
across BBB [99,100] . In order to overcome the trastuzumab inability to cross the BBB and treat brain metastases
of HER2+ breast cancer, BT2111, a novel bioconjugate of trastuzumab was developed by BiOasis Inc.,
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on the hMTf (p97) Transcend vector platform [101] . This platform is an example of an actively targeted
immunotherapy, aiding in enhancing the immunotherapy targetability, ability to cross the BB and clinical
efficacy via the use of the targeting moiety hMTf.

Another complex process involves binding to a primary, tumor-specific receptor activating endocytosis;
[102]
using “Tumor-penetrating peptide” . The prototypic peptide of this class, iRGD (CRGDKGPDC), contains
the integrin-binding RGD motif [103] . The integrin-binding RGD sequence motif binds to αvβ3 and αvβ5
[104]
integrins, which are specifically expressed in tumor endothelial cells [102] . Hamilton et al. demonstrated
that a single dose of iRGD had a significant effect on metastatic tumor progression and nonproliferative
cancer cell retention when applied early in course of tumor development. Proteolytically processed iRGD
also exerts anti-metastatic activity by binding to neuropilin-1 and activating an endocytic bulk transport
pathway through tumor tissue. The iRGB platform offers an innovative dual targeting tool to target the
tumor portion via the integrins and the RGB motif [103] .

Carrier-mediated transcytosis
Naturally, carrier-mediated transcytosis (CMT) enables spontaneous internalization of small
biomolecules [105,106] . CMT takes advantage of the immunological surveillance system of the brain, using
circulating phagocytic cells such as monocytes or macrophages as Trojan horse to deliver drug molecules
into the brain [107] . Such cells have a tendency to endocytose colloidal materials, for example, nano or
microparticles, liposomes, and subsequent exocytosis to release drug and/or colloidal materials to external
media [108] . Fidler and colleagues provided evidence that macrophages of blood monocyte origin can infiltrate
experimental brain metastases while the BBB is intact.

[109]
In 2012, Choi et al. reported the first successful demonstration of the active delivery, using macrophages,
of nanoparticles to brain metastases. Activated macrophages not only cross the BBB but they envelop the