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metastatic cells delivering the loaded nanoparticle to less than a cell width away from the nearest
[109]
metastatic cell .

Cell penetrating peptides
Cell-penetrating peptides (CPP), that show great capacity in BBB transport, have the ability to transport
protein or peptides into cells in a nonspecific, receptor-independent manner and non-immunogenic when
compared with antibodies [110] . Considering their smaller size (up to 30 amino acids in length), cationic and/
or amphipathic CPPs have a greater potential to penetrate the BBB than other transport systems. Short
peptides, as targeted drug delivery vehicles, appear to have some advantages owing to their small size,
efficient tissue penetrability, and minimal toxicity and immunogenicity.

The first CPP, trans-activator of transcription (TAT), derived from human immunodeficiency virus-1, can
[112]
be efficiently taken up from the surrounding media [111] . Morshed et al. used PEGylated gold nanoparticle
conjugated to TAT peptide as well as doxorubicin. This formulation offered extensive accumulation of
particles throughout diffuse intracranial metastatic microsatellites. Moreover, it was shown to destabilize
a brain capillary monolayer increasing its permeability. Fu et al. [113] combined brain metastatic breast
carcinoma cell (231-BR)-binding peptide BRBP1, a cell penetrating peptide TAT, and a proapoptotic peptide
KLA. The composite selectively homed to the tumors in vivo where it induced cellular apoptosis without
significant toxicity on non-tumor tissues. Angiopep-mediated targeting also can be considered as one of the
most promising ways to reach the CNS for the treatment of brain cancer or brain metastases [114] .

Conclusion and future directions
There is a global need for effective and safe pharmaceutical chemotherapeutic agents that have the potential
to target tumors like BCBM.

Conventional chemotherapy, radiation therapy and immunotherapy offers promising options for treating
brain metastases, which is traditionally treated with surgery.

In 2005, the chemotherapy temozolomide (Temodar®) was approved to treat glioblastoma (GBM) patients.
However, over 50% of GBM tumors generate a DNA repair protein (methylguanine methyltransferase)
that effectively combats and neutralizes temozolomide chemotherapy. There are two FDA approved
immunotherapies for brain and nervous system cancers and metastases. Bevacizumab (Avastin®) and
Dinutuximab (Unituxin®). Several other immunotherapies are being used to treat different types of brain
cancers in clinical trials. However, there are no FDA-approved systemic treatments specific to BCBM to
[41]
date . Improved insights into the microenvironment and metastatic cascade processes have resulted in the
development of several novel chemotherapeutic and immunotherapeutic drugs and strategies [35,36,38,39,54] . Such
novel chemotherapeutic and immunotherapeutic strategies adopt active and passive targeting strategies to
enhance the clinical treatment effects.

Surveying the published research papers and patents also revealed a major drawback in the methodology
design, which is the lack of standardization of efficacy and safety profiles. Various sophisticated nano-
systems and conjugates have been studied to either actively or passively target BCBM. However, most of
these complex delivery systems fail to reach the market due to high cost, instability and difficulty of scaling
up. In addition, majority of the reagents used in the formulation of such novel therapeutic systems to
improve the stability; are not included in the FDA approved inactive ingredient database. The main question
of this review is to query the preferential advantage of either active or passive targeting in combating brain
metastases of breast cancer. Such question is a major ongoing debate as revealed by the recent patents and
papers portfolio.