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Page 4 of 14 Kamal et al. J Cancer Metastasis Treat 2019;5:11 I http://dx.doi.org/10.20517/2394-4722.2018.89

Figure 2. Different adopted strategies for actively and passively targeting brain metastases of breast cancer to overcome the blood brain
barrier (BBB) hurdles

Brain metastases of breast cancer are also subject to the limited permeability characteristics of the BBB
in-spite of the formation of the BBTB with altered integrity. MRI data have shown that not all brain
[37]
metastases display elevated BBTB permeability . The changes in BBTB vascular permeability are usually
not homogenous throughout the lesion [38,39] . It was noticed that brain metastases from HER2+ breast cancers
infiltrate brain tissue crossing the endothelial cells without disrupting the BBB, unlike the brain metastases
from triple negative or basal-type breast cancers that often disrupt the BBB [8,40] [Figure 1].

TARGETING BRAIN METASTASES
[41]
Although, there are no FDA-approved systemic treatments for BCBM to date , patents and studies in
the past years have shown promising progress and well-established techniques to overcome the BBB/
BBTB . There are two general strategies adopted to facilitate crossing the BBB; invasive and non-invasive
[42]
[43]
techniques . The invasive techniques rely primarily on disrupting the BBB integrity by direct intracranial
drug delivery through intracerebroventricular, intracerebral or intrathecal administration, osmotic pumps
[43]
or biochemical means . But all these approaches are severely limited by poor distribution into brain
parenchyma . On the other hand, non-invasive methods include drug moieties modifications through the
[44]
transformation of the drug into lipophilic analogs, prodrugs, chemical drug delivery, carrier-mediated drug
delivery, receptor/vector-mediated drug delivery and intranasal drug delivery [43,45] .

Diffusion of substances into the brain can be divided into paracellular and transcellular. Generally, BBB
targeting strategies can be categorized into passive (transcellular lipophilic pathway) and active targeting
(mainly; transcytosis) . Figure 2 summarizes the targeting techniques covered in this article.
[46]

Passive targeting
Enhanced permeability and retention phenomenon
Passive targeting depends mainly on the preferential accumulation of drug molecules into tumor cells .
[47]
Enhanced permeability and retention (EPR) phenomenon based on the nanometer size range of the
nanoparticles and two fundamental characteristics of the neoplastic tissues, namely, the leaky vasculature
[48]
and impaired lymphatic drainage. EPR was first described by Maeda and Matsumura . The selective high