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breast cancer and its brain metastasis, multi-talented delivery systems are urgently needed for optimal treatment.
This review focuses on the various active and passive targeting technologies for the treatment of breast cancer
brain metastases in the past decade. A comprehensive summary and examples along with pros and cons of each
system will be discussed. Different treatment modalities and nanotechnology facilities will be demonstrated to aid
in designing the optimal smart, safe, targeted and effective systems to combat brain metastases of breast cancer.

Keywords: Active targeting, passive targeting, brain metastasis, breast cancer

INTRODUCTION
Despite the recent pharmaceutical and medical advances in treatment and diagnosis of different carcinogenic
tissues and their metastases, brain and central nervous system (CNS) primary and metastatic tumors remain
a tough hurdle to overcome due to physiological and anatomical barriers represented by blood brain barrier
(BBB) and the aggressiveness and continuous adaptive evaluation of this tumor tissue.

As systemic therapy of metastatic breast cancer advances, survival rates of patients are enhanced. On
[1]
the other side, the incidence of brain and CNS complications increases . In historical series, the risk of
developing brain metastasis has been estimated among women with stage IV breast cancer to range from
10% to 16% among living making it the second most common cause of metastatic brain tumor after lung
[2-4]
cancer (10%-25%) . The development of breast cancer brain metastases (BCBM) tends to vary by the
subtype. Forty-six percent of patients with advanced triple negative breast cancer, and up to thirty-seven
percent of patients with HER2-positive breast cancer relapse due to intracranial metastases, despite control
[5-8]
of the peripheral tumors .
Treatment options are limited and usually involve multimodality approaches that include surgery,
radiotherapy, radiosurgery, and rarely systemic therapy, depending on the number of CNS lesions [9,10] . The
unpredictable extent of therapeutics that can reach tumor vasculature of BCBM has been the challenge in
developing effective treatments for these patients [11,12] . BBB has always been a challenge to drug delivery
to brain tissues [13-16] . However, during brain metastases, the structure and integrity are altered forming a
[17]
“Blood Brain Tumor Barrier” (BBTB) . The leaky structure of BBTB is an appealing strategy to target brain
[18]
tumors . Approaches to deliver drugs into the brain are being extensively studied [Figure 1].
Beside the common technologies including viral vectors and nanoparticles, novel non-invasive techniques
such as ultrasound alteration and magnetic stimulation have been studied to temporally open the BBB to
enhance brain drug uptake. In this review, we discuss passive and active targeting BCBMs.

BBB AND DRUG DELIVERY
The BBB, as a morphologic and physiologic barrier, protects the brain tissue from the peripheral vasculature,
protecting normal brain function by impeding most compounds from transiting from the blood to the
brain [13,16,18] . There is a common misconception about the nature of BBB as a protective barrier or sac
protecting the brain underneath it. Perhaps, the term BBB was the main reason of such misconception.
The BBB is mainly a fortified special vascular structure in the brain different from the common vascular
structure in the rest of the body. Mainly, the brain capillary endothelial cells (BCECs) form the BBB, besides
other cell types such as pericytes, astrocytes, and neuronal cells; playing an important role in the function
[19]
of the BBB . BCEC have tight junctions that prevent paracellular transport of small and large (water
soluble) compounds from the circulation to the brain except for some very small or gaseous molecules, such
as water and carbon dioxide [17,19,20] . The components of the BBB continuously adapt in response to various
[21]
physiological changes in the brain [Figure 1].