The blood-brain barrier (BBB) has been a great hurdle for brain drug delivery. The BBB in healthy brain is a diffusion barrier essential for protecting normal brain function by impeding most compounds from transiting from the blood to the brain; only small molecules can cross the BBB. Under certain pathological conditions of diseases such as stroke, diabetes, seizures, multiple sclerosis, Parkinson's disease and Alzheimer disease, the BBB is disrupted. The objective of this review is to provide a broad overview on current strategies for brain drug delivery and related subjects from the past five years. It is hoped that this review could inspire readers to discover possible approaches to deliver drugs into the brain. After an initial overview of the BBB structure and function in both healthy and pathological conditions, this review re-visits, according to recent publications, some questions that are controversial, such as whether nanoparticles by themselves could cross the BBB and whether drugs are specifically transferred to the brain by actively targeted nanoparticles. Current non-nanoparticle strategies are also reviewed, such as delivery of drugs through the permeable BBB under pathological conditions and using non-invasive techniques to enhance brain drug uptake. Finally, one particular area that is often neglected in brain drug delivery is the influence of aging on the BBB, which is captured in this review based on the limited studies in the literature.

Disorders of the brain constitute the most debilitating situation globally with increased mortality rates every year, while brain physiology and cumbersome drug development processes exacerbate this. Although blood-brain barrier (BBB) and its components are important for brain protection, their complexity creates major obstacles for brain drug delivery, and the BBB is the primary cause of treatment failure, leading to disease progression. Therefore, developing an ideal platform that can predict the behavior of a drug delivery system in the brain at the early development phase is extremely crucial. In this direction, in the last two decades, numerous in vitro BBB models have been developed and investigated by researchers to understand the barrier properties and how closely the in vitro models mimic in vivo BBB. In-vitro BBB models mainly involve the culture of endothelial cells or their coculture with other perivascular cells either in two or three-dimensional platforms. In this article, we have briefly summarized the fundamentals of BBB and outlined different types of in vitro BBB models with their pros and cons. Based on the available reports, no model seems to be robust that can truly mimic the entire properties of the in vivo BBB microvasculature. However, human stem cells, coculture and threedimensional models have been found to mimic the complexity of the barrier integrity not completely but more precisely than other in vitro models. More studies aiming towards combining these models together would be needed to develop an ideal in vitro model that can overcome the existing limitations and unravel the mysterious BBB vasculature.

Most prostate cancer patients develop resistance to anti-androgen therapy. This is referred to as castration-resistant prostate cancer (CRPC). Docetaxel (DTX) is the mainstay treatment against CRPC. However, over time patients eventually develop DTX resistance, which is the cause of the cancer-related mortality. Curcumin (CUR) as a natural compound has been shown to have very broad pharmacological activities, e.g., anti-inflammatory and antioxidant properties. However, CUR is very hydrophobic. The objective of this study was to develop CUR nanoparticles (NPs) and evaluate their cytotoxicity in DTX-resistant CRPC cells for the treatment of DTX-resistant CRPC. We tested solubility of CUR in different lipids and surfactants. Finally, Miglyol 812 and D-alpha-tocopheryl poly (ethylene glycol) succinate 1000 (TPGS) were chosen to prepare lipid-based NPs for CUR. We fully characterized CUR NPs that had particle size < 150 nm, high drug loading (7.5%), and entrapment efficiency (90%). Moreover, the CUR NPs were successfully lyophilized without using cryoprotectants. We tested the cytotoxicity of blank NPs, free CUR, and CUR NPs in sensitive DU145 and PC3 cells as well as their matching docetaxel-resistant cells. Cytotoxicity studies showed that blank NPs were very safe for all tested prostate cancer cell lines. Free CUR overcame the resistance in PC3 cells, but not in DU145 cells. In contrast, CUR NPs significantly increased CUR potency in all tested cell lines. Importantly, CUR NPs completely restored CUR potency in both resistant DU145 and PC3 cells. These results demonstrate that the CUR NPs have potential to overcome DTX resistance in CRPC.