Solutes transport against a concentration gradient. tool that can be used for screening CNS nanoparticles or therapeutics prior toin vivoand clinical investigation. A discussion of this novel model is included. Keywords:blood-brain barrier (BBB), brain cancer, central nervous system (CNS), convection enhanced delivery (CED), flow-basedin vitroBBB model, nanoparticle == 1. Introduction == Recent development of nanotechnology in pharmaceutical and biomedical research has led to the creation of a number of nanostructured diagnostic and therapeutic agents, which could benefit the treatment of many central nervous system (CNS) diseases. Until recently, application of nanotechnology in the CNS has been primarily focused on brain cancer because of life-threatening Dxd risks associated with this disease. An efficient drug delivery to the brain tumor mass remains a challenging clinical problem. In particular, the blood-brain barrier (BBB), the blood cerebral spinal fluid, and blood-tumor barrier all hamper the successful treatment of brain tumors by severely limiting access of therapeutic or diagnostic agents into the brain [1]. To overcome these limitations, several types of nanoparticles such as linear polymers, hyperbranched polymers, dendrimers, liposomes and micelles have been synthesized or engineered [2]. To bypass or cross the BBB more effectively, novel administration routes and transport mechanisms for nanoparticle-mediated CNS delivery have been actively explored. These include temporary disruption of the BBB to increase permeability, the use of impregnated polymers for local drug administration, convection-enhanced delivery (CED), and intranasal delivery. This review begins with a brief introduction to the BBB and then discusses the latest application of nanoparticles for the treatment and Dxd diagnosis of CNS diseases in the context of brain tumors. New routes employed for the administration of nanoparticles are also described in detail. Given the complexity of the CNS and presence of the Dxd BBB, screening and pre-optimizing nanoparticles-based agents designed to be administered systemically using anin vitromodel could be a suitable approach prior toin vivoand clinical examination. A discussion of a dynamicin vitro(DIV) BBB model capable of mimicking features of the human BBB is included in this review. == 2. The blood-brain barrier == Some speculate that strong selective pressures must have existed to allow such a complex structure as the BBB to evolve. The Dxd CNS has no lymphatic system or other way of parenchymal drainage and is enclosed within the cranium, a rigid non-expandable structure. A net influx of molecules into the CNS would increase osmolarity and allow water from the vasculature to enter the brain, leading to an elevation of intracranial pressure. Evolution of the BBB fortunately makes large increases in intracranial pressure rare occurrences. Importantly, the BBB serves to prevent potentially harmful toxins from reaching the brain. Scientific investigation in identifying the BBB dates back to the 19thcentury. In 1885, Paul Ehrlich, a bacteriologist, observed that aniline dyes intravenously injected into animals colored all organs Dxd with the exception of the brain and spinal cord [3,4]. Today we know that the BBB is composed of microvascular endothelium, basement membrane and neuroglial structures such as astrocytes, pericytes and microglia. The monolayer of microvascular endothelial cells (ECs) lines the intraluminal space of brain capillaries and the endothelial cells are packed close together, forming tight junctions. The EC layer has a luminal (inside) and abluminal (outside) compartment, separated by 300 to 500 nm of cytoplasm between the vascular system and the brain. Tight junctions consist of occludin and claudin adherent junctions and junctional adhesion molecules. There Rabbit Polyclonal to CAMK5 are two fundamental morphological characteristics that separate the brain from peripheral EC. First, the cytoplasm of brain microvascular ECs has rare pinocytic vesiclesfluid-filled cell membrane invaginations that allow certain compounds to cross the BBB. These ECs also contain a greater concentration of mitochondria meeting the requirements to actively transport molecules from the blood into the brain and vice versa. Second, in addition to the structural integrity of the BBB, there exists an enzymatic surveillance system that metabolizes drugs and other compounds bypassing the.
