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BARRIERS FOR BRAIN DRUG DELIVERY

Drug delivery to the brain poses a significant challenge. Despite the brain being a highly perfused organ, physiological barriers control the transfer of various substances including nutrients to the brain. The two main barriers contributing to the low brain bioavailability are BBB and blood—cerebrospinal fluid (BCSF) barrier [7]. Besides these barriers preventing therapeutic levels in the brain, the oncogenesis of gliomas is even more complicated [8]. Understanding the morphology and properties of these barriers is essential to successfully deliver drugs to the brain.

PHYSIOLOGY OF THE BLOOD—BRAIN BARRIER

The BBB acts as a neuroprotective shield by filtering harmful substances back into the blood stream and supplying brain tissues with nutrients. The BBB is composed ofmainly

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three layers: an inner endothelial cell layer that forms the wall of brain capillaries, a basement membrane, and end feet processes of astrocytes and pericytes. The endothelial cells comprising the BBB express extensive tight junctions (TJs), have sparse pinocytic vesicular transport, and lack fenestrations unlike other endothelial cells [9]. These cells are mainly responsible for regulating the passage of drugs across the brain, leukocyte migration, and maintaining brain homeostasis crucial for neuronal activity. Pericytes and astro- cytic/glial foot processes surround the brain capillary endothelial cells (BCECs). These cells provide trophic, metabolic, and structural support to the brain. TJs are responsible for limiting paracellular transport of hydrophilic molecules across the BBB due to high trans-endothelial electrical resistance of 1500—2000 U cm2 [10]. TJs also possess an intricate structure of transmembrane proteins including junctional adhesion molecule-1, occludin, and claudin. Moreover, cytoplasmic accessory proteins (zonula occludens-1 and -2, cingulin, AF-6, and 7H6) are also involved. Fig. 4.1 illustrates an overview of the BBB andBCSF barrier [10a,10b]. In addition to BBB andBCSF, there are other barriers such as the blood—brain tumor barrier (BBTB) [1].

The BCSF barrier is the second most important CNS barrier next to BBB. It is formed by the epithelial cells of the choroid plexus. It mainly controls the transport of molecules within the interstitial fluid of the brain parenchyma by regulating the flow between blood and CSF. Facilitated diffusion, active transport, and efflux from blood into the CSF are the mechanisms for molecular transport via the choroid plexus [11].

Overview of two major barriers in the central nervous system

Figure 4.1 Overview of two major barriers in the central nervous system: blood—brain barrier and blood—cerebrospinal fluid barrier. (Adapted from Pardridge WM. Why is the global CNS pharmaceutical market so under-penetrated? Drug Discov Today 2002;7(l):5—7 and Bradbury M, Begley DJ, KreuterJ, editors. The blood-brain barrier and drug delivery to the CNS. USA: In forma Healthcare; 2000.)

Conventional Strategies for Brain Drug Delivery

Drug delivery to the CNS is highly challenging. Various drug delivery strategies have been employed to improve patient compliance, prolong drug half-life, minimize healthcare costs, and improve pharmacokinetics of degradable peptides and proteins. These strategies may be classified into two broad categories based on the method of drug delivery used. Invasive methods utilize direct delivery oftherapeutic agents into the brain parenchyma or by disrupting the BBB. On the other hand, noninvasive methods take advantage of endogenous pathways to achieve therapeutic concentrations in the CNS [12].

 
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