Novel Approaches for Brain Drug Delivery System-Review

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International Journal of Pharma Research & Review, June 2013; 2(6):36-44 ISSN: 2278-6074drug efflux transporters expressed in BBBby Pluronic® block copolymers, whichallow for the increased transport of thesubstrates of these transporters to thebrain. The second strategy involves aroundthe design of nanoparticles conjugated withspecific ligands that can target receptors inthe brain microvasculature and carry thedrugs to the brain through the receptormediated transcytosis. The third strategyinvolves artificial hydrophobization ofpeptides and proteins that facilitate thedelivery of these peptides and proteinsacross BBB [3].The parameters considered optimum for acompound to transport across the BBB are:‣ Compound should be unionized.‣ Approximately logP value must be 2.‣ Its molecular weight must be less than400 Da.‣ Cumulative number of hydrogen bondsmust not go beyond 8 to 10.It is estimated only 2% of small molecularweight drug will across BBB.BARRIERS TO CNS DRUG DELIVERYThe failure of systemically delivered drugsto effectively treat many CNS diseases canbe rationalized by considering a number ofbarriers that inhibits drug delivery to theCNS.Blood-Brain Barrier (BBB)Basal membrane and brain cells, such aspericytes and astrocytes, surrounding theendothelial cells further form and maintainan enzymatic and physical barrier known asthe blood–brain barrier (BBB).BBB tight junctions are formed betweenendothelial cells in brain capillaries, thuspreventing paracellular transport ofmolecules into the brain.Fig. 1: Schematic representation of the transport of molecules across the BBBMicro-vessels small in diameter and thinwalls compared to vessels in other organsmake up an estimated 95% of the totalsurface area of the BBB, and represent theprincipal route by which chemicals enterthe brain. In brain capillaries, intercellularcleft, pinocytosis, and fenestrate arevirtually nonexistent; exchange must passtrans-cellularly. Therefore, only lipidsolublesolutes that can freely diffusethrough the capillary endothelial membranemay passively cross the BBB [4].Blood–cerebrospinal fluid barrier(BCSFB)Another barrier between the blood and thebrain is the blood–cerebrospinal fluidbarrier (BCSFB), which separates the bloodfrom cerebrospinal fluid (CSF). However,this barrier is not considered as a mainroute for the uptake of drugs since itssurface area is 5000-fold smaller than thatof the BBB [5–8].CSF can exchange molecules with theinterstitial fluid of the brain parenchyma;the passage of blood-borne molecules intothe CSF is also carefully regulated by theBCB. Physiologically, the BCB is found in theepithelium of the choroids plexus, which isarranged in a manner that limits thepassage of molecules and cells into the CSF[9-11].The choroid plexus and the arachnoidmembrane act together at the barriersbetween the blood and CSF [12].The arachnoid membrane is generallyimpermeable to hydrophilic substances, andits role is formation of the Blood-CSFbarrier, is largely passive. The choroidplexus forms the CSF and actively regulatesthe concentration of molecules in the CSF.Swatantra Bahadur Singh, IJPRR 2013; 2(6) 37
International Journal of Pharma Research & Review, June 2013; 2(6):36-44 ISSN: 2278-6074Fig. 2: Schematic representation of the drug penetrate and impenetrate across the BBB.Fig. 3: Schematic representation of the factors affecting drug transport across the BBB3-Blood-Tumor BarrierIntracranial drug delivery becomes evenmore challenging when the target is a CNStumor. The presence of the BBB in themicrovasculature of CNS tumors has clinicalconsequences (13).In CNS malignancies where the BBB issignificantly compromised, a variety ofphysiological barriers common to all thesolid tumors inhibit drug delivery via thecardiovascular system. Drug delivery toneoplastic cells in a solid tumor iscompromised by a heterogeneousdistribution of microvasculaturethroughout the tumor interstitial, whichleads to spatially inconsistent drug delivery.However, as a tumor grows large, thevascular surface area decreases, leading toreduction in trans-vascular exchange ofblood-borne molecules. At the same time,intra-capillary distance increases, leading toa greater diffusional requirement for drugdelivery to neoplastic cells and due to highinterstitial tumor pressure and theassociated peri-tumoral edema leads toincrease in hydrostatic pressure in thenormal brain parenchyma adjacent to thetumor. As a result, the cerebralmicrovasculature in these tumor adjacentregions of normal brain may be even lesspermeable to drugs than normal brainendothelium, which leads to exceptionallySwatantra Bahadur Singh, IJPRR 2013; 2(6) 38
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