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WIREs Nanomed Nanobiotechnol
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Nanowired drug delivery for neuroprotection in central nervous system injuries: modulation by environmental temperature, intoxication of nanoparticles, and comorbidity factors

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Abstract Recent developments in nanomedicine resulted in targeted drug delivery of active compounds into the central nervous system (CNS) either through encapsulated material or attached to nanowires. Nanodrug delivery by any means is supposed to enhance neuroprotection due to rapid accumulation of drugs within the target area and a slow metabolism of the compound. These two factors enhance neuroprotection than the conventions drug delivery. However, this is still uncertain whether nanodrug delivery could alter the pharmacokinetics of compounds making it more effective or just longer exposure of the compound for extended period of time is primarily responsible for enhanced effects of the drugs. Our laboratory is engaged in understanding of the nanodrug delivery using TiO2 nanowires in CNS injuries models, for example, spinal cord injury (SCI), hyperthermia and/or intoxication of nanoparticles with or without other comorbidity factors, that is, diabetes or hypertension in rat models. Our observations suggest that nanowired drug delivery is effective under normal situation of SCI and hyperthermia as evidenced by significant reduction in the blood–brain barrier (BBB) breakdown, brain edema formation, cognitive disturbances, neuronal damages, and brain pathologies. However, when the pathophysiology of these CNS injuries is aggravated by nanoparticles intoxication or comorbidity factors, adjustment in dosage of nanodrug delivery is needed. This indicates that further research in nanomedicine is needed to explore suitable strategies in achieving greater neuroprotection in CNS injury in combination with nanoparticles intoxication or other comorbidity factors for better clinical practices. WIREs Nanomed Nanobiotechnol 2012, 4:184–203. doi: 10.1002/wnan.172 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease

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The blood–brain barrier (BBB) (a) or brainblood barrier (BBB) (b) appears to be equally regulated strictly by the cerebral endothelium and the tight junctions. Thus, any tracer, for example, Evans blue when injected into the blood stream are unable to cross the BBB from the luminal side of the cerebral endothelium (a). Likewise, dyes or tracers injected into the brain, their passage is stopped from the brain to blood side at the abluminal side of the cerebral endothelium and probably by basement membrane as well (b). It is believed that in neurological diseases both the BBB and the BBB are equally damaged. However, a clear proof or lack of it is still unknown and require further investigations. For details see Refs 18–20. (Reprinted with permission from Ref 18. Copyright Elsevier Academic Press)

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The blood–brain barrier (BBB) comprises endothelial cells (EC) of cerebral capillaries that are connected with tight junctions (a). In addition, the endothelial cells are covered with a thick basement membrane (BM) (a). More than 85% of the endothelial cells are covered by astrocytic end‐feed (Glia) (a) although the real anatomical sites of the BBB are largely confined to the endothelial cell membrane and tight junctions. Thus, the cerebral endothelial cells represent and extended plasma membrane. On the other hand, noncerebral capillaries (b) are comprised of loosely attached endothelial cells with large numbers of pores or vesicles (b) a feature not seen in cerebral capillaries (a). The noncerebral endothelial cells also lack tight junctions. A thin layer of BM surrounds these general capillaries and normally do not offer any resistance to large number of substances between blood and noncerebral tissues. Although. The role of endothelial cell vesicular profiles in transporting big molecules like proteins across the BBB are not well known, the lack of vesicles within the cerebral endothelium in normal conditions support a role of these vesicles in translocating some molecules from blood to brain and vice versa in disease conditions. However, further research on the role of endothelial vesicles and BM is needed to find their participation in BBB transfer during neurological disorders. For details seeRefs 18 and 20. (Reprinted with permission from Ref 20. Copyright 2004 Elsevier Academic Press)

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Diabetes aggravates nanoparticles induced brain damage. Light micrograph from the parietal cerebral cortex showing neuronal changes in nanoparticles or saline treated normal and diabetic rats. Ag and Cu nanoparticles treatment (50 mg/kg, i.p.) for 7 days in normal rats resulted in marked neuronal damages (a, b) in the parietal cerebral cortex (arrows). Several neurons were dark and distorted and the neuropil showed sponginess and edema (a, b). It appears that Ag treatment induce more pronounced neurotoxicity (a) as compared to Cu treatment (b). However, these changes in nerve cell by nanoparticles were exacerbated in diabetic rats (c, d). Thus, nanoparticles treatment in diabetic rats resulted in massive sponginess, vacuolation and profound edema in the neuropil (c, d). Loss of neurons in diabetic rats flowing nanoparticles treatment is clearly seen. Most of the nerve cells seen in the micrograph obtained from the parietal cortex are damaged (arrows). Expansion of the neuropil and massive edema can be seen in the background. In diabetic rats, Ag nanoparticles induced most marked neuropathological changes (c) as compared to Cu nanoparticles administration (d). On the other hand, saline treated normal (f) and diabetic rats (e) showed only a few dark and distorted neurons (arrow heads) in the identical areas of the parietal cerebral cortex (e, f). Bar: a, b = 30 µm, c, d = 40 µm, e, f = 30 µm. (Reprinted with permission from Ref 15. Copyright 2010 American Scientific Publishers)

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Exacerbation of spinal cord pathology after trauma in SiO2 treated rats. High power light micrograph from the T9 segment of 5 h spinal cord traumatized spinal cord in one SiO2 (left) or saline (right) treated rat. In SiO2 treated injured rat showed massive cell and tissue loss, profound sponginess (*) and presence of several dark and dead neurons (arrow) in the neuropil. Nerve cell damage (arrow heads), sponginess and edema were also seen in saline treated traumatized rat (right), however, the magnitude and intensity of cell and tissue damage in saline treated rat is much less severe as compared to SiO2 treated injured spinal cord. Bar = 30 µm. Haematoxylin and Eosin Staining on 3‐µm thick paraffin sections. (Reprinted with permission from Ref 17. Copyright 2009 American Scientific Publisher)

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Nanowired or normal H‐290/51 delivery in heat stress and brain protection in nanoparticles intoxicated rats. Normal H‐290/51 treatment in heat stress 30 min before resulted in good neuroprotection (e) compared to saline treated four heat stressed rat (b). Heat stress alone resulted in marked neuronal damages in the cortex as compared to control (a). This heat induced neuronal damage was further exacerbated by Cu (c) or Ag (d) nanoparticles treatment. Interestingly normal H‐290/51 treated after 30 min in saline treated heat stressed rats resulted in very little neuroprotection (f). However, nanowired H‐290/51 in high doses when given either single doses (after 30 min) or double doses (after 60 min) induced marked neuroprotection following heat stress in Ag treated rats (h). a = saline control; b = 4 h heat stress in saline treated rat; c = Cu treated heat stressed rat; d = Ag treated heat stress rat; e = H‐290/51 pretreatment in saline treated 4 h heat stressed rat; f = H‐290/51 treatment after 30 min heat stress in saline treated rat; g = nanowired H‐290/51 treatment 30 min after heat stress in Ag treated rat; h = nanowired H‐290/51 treatment 30 min and/or 60 min after heat stress in Ag treated rat. Neuronal damage (arrows) is clearly seen in the neuropil. For details see text. Bar: 30 µm. (Reprinted with permission from Ref 65. Copyright 2009 American Scientific Publisher)

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Hyperthermia caused by 4 h heat stress in a biological oxygen demand (BOD) incubator (wind velocity 20–26.5 cm/s, relative humidity 45–47%) markedly induce breakdown of the blood–brain barrier (BBB) permeability to Evans blue albumin (EBA) in almost all brain regions (C.a–d). At the ultrastructural level, leakage of lanthanum, an electron dense particle (black particles, arrows) is frequently seen in the neuropil (B). At the time of the BBB leakage several nerve cells are seen quite distorted in the neuropil and general sponginess and edema is also clearly seen in these heat stressed rats (A). Chronic intoxication of Cu or Ag nanoparticles before heat exposure exacerbated leakage of lanthanum (B.b) and neuronal damages (A.b). This indicates that a combination of nanoparticles and heat exposure worsen brain pathology. Coronal sections of the brain passing through caudate‐putamen (+0.45 from bregma, C.a), hippocampal (−3.25 from bregma, C.b,c), Occipital cortex (C.d), brain stem (C.e), and cerebellum (C.f) levels showed selective pattern of EBA staining in heat stress. Leakage of EBA in the primary somato‐sensory cortex, piriform cortex, hippocampus, thalamus, hypothalamus, brain stem, cerebellum, and amygdala are clearly visible. (Reprinted with permission from Ref 18 and Reprinted with permission from Ref 21. Copyright 2009 American Scientific Publishers)

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Neuroprotective effects of nanowired drug delivery of AP713 in spinal cord injury (SCI) at light (a,b) and electron microscopy (c,d). For morphological studies at light and electron microscopy rats after SCI were perused in situ with 4% buffered paraformaldehyde containing 0.1% glutaraldehyde and 0.25 % picric acid preceded with a brief saline perfusion (at 100 torr, about 150–250 mL each rat). After that, small tissue pieces (2 mm thick) from the T10‐11, T9, and T12 segments were cut and post‐fixed in osmium tetraoxide and embedded in Epon for transmission electron microscopy (TEM). About 1 µm thick sections were cut and stained with Toluidine blue for high‐resolution light microscopy. Small tissue pieces from the dorsal and ventral horn of Epon embedded spinal cords were then cut on ultramicrotome using a diamond knife and sections were collected on a on hole copper grid and processed further with lead citrate and uranyl acetate and examined under a Philips 400 TEM using standard procedures.35,36 Treatment with nanowired AP713 markedly attenuated cell damage in the ventral horn of the spinal cord (a). Low power light micrograph showed several dark and distorted neurons (arrow heads) are seen in the untreated injured rat (b). Sponginess and edema (*) is clearly seen in the untreated animal after 5 h SCI (b). In nanowired AP713 treatment healthy neurons (arrows) are present in the ventral horn and signs of sponginess and edema are largely absent (a). Low power electronmicrograph showed myelin vesiculation (arrow heads) and edema (*) in the untreated injured rat (d). These changes are considerably reduced after injury by nanowired AP713 treatment (c). Thus, in the treated rat spinal cord injury (SCI) was not able to induce much damage to the myelin (arrows) and the signs of sponginess and edema (*) were much less frequent. Bars a, b = 80 µm, c, d = 800 nm (for details see Refs 35,36). (Reprinted with permission from Ref 35. Copyright 2009 American Scientific Publishers)

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Rat model of spinal cord injury (SCI). A longitudinal lesion (L) into the right dorsal horn was made over the T10‐11 segments using a sterile scalpel blade. The depth of the lesion was limited to Rexed's Laminae VIII comprising ≈︁1.5 mm deep (red bar). For morphological assessment, tissue segments from Rostral (T9) or Caudal (T12) to lesion sites were used. For ultrastructural analyses either dorsal (1) or ventral (2) horns of the contralateral side of the cord was examined in control or nanowired drug delivery groups. For details see text. (Reprinted with permission from Ref 18. Copyright 2004 Elsevier Academic Press)

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Motor functions improvement after nanowired drug delivery in spinal cord injury (SCI). Effects of nanowired compounds on Tarlov scale (upper panel) and inclined plane Angle test (lower panel) following spinal cord injury (SCI). The Tarlov scale for hind limb function was graded as Total paraplegia = 0; No spontaneous movement but responds to pinch = 1; Spontaneous movement = 2, Able to support weight but unable to walk = 3; Walk with gross deficits = 4; Walks with mild deficits = 5; Normal walk = 6.35,36 For inclined plane angle test, the animals were placed on an inclined plane platform and the angle of the plane was adjusted as such that animals could stay on the platform for 5 s without falling. Normal animals could stay at an angle of 60° without any problems. Spinal cord injured animals will not stay on the inclined plane angle beyond the 30° or higher. Treatment with drugs may allow animals to stay between 30° and above depending on the magnitude and duration of the neuroprotection offered by the compounds.35,36 ∗︁ = P < 0.05, ANOVA followed by Dunnett's test from control group. For details seeRefs35,36 (Reprinted with permission from Ref 35. Copyright 2009 American Scientific Publishers)

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Titanium (TiO2) nanowires for drug delivery and nanowire Characterizations. Scanning electron microscope (SEM) and transmission electron microscope (TEM) characterizations of the nanowire film, showing an SEM photograph of the white, flexible, and assembled nanowire membrane, and a TEM picture (inset) for confirming the nanowire morphology. (Scale bar: 50 nm). (c) X‐ray powder diffraction (XRD) pattern of titanate nanowire film. (b) An EDX spectrum of the titanate nanowire membrane is shown (a). (Reprinted with permission from Ref 36. Copyright 2009 American Scientific Publisher)

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