Outwitting the Blood-Brain Barrier for Therapeutic Purposes: Osmotic Opening and Other Means

Kroll, Robert A.; Neuwelt, Edward A.

doi:10.1097/00006123-199805000-00082

Cited by 532 publications

(340 citation statements)

References 51 publications

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“…As an adjunctive treatment, mannitol has been frequently used to decrease edema or intracranial pressure with massive brain lesions (McGraw andHoward, 1983, Schwarz et al, 1998). Mannitol has also been used to open the blood-brain barrier (BBB) by temporarily shrinking the tightly coupled endothelial cells that make up the barrier, thus allowing for drugs delivered directly to the brain (Kroll and Neuwelt, 1998). Another suggested mechanism of mannitol's effect on cerebral vasculature is increased endothelial permeability and small vessel dilation (Machi et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Mannitol enhances delivery of marrow stromal cells to the brain after experimental intracerebral hemorrhage

et al. 2008

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Previous studies show that intravascular injection of human bone marrow stromal cells (hBMSCs) significantly improves neurological functional recovery in a rat model of intracerebral hemorrhage (ICH). In the present study, we tested the hypothesis that mannitol improves the efficiency of intraarterial MSC delivery (i.e., fewer injected cells required for therapeutic efficacy) after ICH. There were four post-ICH groups (N=9): group 1, negative control with only intra-arterial injection of 1 million human fibroblasts in phosphate-buffered saline (PBS); group 2, intravenous injection of mannitol alone in PBS (1.5 g/kg); group 3, intra-arterial injection of 1 million hBMSCs alone in PBS; and group 4, intravenous injection of mannitol (1.5 g/kg) in PBS followed by intra-arterial injection of 1 million hBMSCs in PBS. Group 4 exhibited significantly improved neurological functional outcome as assessed by neurological severity score (NSS) and corner test scores. Immunohistochemical staining of group 4 suggested increased synaptogenesis, proliferating immature neurons, and neuronal migration. The number of hBMSCs recruited to the injured region increased strikingly in group 4. Tissue loss was notably reduced in group 4. In summary, the beneficial effects of intra-arterial infusion of MSCs are amplified with intravenous injection of mannitol. Preadministration of mannitol significantly increases the number of hBMSCs located in the ICH region, improves histochemical parameters of neural regeneration, and reduces the anatomical and pathological consequences of ICH.

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Section: Discussionmentioning

confidence: 99%

Mannitol enhances delivery of marrow stromal cells to the brain after experimental intracerebral hemorrhage

et al. 2008

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“…11 By way of its anatomic and physiologic properties, the normal BBB prevents passage of ionized water-soluble compounds with a molecular weight greater than 180 Da. 19 Although the integrity of the barrier is often compromised within or around tumors, this alteration in permeability is variable and heterogeneous, nonetheless greatly limiting drug penetration. 19 More The white arrows depict areas of hypointense signal related to encephalomalacia.…”

Section: Discussionmentioning

confidence: 99%

Enhanced chemotherapy delivery by intraarterial infusion and blood‐brain barrier disruption in the treatment of cerebral metastasis

Fortin

Gendron

Boudrias

et al. 2007

Cancer

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Cationic polyurethane‐fluorinated acrylate hybrid dispersions (PUFA) were prepared by the copolymerization of styrene, butyl acrylate, and 2,2,3,4,4,4‐hexafluorobutyl methacrylate in the medium of crosslinked polyurethane via phase inversion polymerization. The said polyurethane was synthesized in acetone from 2,4‐tolyene diisocyanate, N‐methyldiethanolamine, trimethylolpropane, and soft polyester diol block. The influences of hydrophilic monomer on the surface properties, immersion behaviors, particle size and, zeta potential of the dispersions were investigated. The results show that the addition of hydrophilic monomer can be advantaged to the stability of dispersions and yet will increase the surface free energy by more than 19.9%. The PUFA coating films cured at ambient conditions have the lower surface free energy (less than 0.02033 J/m2). At the same time, there is an obvious mobility of fluorinated groups in fluorinated polymer films. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006

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“…The BTB is highly heterogeneous and its permeability depends on the tumor type and size. 3,4 Permeability of the BTB to contrast agents (CAs) should not be considered as a free access to the brain for all drugs, as was so clearly showed by Lockman et al 5 Many approaches have been developed to deliver drugs across the BBB to maximize drug concentration to the tumor cells. One such strategy is the osmotic BBB disruption (BBBD) consisting in an intraarterial infusion of a hyperosmolar solution (mannitol 25%) that produces a transient increase in BBB permeability via the shrinkage of the endothelial cells leading to the reversible opening of the tight junctions.…”

Section: Introductionmentioning

confidence: 99%

Impact of Drug Size on Brain Tumor and Brain Parenchyma Delivery after a Blood–Brain Barrier Disruption

Blanchette

Tremblay

Lepage

et al. 2014

J Cereb Blood Flow Metab

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Drug delivery to the brain is influenced by the blood-brain barrier (BBB) and blood-tumor barrier (BTB) to an extent that is still debated in neuro-oncology. In this paper, we studied the delivery across the BTB and the BBB of compounds with different molecular sizes in normal and glioma-bearing rats. Studies were performed at baseline as well as after an osmotic BBB disruption (BBBD) using dynamic contrast-enhanced magnetic resonance imaging and two T 1 contrast agents (CAs), Magnevist (743 Da) and Gadomer (17,000 Da). More specifically, we determined the time window for the BBB permeability, the distribution and we calculated the brain exposure to the CAs. A different pattern of accumulation and distribution at baseline as well as after a BBBD procedure was observed for both agents, which is consistent with their different molecular size and weight. Baseline tumor exposure was threefold higher for Magnevist compared with Gadomer, whereas postBBBD tumor exposure was twofold higher for Magnevist. Our study clearly showed that the time window and the extent of delivery across the intact, as well as permeabilized BTB and BBB are influenced by drug size.

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Outwitting the Blood-Brain Barrier for Therapeutic Purposes: Osmotic Opening and Other Means

Abstract: Improving delivery of agents to the brain will play a major role in the therapeutic outcome of brain neoplasms. As techniques for gene therapy are advanced, manipulation of the BBB also may be important in the treatment of central nervous system genetic disorders.

Cited by 532 publications

References 51 publications

Mannitol enhances delivery of marrow stromal cells to the brain after experimental intracerebral hemorrhage

Mannitol enhances delivery of marrow stromal cells to the brain after experimental intracerebral hemorrhage

Enhanced chemotherapy delivery by intraarterial infusion and blood‐brain barrier disruption in the treatment of cerebral metastasis

Impact of Drug Size on Brain Tumor and Brain Parenchyma Delivery after a Blood–Brain Barrier Disruption

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