Targeting Neurotherapeutic Agents Through the Blood-Brain Barrier

Pardridge, William M.

doi:10.1001/archneur.59.1.35

Cited by 93 publications

(42 citation statements)

References 29 publications

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“…Interestingly, despite the fact that this limitation in delivery imposed by the barrier is more and more acknowledged, it remains underdiscussed in the field of neurosciences. 11,12 Intraarterial Chemotherapy and BBBD Different approaches have been advocated to improve delivery across the BBB. One such approach has been extensively tested in the clinic, and is commonly used by our team, both in the preclinical and clinical setting.…”

Section: Figurementioning

confidence: 99%

“…The delivery impediment of therapeutic molecules related to the physicoelectric characteristics of the BBB and the activity of efflux pump systems is such that a significant area under the curve is hard to maintain. [10][11][12] Based on the rationale of bypassing the BBB, different approaches have been proposed. 13 One such approach consists of increasing the effective concentration of a chemotherapy agent by intraarterial (IA) administration.…”

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confidence: 99%

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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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Section: Figurementioning

confidence: 99%

mentioning

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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“…Such transport is strongly limited by the BBB, which exhibits minimal permeability to most drugs and neurotherapeutic agents. 3 As a result, extensive research has been focused on the development of strategies to cross the BBB and deliver therapeutic agents efficiently in the CNS. 2,[4][5][6][7][8][9] Within this context, nanotechnology applied to medicine has the potential to lead to significant advances in the diagnosis and treatment of diseases; as a result of their unique properties, such as size, surface energy, large surface area to volume ratio and the possibility of introducing a variety of surface modifications, engineered nanoparticles offer enormous promise as drug delivery vehicles specifically targeting a range of human diseases.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle accumulation and transcytosis in brain endothelial cell layers

et al. 2013

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The Blood-Brain Barrier (BBB) is a selective barrier, which controls and limits access to the central nervous system (CNS). The selectivity of the BBB relies on specialized characteristics of the endothelial cells that line the microvasculature, including the expression of intercellular tight junctions, which limit paracellular permeability. Several reports suggest that nanoparticles have a unique capacity to cross the BBB. However, direct evidence of nanoparticle transcytosis is difficult to obtain, and we found that typical transport studies present several limitations when applied to nanoparticles. In order to investigate the capacity of nanoparticles to access and transport across the BBB, several different nanomaterials, including silica, titania and albumin-or transferrinconjugated gold nanoparticles of different sizes, were exposed to a human in vitro BBB model of endothelial hCMEC/D3 cells. Extensive transmission electron microscopy imaging was applied in order to describe nanoparticle endocytosis and typical intracellular localisation, as well as to look for evidence of eventual transcytosis. Our results show that all of the nanoparticles were internalised, to different extents, by the BBB model and accumulated along the endo-lysosomal pathway. Rare events suggestive of nanoparticle transcytosis were also observed for several of the tested materials.

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“…66 Although trophic factors generally do not readily penetrate the BBB, there are clever means to link them to an endogenous peptide or peptidomimetic monoclonal antibody that undergoes receptor mediated transcytosis carried into brain. 67 BDNF linked to a monoclonal antibody transported by the transferrin receptor entered the brain of rats and protected the CA1 hippocampal neurons from an ischemic insult. 68 Another Trojan-horse strategy uses nanotechnology, whereby the chemical properties of the trophic factor can be disguised in nanoparticles.…”

Section: Manipulating Trophic Factors For Therapeutic Benefitmentioning

confidence: 99%

Treatment of Parkinson’s Disease with Trophic Factors

2008

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Summary: Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson's disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson's disease and ongoing loss of dopaminergic neurons remains to be proven.

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Targeting Neurotherapeutic Agents Through the Blood-Brain Barrier

Cited by 93 publications

References 29 publications

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

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

Nanoparticle accumulation and transcytosis in brain endothelial cell layers

Treatment of Parkinson’s Disease with Trophic Factors

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