Shuttle‐Mediated Drug Delivery to the Brain

Malakoutikhah, Morteza; Teixidó, Meritxell; Giralt, Ernest

doi:10.1002/anie.201006565

Cited by 75 publications

(71 citation statements)

References 128 publications

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“…An inability to enter the brain through the blood flow, either developing artificial methods for overcoming this barrier are required for such anionic complexes delivery in the brain or the successful RCAs could be conjugated with already established BBB permeating agents. 33 We will also extend these encouraging results by noninvasively mapping of mGluR 5 by MRI in depressed, anxiety, and drug-abuse mouse models. The potential development of medications for the treatment of addiction and other neuropsychiatric disorders, these imaging probes could also provide new pathological information of the brain.…”

Section: ■ Summary and Conclusionmentioning

confidence: 88%

Microscopic Visualization of Metabotropic Glutamate Receptors on the Surface of Living Cells Using Bifunctional Magnetic Resonance Imaging Probes

Mishra¹,

Mishra²,

Gottschalk

et al. 2013

ACS Chem. Neurosci.

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A series of bimodal metabotropic glutamate-receptor targeted MRI contrast agents has been developed and evaluated, based on established competitive metabotropic Glu receptor subtype 5 (mGluR 5 ) antagonists. In order to directly visualize mGluR 5 binding of these agents on the surface of live astrocytes, variations in the core structure were made. A set of gadolinium conjugates containing either a cyanine dye or a fluorescein moiety was accordingly prepared, to allow visualization by optical microscopy in cellulo. In each case, surface receptor binding was compromised and cell internalization observed. Another approach, examining the location of a terbium analogue via sensitized emission, also exhibited nonspecific cell uptake in neuronal cell line models. Finally, biotin derivatives of two lead compounds were prepared, and the specificity of binding to the mGluR 5 cell surface receptors was demonstrated with the aid of their fluorescently labeled avidin conjugates, using both total internal reflection fluorescence (TIRF) and confocal microscopy.

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Section: ■ Summary and Conclusionmentioning

confidence: 88%

Microscopic Visualization of Metabotropic Glutamate Receptors on the Surface of Living Cells Using Bifunctional Magnetic Resonance Imaging Probes

Mishra¹,

Mishra²,

Gottschalk

et al. 2013

ACS Chem. Neurosci.

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“…Moreover, they are not suitable for chronic treatments. [2] Despite the presence of the BBB, the brain is not fully insulated. This organ requires essential nutrients and ions to carry out its activity and to maintain CNS homeostasis.…”

mentioning

confidence: 99%

“…These nutrients are supplied by a number of specialized endogenous transport mechanisms located at the BBB and are potential drug-delivery gates for therapeutic treatments of CNS disorders. [2,3] Among them, receptor-mediated transcytosis is known to be suitable for the transport of large therapeutic agents, since it is vesicular-based, in addition to providing selectivity, a key issue in drug targeting. However, this type of transport is limited by the presence of endogenous substrates, which usually saturate receptors under physiological conditions.…”

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confidence: 99%

Applying the Retro‐Enantio Approach To Obtain a Peptide Capable of Overcoming the Blood–Brain Barrier

et al. 2015

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The blood-brain barrier (BBB) is a formidable physical and enzymatic barrier that tightly controls the passage of molecules from the blood to the brain. In fact, less than 2 % of all potential neurotherapeutics are able to cross it. Here, by applying the retro-enantio approach to a peptide that targets the transferrin receptor, a full protease-resistant peptide with the capacity to act as a BBB shuttle was obtained and thus enabled the transport of a variety of cargos into the central nervous system.

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“…1 and 2 , blood-brain barrier (BBB) functionally limits the access of many reagents to the brain. Clearly, strategies that overcome the druglimiting aspects of the BBB could be important components to future treatment of CNS-based disease (Bisht 2011 ;Frank et al 2011 ;Jain and Jain 2011 ;Malakoutikhah et al 2011 ;Rajadhyaksha et al 2011 ;Shinde et al 2011 ;Tian et al 2011 ;Tucker 2011 ). Signifi cant progress in the development of protein, peptide, antibody, protein fusion, stem cell, viral, gene, and other therapeutic modalities (biotherapeutics) has redefi ned the landscape of investigational clinical drugs for non-CNS indications (Schneider et al 2010 ), and a substantial portion of successful new pharmaceutical treatments are expected to be biotherapies (Zhong et al 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacoeconomic Considerations in CNS Drug Development

Gray

2013

Drug Delivery to the Brain

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Recent advances in understanding of the blood-brain barrier (BBB) suggest that we are entering an era in which basic discoveries of BBB structure and function may be parlayed into meaningful disease applications. The development of impactful human therapies is a diffi cult and lengthy process; nonetheless, many researchers desire to see their work applied to the treatment of human disease. Signifi cant fi nancial reward will follow functional solutions to BBB delivery challenges; however, validating a trans-BBB delivery strategy to support and sustain a clinical program is costly and risky and requires multidisciplinary expertise. Investigators must necessarily garner funding and expertise for such campaigns, mainly through government grants, private investment fi rms, and industrial partnerships. Among the many considerations for researchers looking to advance brain delivery technology are the commercial aspects of the technology and the requirements attached to the funding mechanisms for clinical development. Early choices about delivery modality and target therapy (indication) have important consequences for the development process. An understanding of the forces that currently drive the pricing of therapeutics and the factors considered by potential investors who can fund expensive clinical development programs is helpful for framing a discussion about the pharmacoeconomics of BBB delivery. Complex multimodal delivery technologies may have added challenges for demonstrating safety and signifi cantly higher drug manufacturing costs that can infl uence the risk-benefi t analysis made by potential investors. Both the therapeutic application and the delivery system infl uence the path to generating commercial or government interest in advancing a particular brain delivery approach toward the clinic.

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Shuttle‐Mediated Drug Delivery to the Brain

Cited by 75 publications

References 128 publications

Microscopic Visualization of Metabotropic Glutamate Receptors on the Surface of Living Cells Using Bifunctional Magnetic Resonance Imaging Probes

Microscopic Visualization of Metabotropic Glutamate Receptors on the Surface of Living Cells Using Bifunctional Magnetic Resonance Imaging Probes

Applying the Retro‐Enantio Approach To Obtain a Peptide Capable of Overcoming the Blood–Brain Barrier

Pharmacoeconomic Considerations in CNS Drug Development

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