MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery

Oller‐Salvia, Benjamí; Sánchez‐Navarro, Macarena; Ciudad, Sonia; Guiu, Marc; Arranz‐Gibert, Pol; Garcia, C. L.; Gomis, Roger R.; Cecchelli, Roméo; García, Jesús; Giralt, Ernest; Teixidó, Meritxell

doi:10.1002/anie.201508445

Cited by 74 publications

(59 citation statements)

References 23 publications

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“…The peptide was added to the donor compartment (apical) at 50 µM, and its recovery in the acceptor compartment (basal) was quantified by UPLC. The permeability obtained was (4.4 ± .6) × 10 −6 cm/s, which is of the same order of magnitude as other known BBB shuttles, such as MiniAp4 with a value of (6.7 ± .6) × 10 −6 cm/s . When performing the assay at 4°C, the permeability was reduced by 40%, implying that the peptide internalized through an active mechanism.…”

Section: Resultssupporting

confidence: 53%

“…Also, by lowering the temperature to 4°C, the uptake of GFP‐SGV remained at the same levels as GFP alone (731 ± 108 fmol GFP/mg protein). When comparing with other BBB shuttles, such as MiniAp4, the increase in protein uptake is of the same order of magnitude . These observations indicate that SGV also facilitates the internalization of GFP in bEnd.3 cells, thereby opening the door to the transport of other cargoes, including proteins for protein replacement therapy.…”

Section: Resultsmentioning

confidence: 63%

“…Once the endothelial cells are differentiated, these are placed in new wells, without the pericytes, to perform the assay. This BBB model was used in the validation of several BBB shuttles, such as THRre and MiniAp‐4 …”

Section: Introductionmentioning

confidence: 99%

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Phage display as a tool to discover blood–brain barrier (BBB)‐shuttle peptides: panning against a human BBB cellular model

et al. 2017

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Most potential drugs for the treatment of central nervous system disorders do not cross the blood-brain barrier (BBB). Much research effort has been devoted to the discovery of new BBB-shuttle peptides-most of which have been identified by phage display. Here we report for the first time on the use of phage display against a human BBB cellular model which mimics the characteristics of the BBB. From the panning experiment of a 12-mer library, the SGVYKVAYDWQH (SGV) peptide sequence was selected and its permeability validated in the aforementioned model. Furthermore, internalization studies suggested that SGV internalizes through a clathrin-mediated mechanism and that it increases the uptake of a cargo in endothelial cells. These results highlight the usefulness of in vitro BBB models for the discovery of BBB-shuttle peptides through phage display libraries.

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Section: Resultssupporting

confidence: 53%

Section: Resultsmentioning

confidence: 63%

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Phage display as a tool to discover blood–brain barrier (BBB)‐shuttle peptides: panning against a human BBB cellular model

et al. 2017

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“…[48] In a different approach, Oller-Salvia et al synthesized a peptidomimetic motif inspired from bee venom, that was resistant to serum proteases and increased the translocation of 12 nm gold (Au) NPs by 20 times in a human cellbased BBB model. [49] Aptamers, also referred to as 'chemical Abs', [50] are short single-stranded (ss) nucleic acid sequences (ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) oligonucleotides) that can be engineered to have high (e.g., nano-to picomolar) affinity to their receptors. Compared to Abs and similar molecules, aptamers can often be synthesized at a lower cost and can be easier to scale up for production, as well as being typically more stable at high temperature.…”

Section: Targeting Ligandsmentioning

confidence: 99%

Particle Targeting in Complex Biological Media

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Bertleff‐Zieschang

Braunger

et al. 2017

Adv Healthcare Materials

100

102

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Over the past few decades, nanoengineered particles have gained increasing interest for applications in the biomedical realm, including diagnosis, imaging, and therapy. When functionalized with targeting ligands, these particles have the potential to interact with specific cells and tissues, and accumulate at desired target sites, reducing side effects and improve overall efficacy in applications such as vaccination and drug delivery. However, when targeted particles enter a complex biological environment, the adsorption of biomolecules and the formation of a surface coating (e.g., a protein corona) changes the properties of the carriers and can render their behavior unpredictable. For this reason, it is of importance to consider the potential challenges imposed by the biological environment at the early stages of particle design. This review describes parameters that affect the targeting ability of particulate drug carriers, with an emphasis on the effect of the protein corona. We highlight strategies for exploiting the protein corona to improve the targeting ability of particles. Finally, we provide suggestions for complementing current in vitro assays used for the evaluation of targeting and carrier efficacy with new and emerging techniques (e.g., 3D models and flow‐based technologies) to advance fundamental understanding in bio‐nano science and to accelerate the development of targeted particles for biomedical applications.

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“…4 In addition to antibody-based BBB-shuttles, peptide shuttles have shown promise for cargo delivery across the BBB. 5 Peptides are easier to characterize than antibodies and can be prepared by chemical synthesis, enabling the incorporation of diverse chemical moieties to modulate the shuttle’s properties.…”

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confidence: 99%

Perfluoroarene–Based Peptide Macrocycles to Enhance Penetration Across the Blood–Brain Barrier

et al. 2017

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Here we describe the utility of peptide macrocyclization through perfluoroaryl-cysteine SNAr chemistry to improve the ability of peptides to cross the blood–brain barrier. Multiple macrocyclic analogues of the peptide transportan-10 were investigated that displayed increased uptake in two different cell lines and improved proteolytic stability. One of these analogues (M13) exhibited substantially increased delivery across a cellular spheroid model of the blood–brain barrier. Through ex vivo imaging of mouse brains, we demonstrated that this perfluoroarene-based macrocycle of TP10 exhibits increased penetration of the brain parenchyma following intravenous administration in mice. Finally, we evaluated macrocyclic analogues of the BH3 domain of the BIM protein to assess if our approach would be applicable to a peptide of therapeutic interest. We identified a BIM BH3 analogue that showed increased penetration of the brain tissue in mice.

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MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery

Cited by 74 publications

References 23 publications

Phage display as a tool to discover blood–brain barrier (BBB)‐shuttle peptides: panning against a human BBB cellular model

Phage display as a tool to discover blood–brain barrier (BBB)‐shuttle peptides: panning against a human BBB cellular model

Particle Targeting in Complex Biological Media

Perfluoroarene–Based Peptide Macrocycles to Enhance Penetration Across the Blood–Brain Barrier

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