Chemical Optimization of New Ligands of the Low-Density Lipoprotein Receptor as Potential Vectors for Central Nervous System Targeting

Malcor, Jean‐Daniel; Payrot, Nadine; David, Marion; Faucon, Aude; Abouzid, Karima; Jacquot, Guillaume; Floquet, Nicolas; Debarbieux, Franck; Rougon, Geneviève; Martinez, Jean; Khrestchatisky, Michel; Vlieghe, Patrick; Lisowski, Vincent

doi:10.1021/jm2014919

Cited by 75 publications

(91 citation statements)

References 65 publications

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“…COG133 has been shown to transport across the BBB, but lost targeting specificity when conjugated to liposomes [98]. Peptide-22 is a cyclic 8-mer peptide which was optimized to bind LDLR with high affinity and without competition of endogenous LDL [80]. With regard to delivery of therapeutics for brain cancer, peptide-22 modified polymeric nanoparticles loaded with paclitaxel were trafficked across an in vitro BBB model through clathrin- and caveolae-mediated endocytosis [116].…”

Section: Methods To Overcome the Bbb For Delivery Of Therapeutics To mentioning

confidence: 99%

Promising Approaches to Circumvent the Blood–Brain Barrier: Progress, Pitfalls and Clinical Prospects in Brain Cancer

Papademetriou

Porter

2015

Ther. Deliv.

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Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood–brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future.

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Section: Methods To Overcome the Bbb For Delivery Of Therapeutics To mentioning

confidence: 99%

Promising Approaches to Circumvent the Blood–Brain Barrier: Progress, Pitfalls and Clinical Prospects in Brain Cancer

Papademetriou

Porter

2015

Ther. Deliv.

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“…Such data involve LRP1 in a bi-directional transport across the BBB depending on its ligands. biOasis develops the Transcend technology using a protein melanotransferrin for the transport of biologics such as lysosomal enzymes and antibodies across the BBB 33 while VECT-HORUS develops peptide vectors that target the LDLR 34 . There is data suggesting that the LRP and LDLR can be used to transport different molecules such as lysosomal enzymes 35,36 or nanoparticle complexes across the BBB 37 .…”

Section: Introductionmentioning

confidence: 99%

Setting-up an <em>In Vitro</em> Model of Rat Blood-brain Barrier (BBB): A Focus on BBB Impermeability and Receptor-mediated Transport

Molino¹,

Jabès²,

Lacassagne

et al. 2014

JoVE

Self Cite

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Citation: Molino, Y., Jabès, F., Lacassagne, E., Gaudin, N., Khrestchatisky, M. Setting-up an In Vitro Model of Rat Blood-brain Barrier (BBB): A Focus on BBB Impermeability and Receptor-mediated Transport. J. Vis. Exp. (88), e51278, doi:10.3791/51278 (2014). AbstractThe blood brain barrier (BBB) specifically regulates molecular and cellular flux between the blood and the nervous tissue. Our aim was to develop and characterize a highly reproducible rat syngeneic in vitro model of the BBB using co-cultures of primary rat brain endothelial cells (RBEC) and astrocytes to study receptors involved in transcytosis across the endothelial cell monolayer. Astrocytes were isolated by mechanical dissection following trypsin digestion and were frozen for later co-culture. RBEC were isolated from 5-week-old rat cortices. The brains were cleaned of meninges and white matter, and mechanically dissociated following enzymatic digestion. Thereafter, the tissue homogenate was centrifuged in bovine serum albumin to separate vessel fragments from nervous tissue. The vessel fragments underwent a second enzymatic digestion to free endothelial cells from their extracellular matrix. The remaining contaminating cells such as pericytes were further eliminated by plating the microvessel fragments in puromycin-containing medium. They were then passaged onto filters for co-culture with astrocytes grown on the bottom of the wells. RBEC expressed high levels of tight junction (TJ) proteins such as occludin, claudin-5 and ZO-1 with a typical localization at the cell borders. The transendothelial electrical resistance (TEER) of brain endothelial monolayers, indicating the tightness of TJs reached 300 ohm·cm 2 on average. The endothelial permeability coefficients (Pe) for lucifer yellow (LY) was highly reproducible with an average of 0.26 ± 0.11 x 10 -3 cm/min. Brain endothelial cells organized in monolayers expressed the efflux transporter P-glycoprotein (P-gp), showed a polarized transport of rhodamine 123, a ligand for P-gp, and showed specific transport of transferrin-Cy3 and DiILDL across the endothelial cell monolayer. In conclusion, we provide a protocol for setting up an in vitro BBB model that is highly reproducible due to the quality assurance methods, and that is suitable for research on BBB transporters and receptors.

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“…In addition to this derivatization, the modified BSAs (BSA‐cyclooctyne, BSA‐KAT and BSA‐hydroxylamine) were also labeled with rhodamine OPfp 12 or fluorescein NHS 13 esters in order to visualize and distinguish the proteins in the hydrogel after immobilization ( Scheme and Fig. ) …”

Section: Resultsmentioning

confidence: 99%

Potassium Acyltrifluoroborate (KAT) Ligations are Orthogonal to Thiol‐Michael and SPAAC Reactions: Covalent Dual Immobilization of Proteins onto Synthetic PEG Hydrogels

Mazunin

Bode

2017

Helvetica Chimica Acta

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The covalent immobilization of peptides, proteins, and other biomolecules to hydrogels provides a biologically mimicking environment for cell and tissue growth. Bioorthogonal chemical reactions can serve as a tool for this, but the paucity of such reactions and mutual incompatibilities limits the number of distinct molecules that can be introduced. We now report that the potassium acyltrifluoroborate (KAT) amide‐forming ligation is orthogonal to both thiol‐Michael and strain promoted azide alkyne cycloadditions (SPAAC) and the requisite functional groups – KATs and hydroxylamines – are stable and compatible to hydrogel formation, protein modification, and post‐assembly immobilization of biomolecules onto hydrogels. In combination these ligations enables stepwise covalent protein immobilization of multiple BSA‐derivatives onto the hydrogel scaffold regardless of the order of addition.

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Chemical Optimization of New Ligands of the Low-Density Lipoprotein Receptor as Potential Vectors for Central Nervous System Targeting

Cited by 75 publications

References 65 publications

Promising Approaches to Circumvent the Blood–Brain Barrier: Progress, Pitfalls and Clinical Prospects in Brain Cancer

Promising Approaches to Circumvent the Blood–Brain Barrier: Progress, Pitfalls and Clinical Prospects in Brain Cancer

Setting-up an <em>In Vitro</em> Model of Rat Blood-brain Barrier (BBB): A Focus on BBB Impermeability and Receptor-mediated Transport

Potassium Acyltrifluoroborate (KAT) Ligations are Orthogonal to Thiol‐Michael and SPAAC Reactions: Covalent Dual Immobilization of Proteins onto Synthetic PEG Hydrogels

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