Multivalent glibenclamide to generate islet specific imaging probes

Article Article scientifique Article Multivalent glibenclamide to generate islet specific imaging probes eng 2016 author Babic Andréj 742457 author Lamprianou Smaragda 689484 author Vinet Laurent 698286 author Stransky-Heilkron Nathalie Martine 649198 author Xayaphoummine Céline 736276 author Campo Molina Marino Andres 618771 author Glombik Heiner author Schulte Anke author Juretschke Hans-Paul author Montet Xavier Cédric Rodolphe 58743 author Meda Paolo 26346 author Lange Norbert 135650 1-12 10.1016/j.biomaterials.2015.10.006 26474038 0142-9612 The monitoring of diabetes mellitus, as it develops and becomes clinically evident, remains a major challenge for diagnostic imaging in clinical practice. Here we present a novel approach to beta-cell imaging by targeting the sulphonylurea receptor subtype 1 (SUR1), using multivalent derivatives of the anti-diabetic drug glibenclamide. Since glibenclamide has a high affinity for SUR1 but does not contain a suitable functional group to be linked to an imaging probe, we have synthesized 11 glibenclamide derivatives and evaluated their affinity to SUR1 in MIN6 cells. The most promising compound has been used to obtain multivalent glibenclamide-polyamidoamine (PAMAM) derivatives, containing up to 15 sulphonylurea moieties per dendrimer. The remaining functional groups on the dendrimers can consecutively be used for labeling with reporter groups for different imaging modalities, thus allowing for multifunctional imaging, and for the modification of pharmacokinetic properties. We synthesized fluorochrome-labeled multivalent probes, that demonstrate in cellular assays affinities to SUR1 in the nanomolar range, superior to native glibenclamide. The probes specifically label MIN6 cells, but not HeLa or PANC-1 cells which do not express SUR1. A very low cytotoxicity of the multivalent probes is demonstrated by the persistent release of insulin from MIN6 cells exposed to high glucose concentrations. Furthermore, the probes display positive labeling of beta-cells of primary mouse and human islet-cells ex vivo and of islets of Langerhans in vivo. The data document that multivalent probes based on glibenclamide derivatives provide a suitable platform for further developments of cell-specific probes, and can be adapted for multiple imaging modalities, including those that are now used in the clinics. Animals Cell Death/drug effects Dendrimers/chemistry Diagnostic Imaging Fluorescent Dyes/chemical synthesis/chemistry Glyburide/chemical synthesis/chemistry/pharmacology HeLa Cells Humans Islets of Langerhans/drug effects/metabolism Ligands Mice Microscopy Confocal Molecular Probes/chemistry Organ Specificity/drug effects Sulfonylurea Receptors/metabolism Dewey 576.5 Dewey 615 Dewey 616.07 Dewey 616.0757 31 Section des sciences pharmaceutiques 17 135 Département de médecine génétique et développement 21D 137 Département de pathologie et immunologie 21F 62 Département de radiologie et informatique médicale 227 false 926 Imagerie per-opératoire multi-modalité en radiologie interventionnelle 949 Biomaterials 75 b8f85c3d-7d5f-48d8-a343-c9bd5b598e9b Article (Published version) Restricted 1-s2.0-S0142961215008108-main.pdf 2131200 application/pdf restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de radiologie et informatique médicale

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Multivalent glibenclamide to generate islet specific imaging probes	Biomaterials	2016	527	0
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