title: Cyclic RGD peptides target human trabecular meshwork cells while ameliorating connective tissue growth factor-induced fibrosis.
abstract: The major risk factor for primary open-angle glaucoma is increased intraocular pressure stemming from elevated outflow resistance in the trabecular meshwork (TM) region. Integrins play a pivotal role in the TM by influencing its biological properties and growth factor signaling. Pathologic changes in the TM are partially mediated by growth factors like connective tissue growth factor (CTGF). Specific targeting of TM cells could play a critical clinical role by increasing the therapeutic efficacy of nanoparticles, e.g. for nonviral gene delivery. Quantum dots with cyclo(RGDfC) covalently immobilized to their surface effectively targeted cultured TM cells and were rapidly and efficiently endocytosed by binding to αvβ3and αvβ5integrins. Compared to the integrin-overexpressing U87-MG cell line, the association of RGD-modified nanoparticles with the TM cells was significantly higher. Binding and uptake into TM cells was receptor-mediated and suppressible with free peptide. Soluble cyclic RGD peptides effectively attenuated CTGF-mediated effects and inhibited CTGF signaling. Due to their antagonism for αvβ3 and αvβ5 integrins, these cyclic RGD pentapeptides effectively ameliorated the CTGF-induced effects and strongly promoted specific nanoparticle association. Thus, cyclic RGD peptides are powerful multifunctional ligands for both addressing nanomaterials to the TM and interfering with pathologic CTGF signaling upon arrival.
authors.affiliation: a Department of Pharmaceutical Technology , University of Regensburg , Regensburg , Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Hennig
authors.affiliation: b Department for Human Anatomy and Embryology , University of Regensburg , Regensburg , Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kuespert
authors.affiliation: a Department of Pharmaceutical Technology , University of Regensburg , Regensburg , Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Haunberger
authors.affiliation: a Department of Pharmaceutical Technology , University of Regensburg , Regensburg , Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Goepferich
authors.affiliation: b Department for Human Anatomy and Embryology , University of Regensburg , Regensburg , Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Fuchshofer
mesh_terms: D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors*; D004337:Drug Carriers / Q000737:chemistry*; D004705:Endocytosis; D005355:Fibrosis; D005434:Flow Cytometry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D018613:Microscopy, Confocal; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D011485:Protein Binding; D045663:Quantum Dots / Q000737:chemistry*; D019030:Receptors, Vitronectin / Q000378:metabolism; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*
chemical_list: D004337:Drug Carriers; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; C507169:cyclic arginine-glycine-aspartic acid peptide; C064660:integrin alphaVbeta5; D055513:Connective Tissue Growth Factor
keywords: CTGF; active targeting; cyclo(RGDfC); gene delivery; glaucoma; nanoparticles; quantum dots; receptor-mediated endocytosis; αvβ3 integrin