Hennig Robert, Kuespert Sabrina, Haunberger Alexandra, Goepferich Achim, Fuchshofer Rudolf
a Department of Pharmaceutical Technology , University of Regensburg , Regensburg , Germany.
b Department for Human Anatomy and Embryology , University of Regensburg , Regensburg , Germany.
J Drug Target. 2016 Dec;24(10):952-959. doi: 10.3109/1061186X.2016.1163709. Epub 2016 Mar 27.
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 αβ and αβ integrins. 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.
原发性开角型青光眼的主要危险因素是小梁网（TM）区域流出阻力升高导致的眼压升高。整合素通过影响TM的生物学特性和生长因子信号传导在TM中发挥关键作用。TM的病理变化部分由结缔组织生长因子（CTGF）等生长因子介导。特异性靶向TM细胞可能通过提高纳米颗粒的治疗效果发挥关键的临床作用，例如用于非病毒基因递送。表面共价固定有环（RGDfC）的量子点有效地靶向培养的TM细胞，并通过与αβ和αβ整合素结合而迅速有效地被内吞。与整合素过表达的U87-MG细胞系相比，RGD修饰的纳米颗粒与TM细胞的结合显著更高。TM细胞的结合和摄取是受体介导的，可被游离肽抑制。可溶性环RGD肽有效地减弱了CTGF介导的作用并抑制了CTGF信号传导。由于它们对αvβ3和αvβ5整合素的拮抗作用，这些环RGD五肽有效地改善了CTGF诱导的作用并强烈促进了特异性纳米颗粒结合。因此，环RGD肽是强大的多功能配体，既可以将纳米材料靶向到TM，又可以在到达后干扰病理性CTGF信号传导。
