Cyclic RGD peptides target human trabecular meshwork cells while ameliorating connective tissue growth factor-induced fibrosis
Cyclic RGD peptides target human trabecular meshwork cells while ameliorating connective tissue growth factor-induced fibrosis
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DOI：
10.3109/1061186x.2016.1163709
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发表时间：
2016-01-01
影响因子：
4.5
通讯作者：
Fuchshofer, Rudolf
中科院分区：
文献类型：
--
作者：
Hennig, Robert;Kuespert, Sabrina;Fuchshofer, Rudolf
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 的病理变化部分是由结缔组织生长因子 (CTGF) 等生长因子介导的。 TM细胞的特异性靶向可以通过提高纳米粒子的治疗功效来发挥关键的临床作用，例如用于非病毒基因传递。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α（v）β（3）和α（v）β（5）整合素结合而被快速有效地内吞。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 细胞的关联显着更高。 TM 细胞的结合和摄取是受体介导的，并且可以用游离肽抑制。可溶性环状 RGD 肽可有效减弱 CTGF 介导的作用并抑制 CTGF 信号传导。由于它们对 α(v)β(3) 和 α(v)β(5) 整联蛋白具有拮抗作用，这些环状 RGD 五肽有效改善了 CTGF 诱导的效应，并强烈促进了特定的纳米颗粒缔合。因此，环状 RGD 肽是强大的多功能配体，既可以将纳米材料定位到 TM，又可以在到达时干扰病理性 CTGF 信号传导。
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 alpha(v)beta(3) and alpha(v)beta(5) 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 alpha(v)beta(3) and alpha(v)beta(5) 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.