Efficient ocular drug delivery to the posterior segment of the eye by topical administration is a great challenge to pharmacologists. To explore drug delivery system of organic-inorganic hybrid nanocomposites for the efficient delivery of dexamethasone disodium phosphate (DEXP), a targeted hybrid nanocomposite based on layered double hydroxide (LDH) and functional carboxymethyl chitosan (CMCS) derivatives was designed. A special substrate of peptide transporter-1 (PepT-1) and glutathione was modified on CMCS. CMCS-glutathione-glycylsarcosine (CMCG-GS) and CMCS-glutathione-valyl-valine (CMCG-VV)-LDH hybrid nanocomposites were prepared and structurally confirmed. The in vitro experiments on human conjunctival epithelial cells showed noncytotoxicity (LDH concentration ≤100.0 µg/mL) and enhanced permeability for hybrid nanocomposites. Additionally, cellular uptake of the CMCG-GS-DEXP-LDH (10:1) nanocomposite eye drops involved clathrin-mediated endocytosis and PepT-1 mediated actively targeting transport. Results of the in vivo precorneal retention study showed an 8.35-fold, 2.87-fold and 2.58-fold increase of AUC0-6 h, Cmax and MRT for CMCG-GS-DEXP-LDH (10:1) hybrid nanocomposite eye drops, respectively, compared to that of the commercial product. Fluorescence imaging of fluorescein isothiocyanate isome (FITC)-loaded LDH hybrid nanocomposites demonstrated that FITC could diffuse into the choroid-retina with the shelter of LDH and CMCG-GS. The presence of a strong fluorescence signal of FITC-conjugated LDH hybrid nanocomposites in the sclera revealed that integral LDH nanocarrier reached the sclera. In the tissue distribution evaluation of rabbit's eyes, DEXP of CMCG-GS-DEXP-LDH (10:1) nanocomposites group retained in the target of the choroid-retina for 3 h with final concentration at 120.04 ng/g. Furthermore, the results of fluorescence imaging and tissue distribution suggested that the intraocular transport pathway for the hybrid nanocomposites is the conjunctival-scleral route. Consequently, the developed hybrid nanocomposites offer a simple and efficient strategy for topically administered drug delivery to the posterior segment of the eye. STATEMENT OF SIGNIFICANCE: Efficient ocular drug delivery to the posterior segment of the eye by topical administration is a great challenge to pharmacologists. In this manuscript, hybrid nanocomposite based on layered double hydroxide (LDH) and functional carboxymethyl chitosan (CMCS) derivatives were designed. The multifunctional properties of these hybrid nanocomposites were attributed to active targeting, bioadhesive capacity and penetration enhancement. Visualization of transport routes of fluorescein isothiocyanate-conjugated LDH hybrid nanocomposites demonstrated that the integral LDH nanocarrier reached the sclera through the conjunctival-scleral pathway, and the loaded drug could further diffuse to the retina. The multifunctional CMCS derivatives-LDH hybrid nanocomposites could be applied for the efficient drug delivery to the posterior segment of the eye through noninvasive topical instillation.

中文翻译：

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多功能羧甲基壳聚糖衍生物层状双氢氧化物杂化纳米复合材料，可有效地将药物递送至眼后段。

通过局部给药将眼药有效地递送到眼睛的后段对药理学家是巨大的挑战。为了探索有机-无机杂化纳米复合材料的药物递送系统，以有效地递送地塞米松磷酸二钠（DEXP），设计了一种基于层状双氢氧化物（LDH）和功能性羧甲基壳聚糖（CMCS）衍生物的靶向杂化纳米复合材料。在CMCS上修饰了肽转运蛋白1（PepT-1）和谷胱甘肽的特殊底物。制备了CMCS-谷胱甘肽-糖基肌氨酸（CMCG-GS）和CMCS-谷胱甘肽-缬氨酸-缬氨酸（CMCG-VV）-LDH杂化纳米复合材料。在人结膜上皮细胞上进行的体外实验显示出无细胞毒性（LDH浓度≤100.0µg / mL）并提高了杂化纳米复合材料的通透性。另外，细胞对CMCG-GS-DEXP-LDH（10：1）纳米复合滴眼液的吸收涉及网格蛋白介导的内吞作用和PepT-1介导的主动靶向转运。体内角膜前保留研究的结果显示，CMCG-GS-DEXP-LDH（10：1）杂合纳米复合滴眼液的AUC0-6 h，Cmax和MRT分别增加了8.35倍，2.87倍和2.58倍。与商业产品相比。负载异硫氰酸荧光素（FITC）的LDH杂化纳米复合材料的荧光成像表明，FITC可以通过LDH和CMCG-GS的掩体扩散到脉络膜视网膜中。巩膜中FITC共轭LDH杂合纳米复合材料的强荧光信号的存在表明完整的LDH纳米载体到达巩膜。在兔眼的组织分布评估中，CMCG-GS-DEXP-LDH的DEXP（10：1）纳米复合物组保留在脉络膜视网膜靶中3 h，最终浓度为120.04 ng / g。此外，荧光成像和组织分布的结果表明，杂化纳米复合材料的眼内转运途径是结膜-巩膜途径。因此，开发的杂化纳米复合材料为将药物局部给药至眼后段提供了一种简单有效的策略。意义声明：通过局部给药将眼药有效地递送到眼睛的后段，对药理人员来说是一个巨大的挑战。在该手稿中，设计了基于层状双氢氧化物（LDH）和功能性羧甲基壳聚糖（CMCS）衍生物的杂化纳米复合材料。这些杂化纳米复合材料的多功能特性归因于主动靶向，生物粘附能力和渗透增强。荧光素异硫氰酸酯共轭LDH杂合纳米复合材料的运输路线的可视化表明，完整的LDH纳米载体通过结膜-巩膜途径到达巩膜，并且负载的药物可以进一步扩散到视网膜。多功能CMCS衍生物-LDH杂化纳米复合材料可用于通过无创局部滴注将药物有效递送至眼后段。荧光素异硫氰酸酯共轭LDH杂合纳米复合材料的运输路线的可视化表明，完整的LDH纳米载体通过结膜-巩膜途径到达巩膜，并且负载的药物可以进一步扩散到视网膜。多功能CMCS衍生物-LDH杂化纳米复合材料可用于通过无创局部滴注将药物有效递送至眼后段。荧光素异硫氰酸酯共轭LDH杂合纳米复合材料的运输路线的可视化表明，完整的LDH纳米载体通过结膜-巩膜途径到达巩膜，并且负载的药物可以进一步扩散到视网膜。多功能CMCS衍生物-LDH杂化纳米复合材料可用于通过无创局部滴注将药物有效递送至眼后段。