In the retinal pigment epithelium of patients with age-related macular degeneration (AMD), excess N-retinylidene-N-retinylethanolamine (A2E), a dimer of all-trans-retinal, accumulats to induce inflammatory cytokine secretion and phototoxic effects. Therefore, the reduction of intracellular A2E is a promising approach for the prevention and treatment of AMD. In this study, acid-labile β-cyclodextrin (β-CD)-threaded polyrotaxanes (PRXs) were synthesized and investigated their effects on the removal of A2E accumulated in retinal pigment epithelium cells (ARPE-19) in comparison to nonlabile PRXs and 2-hydroxypropyl β-CD (HP-β-CD) were examined. GC-MS and HPLC studies strongly suggest that the acid-labile PRXs dissociated into their constituent molecules in cells by lysosomal acidification and threaded β-CDs were considered to be released from the PRXs. The released β-CDs formed an inclusion complex with A2E, which promoted the excretion of A2E. Indeed, the acid-labile PRXs effectively reduced intracellular A2E level at approximately a 10-fold lower concentration than HP-β-CD. Accompanied with A2E removal, the toxicity and phototoxicity of A2E were attenuated by treatment with acid-labile PRXs. Because the nonlabile PRX failed to reduce intracellular A2E level and attenuate phototoxicity, intracellular release of threaded β-CDs from the acid-labile PRX might contribute to reducing intracellular A2E. We conclude that acid-labile PRXs are promising candidates for the treatment of macular diseases through the removal of toxic metabolites.

中文翻译：

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酸诱导的β-环糊精-螺纹聚轮烷的细胞内解离，旨在通过促进排泄来减轻类视黄醇的光毒性。

在患有年龄相关性黄斑变性（AMD）的患者的视网膜色素上皮中，过量的N-维甲酸-N-维甲酸乙醇胺（A2E）是全反式的二聚体-视网膜，累积诱导炎症性细胞因子分泌和光毒性作用。因此，减少细胞内A2E是预防和治疗AMD的有前途的方法。在这项研究中，合成了酸不稳定的β-环糊精（β-CD）螺纹聚轮烷（PRXs），并研究了与不稳定的PRX和2相比，它们对去除视网膜色素上皮细胞（ARPE-19）中积累的A2E的影响。检查了-羟丙基β-CD（HP-β-CD）。GC-MS和HPLC研究强烈表明，通过溶酶体酸化作用，酸不稳定的PRX在细胞中解离成其组成分子，并且认为带线的β-CD从PRX释放。释放的β-CD与A2E形成包合物，从而促进A2E的排泄。确实，酸不稳定的PRX可以有效降低细胞内A2E水平，其浓度比HP-β-CD低约10倍。伴随着A2E的去除，酸不稳定的PRX可以减弱A2E的毒性和光毒性。由于不稳定的PRX无法降低细胞内A2E的水平并减弱光毒性，因此从酸不稳定的PRX内释放线状β-CD可能会有助于降低细胞内的A2E。我们得出结论，酸不稳定的PRXs通过去除有毒代谢物，有望成为治疗黄斑疾病的有前途的候选药物。由于不稳定的PRX无法降低细胞内A2E的水平并减弱光毒性，因此从酸不稳定的PRX内释放线状β-CD可能会有助于降低细胞内的A2E。我们得出结论，酸不稳定的PRXs通过去除有毒代谢物，有望成为治疗黄斑疾病的有前途的候选药物。由于不稳定的PRX无法降低细胞内A2E的水平并减弱光毒性，因此从酸不稳定的PRX内释放线状β-CD可能会有助于降低细胞内的A2E。我们得出结论，酸不稳定的PRXs通过去除有毒代谢物，有望成为治疗黄斑疾病的有前途的候选药物。