Acid-Induced Intracellular Dissociation of β‑Cyclodextrin-Threaded Polyrotaxanes Directed toward Attenuating Phototoxicity of Bisretinoids through Promoting Excretion

• Published in: Molecular pharmaceutics Vol. 14; no. 12; pp. 4714 - 4724
• Main Authors: Tamura, Atsushi, Ohashi, Moe, Nishida, Kei, Yui, Nobuhiko
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 04-12-2017
• Subjects: Acids - chemistry; beta-Cyclodextrins - chemistry; beta-Cyclodextrins - pharmacology; beta-Cyclodextrins - therapeutic use; Cell Line; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Humans; Hydrogen-Ion Concentration; Macular Degeneration - drug therapy; Macular Degeneration - pathology; Photosensitivity Disorders - drug therapy; Photosensitivity Disorders - pathology; Retinal Pigment Epithelium - cytology; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Retinoids - chemistry; Retinoids - metabolism; Retinoids - toxicity; Rotaxanes - chemistry; Rotaxanes - pharmacology; Rotaxanes - therapeutic use; triphenylmethyl group; phototoxicity; retinoid; age-related macular degeneration; polyrotaxane; cyclodextrin
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.7b00859

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.