Cholesterol-Lowering Effect of Octaarginine-Appended β-Cyclodextrin in <i>Npc1</i>-Trap-CHO Cells

Abstract

Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder, which is an inherited disease characterized by the accumulation of unesterified cholesterol in endolysosomes. Recently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) has been used for the treatment of NPC, and ameliorated a hepatosplenomegaly in the patients. However, to obtain the treatment efficacy, a high dose of HP-β-CyD was necessary. Therefore, the decrease in dose by using active intracellular delivery system of β-CyD to NPC cells is expected. In this study, to efficiently deliver β-CyD to NPC-like cells, we newly synthesized octaarginine (R8)-appended β-CyD with a spacer of γ-aminobutyric acid (R8-β-CyD) and evaluated its cytotoxicity, intracellular distribution, endocytosis pathway and cholesterol-lowering effect in Npc1-trap-Chinese hamster ovary (CHO) cells, cholesterol-accumulated cells through the impairment of NPC1 function. R8-β-CyD did not show cytotoxicity in the cells. In addition, Alexa568-labeled R8-β-CyD was actively internalized into Npc1-trap-CHO cells, possibly through micropinocytosis. Notably, R8-β-CyD significantly decreased intracellular cholesterol content compared with HP-β-CyD. These results suggest that R8-β-CyD may be a promising therapeutic agent for ameliorating cholesterol accumulation in NPC.

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

“…Indeed, the octaarginine-appended β-cyclodextrin (R8-β-CD) has recently been tested in vitro in cells where cholesterol gets accumulated into CHO cells through the impairment of the NPC1 function. R8-β-CD displayed no cell toxicity, was endocytosed within the cell via its peptide moiety (R8) and was able to efficiently reduce intracellular cholesterol pool [57].…”

Cyclodextrin-Based Molecular Accessories for Drug Discovery and Drug Delivery

“…Recently, CyDs and their derivatives are expected as APIs against various diseases such as Niemann-Pick disease type C (NPC), [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] Alzheimer's disease, [53][54][55][56][57][58] leukemia, 59) cerebral ischemic injury, 60) chronic renal failure, 61) hyperlipidemia, 62) atherosclerosis, 63) AIDS, 64,65) diabetic kidney disease, 66) influenza, 67) sterility, [68][69][70] peripheral artery disease, 71) bacterial growth, 72) solid cancers, [73][74][75][76][77][78] GM1-gangliosidosis, 79) septic shock, [80][81][82] α-synucleinopathy, 83) hypervitaminosis, 84) and transthyretin-related familial amyloidotic polyneuropathy (FAP).…”

Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules

“…Recently, various bioactivities of CyDs have been demonstrated, and CyDs have been used as active pharmaceutical ingredients (APIs) against Niemann-Pick disease type C (NPC), [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] leukemia, 77) hyperlipidemia, 78) Alzheimer's disease, [79][80][81][82][83][84] cerebral ischemic injury, 85) atherosclerosis, 86) diabetic kidney disease, 87) chronic renal failure, 88) AIDS, 89,90) influenza, 91) peripheral artery disease, 92) sterility, [93][94][95] solid cancers, [96][97][98][99][100][101] bacterial growth, 102) α-synucleinopathy, 103) GM1-gangliosidosis, 104) septic shock, [105][106][107] hypervitaminosis, 108) and transthyretin-related familial amyloidotic polyneuropathy (FAP) …”