Lysosomal-specific Cholesterol Reduction by Biocleavable Polyrotaxanes for Ameliorating Niemann-Pick Type C Disease

Abstract

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal trafficking disorder, in which the cholesterols are abnormally accumulated in lysosomes. Recently, the β-cyclodextrin (CD) derivatives are revealed to show therapeutic effect for NPC disease through the removal of accumulated cholesterols in lysosomes. Herein, to enhance the therapeutic effect and reduce the toxicity of β-CD derivatives, biocleavable Pluronic/β-CD-based polyrotaxanes (PRXs) bearing terminal disulfide linkages that can release threaded β-CDs in lysosomes were developed. The biocleavable PRXs show negligible interaction with the plasma membrane, leading to avoiding the toxicity of β-CDs derived from their hydrophobic cavity. Additionally, lysosomal release of threaded β-CDs from biocleavable PRXs by the intracellular cleavage of terminal disulfide linkages is found to achieve approximately 100-fold higher cholesterol removal ability from NPC disease-derived cells than β-CD derivatives. Consequently, the biocleavable PRXs is considered to be a noninvasive and effective therapeutics for NPC disease.

Lysosomal pH-inducible supramolecular dissociation of polyrotaxanes possessing acid-labile N-triphenylmethyl end groups and their therapeutic potential for Niemann-Pick type C disease

“…[24–26] We have previously reported that biocleavable PRXs composed of an axle polymer bearing intracellularly cleavable linkers, threading β-CDs, and bulky stopper molecules are able to dissociate in intracellular environments (Figure 1). [27] Our previous reports demonstrate that the PRX structure masks the toxic effect of β-CDs because the hydrophobic cavity of threaded β-CDs is occupied by a linear polymer chain to perturb the interaction with the plasma membranes (i.e. cholesterol in membranes).…”

“…This local release of abundant β-CDs from the biocleavable PRXs leads to cholesterol reducing ability at a 100-fold lower concentration of clinically studied HP-β-CD and improvements in the impaired autophagy in NPC disease-derived cells. [27,28] Therefore, the biocleavable PRXs are expected to be promising noninvasive and effective therapeutics for the treatment of NPC disease.…”

“…To date, various cleavable linkers, such as reduction-cleavable disulfide linkages,[27–29] pH-cleavable ester linkages,[30,31] and acid-cleavable hydrazone and ketal linkages,[32–34] have been introduced into the axle polymer of the PRXs to acquire stimuli-dependent dissociative characteristics. Among these, acid-cleavable linkages are of interest to induce lysosomal dissociation of the PRXs because the pH value in lysosomes is maintained at approximately 4.5 to 5.0 by the influx of protons through vacuolar-type H + -ATPase (V-ATPase).…”

“…[27,28,34] It is known that the Trt group is used as a protective group for hydroxyl, thiol, and primary amino groups and is usually deprotected under strongly acidic conditions. [38] However, we found that the N -Trt end groups in PRXs were cleaved under mildly acidic pH conditions, such as conditions near lysosomal pH (i.e.…”

Potential Use of Cyclodextrins as Drug Carriers and Active Pharmaceutical Ingredients

“…For example, Thompson and colleagues 60,61) demonstrated that pluronic-based β-CyD polyrotaxanes as well as HP-β-CyD polyrotaxanes may be promising vehicles for delivery of β-CyD and HP-β-CyD for mobilization of accumulated cholesterol from NPC fibroblasts. Moreover, Tamura and Yui 62,63) reported that β-CyD-threaded biocleavable polyrotaxanes ameliorate impaired autophagic flux in NPC. Taken together, these supramolecules may have potentials as novel drugs for the treatment of NPC.…”