Acid-labile polyrotaxane exerting endolysosomal pH-sensitive supramolecular dissociation for therapeutic applications

Abstract

pH-sensitive polymeric materials are rational designs for therapeutics, because they can change their intrinsic properties selectively in response to pH changes in targeted tissues and organelles, such as tumor tissue, skin, inflammation sites, and intracellular endosomes and lysosomes. Herein, we describe a novel acid-labile Pluronic/β-cyclodextrin (β-CD)-based polyrotaxane (PRX) showing the dissociation of supramolecular interlocked structures in response to a pH change with a narrow acidic range for biomedical applications. Acid cleavable ketal linkages were introduced into both terminals of the axle polymer of the PRX (ket-PRX) to acquire acid sensitivity. The ket-PRX was sufficiently stable and maintained its supramolecular structure under physiological conditions (pH 7.4), whereas the dissociation of the ket-PRX was observed under weakly acidic pH conditions (pH 5.0) due to the cleavage of the ketal linkages. Concomitant with this supramolecular dissociation it was found that the ket-PRX released β-CDs to form an inclusion complex with guest molecules specifically under weakly acidic pH conditions. As one of the possible intracellular therapeutic applications, it was confirmed that the ket-PRX showed superior reduction of lysosomal cholesterols in Niemann–Pick type C disease in comparison with β-CD derivatives, presumably due to the local release of β-CDs from the ket-PRX in response to the weakly acidic pH in endosomes and/or lysosomes. Altogether with these results, it is concluded that the ket-PRX exerting pH-sensitive dissociation is an attractive candidate as a potential therapeutic biomaterial.