Biopolymers, Bio-related Polymer Materials

Rational design of stimuli-cleavable polyrotaxanes for therapeutic applications


Polyrotaxanes (PRXs), comprising many cyclic molecules threaded onto a linear polymer chain capped with bulky stopper molecules, have attracted considerable attention in the design of biomaterials. If cleavable linkages are included between the axle polymer terminals and bulky stopper molecules, PRXs acquire a stimuli-responsive dissociation ability. Such stimuli-cleavable PRXs can dissociate into their constituent molecules in response to various chemical and physical stimuli, such as the reductive intracellular environment and the acidic lysosomal environment. In this focus review, the basic principle of stimuli-cleavable PRX design and characteristics of stimuli-cleavable PRXs as drug delivery carriers are described. Additionally, recent progress in the use of β-cyclodextrin-threaded stimuli-cleavable PRXs as a therapeutic agent for treating Niemann–Pick-type C (NPC) disease, a family of lysosomal storage disorders characterized by lysosomal accumulation of cholesterol, is described. The lysosomal release of threaded β-cyclodextrins from PRXs leads to the formation of an inclusion complex with the cholesterols that accumulate in NPC disease, promoting extracellular excretion of cholesterols. Interestingly, these stimuli-cleavable PRXs improve impaired autophagic functions in NPC disease in addition to reducing cholesterol. Therefore, stimuli-cleavable PRXs are promising candidates for the treatment of intractable metabolic disorders.

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This work was financially supported by a Grant-in-Aid for Young Scientists (A) from the Japan Society for the Promotion of Science (JSPS) (No 16H05910, to AT); Grant-in-Aid for Young Scientists (B) from JSPS (No 26750155, to AT); Azuma Medical & Dental Research Grant (to AT).

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Correspondence to Atsushi Tamura.

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Tamura, A., Yui, N. Rational design of stimuli-cleavable polyrotaxanes for therapeutic applications. Polym J 49, 527–534 (2017).

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