Polyrotaxanes (PRXs) are a class of supramolecular threaded macromolecules, in which cyclic molecules are threaded onto the main- or side-chain of polymers. To date, various studies have been conducted on the synthesis of PRXs, and various combinations of cyclic molecules and polymers that can form a PRX have been discovered. Among these combinations, PRXs composed of cyclodextrins (CDs) and a linear polymer have attracted much attention and have been investigated by many researchers. Because of the non-covalently associated characteristic of PRXs, these supermolecules exhibit unique properties, such as the dynamic motion of the threaded cyclic molecules along a polymer axle and complete dissociation of the supramolecular structure, that are never observed in other synthetic polymers. These inherent properties of PRXs are of interest in the design of novel biomaterials, such as hydrogels, scaffolds in tissue engineering, drug delivery carriers, and polymer–drug conjugates. Thus, various studies have been conducted to utilize PRXs as a framework for biomaterials. In this review, we describe the recent progress in biomaterial application of PRXs such as drug delivery and gene delivery.

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal trafficking disorder, in which the cholesterols are abnormally accumulated in lysosomes. Recently, the [bgr]-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 [bgr]-CD derivatives, biocleavable Pluronic/[bgr]-CD-based polyrotaxanes (PRXs) bearing terminal disulfide linkages that can release threaded [bgr]-CDs in lysosomes were developed. The biocleavable PRXs show negligible interaction with the plasma membrane, leading to avoiding the toxicity of [bgr]-CDs derived from their hydrophobic cavity. Additionally, lysosomal release of threaded [bgr]-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 [bgr]-CD derivatives. Consequently, the biocleavable PRXs is considered to be a noninvasive and effective therapeutics for NPC disease.

Niemann-Pick type C (NPC) disease is characterized by the lysosomal accumulation of cholesterols and impaired autophagic flux due to the inhibited fusion of autophagosomes to lysosomes. We have recently developed β-cyclodextrin (β-CD)-threaded biocleavable polyrotaxanes (PRXs), which can release threaded β-CDs in response to intracellular environments as a therapeutic for NPC disease. The biocleavable PRXs exhibited effective cholesterol reduction ability and negligible toxic effect compared with hydroxypropyl-β-CD (HP-β-CD). In this study, we investigated the effect of biocleavable PRX and HP-β-CD on the impaired autophagy in NPC disease. The NPC patient-derived fibroblasts (NPC1 fibroblasts) showed an increase in the number of LC3-positive puncta compared with normal fibroblasts, even in the basal conditions; the HP-β-CD treatment markedly increased the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts, indicating that autophagic flux was further perturbed. In sharp contrast, the biocleavable PRX reduced the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts through an mTOR-independent mechanism. The mRFP-GFP-LC3 reporter gene expression experiments revealed that the biocleavable PRX facilitated the formation of autolysosomes to allow for autophagic protein degradation. Therefore, the β-CD-threaded biocleavable PRXs may be promising therapeutics for ameliorating not only cholesterol accumulation but also autophagy impairment in NPC disease.

ABA block copolymers composed of highly methylated polyrotaxane and hydrophobic anchoring terminal segments containing 2-methacryloyloxyethyl phosphorylcholine (MPC) and n-butyl methacrylate (PMB) (OMe-PRX-PMB) were synthesized as a platform of molecularly dynamic biomaterials. A contact angle measurement indicated that polymer surfaces with higher molecular mobility factors (M_f) estimated from quartz crystal microbalance with dissipation (QCM-D) measurements showed more significant changes in hydrophilicity in response to an environmental change between air and water; the OMe-PRX-PMB surface showed the highest M_f among the prepared polymer surfaces. Fibrinogen adsorption and its conformational analysis estimated by QCM-D and enzyme-linked immunosorbent assay revealed that large amounts of fibrinogen adsorption occurred in a soft manner on the OMe-PRX-PMB surface and that the antibody binding to the C-terminus of the fibrinogen γ chains responsible for platelet adhesion and activation decreased as the M_f value increased. Furthermore, it was found that the OMe-PRX-PMB surface showed low platelet adhesion and high fibroblast adhesion, suggesting that molecular movement on biomaterial surfaces could be one of the key parameters in the regulation of a non-specific biological response.