Oligo(ethylene glycol)-modified β-cyclodextrin-based polyrotaxanes for simultaneously modulating solubility and cellular internalization efficiency.

We developed stimuli-labile polyrotaxanes (PRXs) composed of β-cyclodextrin (β-CD), Pluronic as an axle polymer, and acid-cleavable N-triphenylmethyl groups as bulky stopper molecules, and found that the PRXs are potent therapeutics for Niemann-Pick type C disease, because the PRX can effectively reduce intracellular cholesterol through the intracellular release of threaded β-CDs. In general, the PRXs need to be chemically modified with hydrophilic functional groups because PRXs are not soluble in aqueous media. Herein, four series of oligo(ethylene glycol)s (OEGs) with different ethylene glycol repeating unit (2 or 3) and chemical structure of OEG terminal (hydroxy or methoxy) were modified onto the threaded β-CDs in PRX. The effects of the structure of OEG on the aqueous solubility, toxicity, and cellular internalization efficiency of OEG-modified PRXs were investigated to optimize the chemical structure of OEG. The hydroxy-terminated OEG-modified PRXs showed excellent solubility in aqueous media and no toxicity, regardless of the number of ethylene glycol repeating units. In the case of the methoxy-terminated OEG-modified PRXs, sufficient solubility in aqueous media and negligible toxicity were observed when the number of ethylene glycol repeating units was 3, while low solubility and toxicity were observed when the ethylene glycol repeating unit was 2. Additionally, cellular uptake levels of methoxy-terminated OEG-modified PRXs in RAW264.7 cells were higher than those of hydroxy-terminated OEG-modified PRXs. Consequently, the chemical structure of the OEG strongly affects the chemical and biological properties of the PRXs, and that a methoxy-terminated OEG with 3 ethylene glycol repeating units is the most preferable modification of PRXs, since the resultant PRX is sufficiently soluble in aqueous media, non-toxic, and possesses high cellular internalization efficiency.