Polycaprolactone/α-cyclodextrin polyrotaxanes with cellular uptake enhancing properties

Biodegradable poly(ε-caprolactone) (PCL) was rotaxanated with α-cyclodextrin (α-CD) and an α-CD/2-hydroxypropyl-α-CD (HP-α-CD) mixture. Stoppering was achieved using 2-mercaptosuccinic acid (MSA) via disulfide linkage. The structures of these polymeric supramolecular entities were confirmed by ¹H NMR, with 75-80 wt% threaded CD, while the molar mass of the polyrotaxanes was around 18 kDa, determined by gel permeation chromatography. The aqueous solubility was as low as 20.2 ± 1.2 g L^-1 for the α-CD-based polyrotaxane but considerably increased to 74.7 ± 6.0 g L^-1 by the introduction of threaded HP-α-CD into the polymeric axis. Dethreading of the polyrotaxanes was triggered by the removal of the stopper molecules via disulfide-exchange reactions using glutathione. Additionally, the polyester axis proved to be fully degradable by lipase. Cellular uptake of these polyrotaxanes was investigated by flow cytometry and confocal microscopy. The results showed an almost up to 50-fold higher cellular uptake of polyrotaxanes than free CD. These disulfide end-stoppered polyrotaxanes of biodegradable PCL represent a promising tool for intracellular delivery of CDs and offer novel treatment possibilities for lysosomal storage dysfunctions.