Supermolecule—Drug Conjugates Based on Acid-Degradable Polyrotaxanes for pH-Dependent Intracellular Release of Doxorubicin

Abstract

Doxorubicin (DOX)-conjugated acid-degradable polyrotaxanes (PRXs) were designed as supramolecular drug carriers capable of releasing drugs in acidic cellular environments. Acid-degradable PRXs composed of α-cyclodextrin (α-CD) as a cyclic molecule, poly(ethylene glycol) (PEG) as a polymer axis, and N-triphenylmethyl (N-Trt) groups as an acid-labile stopper molecules were synthesized and DOX was conjugated with the threaded α-CDs in the PRXs. Because the acid-induced cleavage of N-Trt groups in PRXs leads to PRX dissociation, the DOX-modified α-CDs were released under acidic conditions (pH 5.0). The cytotoxicity of DOX-conjugated PRXs in colon-26 cells revealed significant cell death for DOX-conjugated PRXs after 48 h of treatment. Confocal laser scanning microscopy (CLSM) analysis revealed that the fluorescence signals derived from DOX-conjugated PRXs were observed in cellular nuclei after 48 h, suggesting that the DOX-modified α-CDs were released and accumulated in cellular nuclei. These results confirmed that acid-degradable PRXs can be utilized as drug carriers capable of releasing drug-modified α-CDs in acidic lysosomes and eliciting cytotoxicity. Overall, acid-degradable PRXs represent a promising supramolecular framework for the delivery and intracellular release of drug-modified α-CDs, and PRX–drug conjugates are expected to contribute to the development of pH-responsive drug carriers for cancer therapy.

Supramolecular nanoarchitectonics of propionylated polyrotaxanes with bulky nitrobenzyl stoppers for light-triggered drug release

“…Our group has developed anticancer drug-conjugated acid-degradable PRXs to promote the intracellular release of anticancer drugs. 35 However, the cytotoxicity of drug-conjugated PRX is lower than that of free drugs, presumably because the number of modified drugs on PRX is limited. In contrast, photodegradable Pr-PD-PRX can encapsulate large amount of hydrophobic drugs in the hydrophobic domain and release all drugs upon UV irradiation.…”

Suppression of Supramolecular Disassembly of Pseudopolyrotaxane Nanosheet by End-Capping via Amine–Epoxy Click Reaction of Bifunctional Epoxy

“…Harada et al reported that PR could be synthesized using a simple method by capping the axis ends of an inclusion complex of CD and linear polymers . Since then, CD-based PR and PPR have been extensively studied. − CD-based PRs enhance the mechanical properties of polymer materials owing to their ring mobility along the axis. ,, Yui et al reported the stimulation-triggered release of CDs from axis polymers, which can be used in drug delivery systems (DDSs). , The axis-end structure of CD-based PR and PPR is important for threading, holding, and releasing the CDs. ,,, …”

“…23,25,26 Yui et al reported the stimulation-triggered release of CDs from axis polymers, which can be used in drug delivery systems (DDSs). 13,27 The axis-end structure of CD-based PR and PPR is important for threading, holding, and releasing the CDs. 13,21,28,29 Recently, we reported a series of CD-based topological supramolecular nanosheets called pseudopolyrotaxane nanosheets (PPRNSs) (Figure 1a).…”