Supramolecular Nanoparticles Constructed by DOX-Based Prodrug with Water-Soluble Pillar[6]arene for Self-Catalyzed Rapid Drug Release

Abstract

The constructing of novel supramolecular prodrug nanoparticles based on the host–guest interaction of water-soluble pillar[6]arene (WP6) and novel doxorubicin (DOX)-based prodrugs (G1 or G2) is reported, in which these two kinds of prodrugs are synthesized by conjugating DOX with a flexible alkyl chain or a short EGn chain via an acid-cleavable hydrazone bond. The obtained supramolecular nanoparticles are stable under physiological conditions, whereas the cumulative release of DOX is approximate to 100% within 30 min at pH 5.5 by simulating the endolysosomal environment at 37 °C. It is noteworthy that WP6 can efficiently catalyze the cleavage of hydrazone bond of the prodrug G1 or G2 via a favored intramolecular process under acidic conditions. Moreover, intracellular localization experiments demonstrated that these two nanoparticles, taken up by cancer cells via endocytosis, can lead to efficient DOX accumulation in SKOV3 cancer cells. Cytotoxicity experiments further suggest that these nanoparticles can efficiently inhibit the proliferation of cancer cells and exhibit potent antitumor activity.