A temperature-sensitive HA-anchoring supramolecular nanocarrier for targeted delivery of the anti-liver cancer drug doxorubicin

Supramolecular nanocarriers (NCs) that are capable of responding to stimuli and actively targeting specific cells have garnered significant interest in recent years. However, designing multi-stimuli responsive nanocarriers with active targeting capabilities remains a challenge. To address this issue, we developed a temperature/enzyme dual-stimuli responsive supramolecular nanocarrier (AβCD/HA NC) through the electrostatic interaction between a cationic heptakis-(6-amino-6-deoxy)-β-cyclodextrin (AβCD) and anionic hyaluronic acid (HA). The AβCD/HA NC exhibited temperature/enzyme co-triggered assembly/disassembly behavior, which facilitated the loading, delivery, and release of the first-line anti-liver cancer drug doxorubicin (DOX). The release rate of DOX from the DOX-loaded AβCD/HA NC was found to be 82.4% at T = 45 °C and with the addition of hyaluronidase (HAase). During the uptake studies conducted on SMMC-7721 liver cancer cells, it was observed that the AβCD/HA NC significantly enhances the intracellular uptake of DOX, and the DOX present in the NC can efficiently be delivered to the cell nucleus. The cellular viability assay (MTS) demonstrated that the DOX-loaded NC not only provided a better inhibitory effect on SMMC-7721 liver cancer cells than free DOX and cisplatin, but also exhibited only one-tenth of the cytotoxicity of free DOX in BEAS-2B normal human epithelial cells. Our findings suggest that the AβCD/HA NC holds great promise for the targeted treatment of liver cancer cells. The anti-liver cancer nanocarrier (AβCD/HA NC) was equipped with both HAase and temperature sensitivity, which could effectively and actively target specific cells, thus promising for targeted therapy of liver cancer cells.