Cyclic RGD-Conjugated Hyaluronate Dot Bearing Cleavable Doxorubicin for Multivalent Tumor Targeting

In this study, we developed an extremely small-sized water-soluble hyaluronate dot (dHA) conjugated with cyclic RGD (cRGD) and cleavable doxorubicin (DOX, as a model antitumor drug), named cRGD@dHA-c-DOX. This dot with HA moieties (as specific ligands to tumor CD44 receptors) and cRGD moieties (as specific ligands to tumor integrin αvβ3) was designed to enable multivalent tumor targeting. In particular, the imine bonds, linking the DOX and dHA, can exhibit cleavage performance at endosomal pH, resulting in pH-triggered DOX release from cRGD@dHA-c-DOX. We demonstrated that cRGD@dHA-c-DOX resulted in highly improved cellular uptake and cell death in MDA-MB-231 tumor cells (CD44+, integrin αvβ3+) compared to those in Huh7 tumor cells (CD44-, integrin αvβ3-). In vivo studies using MDA-MB-231 tumor-bearing mice revealed that cRGD@dHA-c-DOX enhanced the tumor inhibition efficacy. These results suggest that cRGD@dHA-c-DOX can be utilized as a promising multivalent tumor-targeting drug carrier for highly efficient tumor treatment.