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 α_vβ₃) 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 α_vβ₃+) compared to those in Huh7 tumor cells (CD44-, integrin α_vβ₃-). 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.