A Targeted and pH-Responsive Bortezomib Nanomedicine in the Treatment of Metastatic Bone Tumors

Bortezomib is a boronate proteasome inhibitor widely used as an efficient anticancer drug; however, the clinical use of bortezomib is hampered by its adverse effects such as hematotoxicity and peripheral neuropathy, and low efficacy on solid tumors due to unfavorable pharmacokinetics and poor penetration in the solid tumors. In this study, we developed a tripeptide Arg–Gly–Asp (RGD)-targeted dendrimer conjugated with catechol and poly(ethylene glycol) groups for the targeted delivery of bortezomib to metastatic bone tumors. Bortezomib was loaded on the dendrimer via a boronate–catechol linkage with pH-responsive property, which plays an essential role in the control of bortezomib loading and release. The nontargeted bortezomib nanomedicine showed minimal cytotoxicity at pH 7.4, but significantly increased anticancer activity when cyclic RGD (cRGD) moieties were anchored on the dendrimer surface. The ligand cRGD enabled efficient internalization of the bortezomib complex by breast cancer cells such as MDA-MB-231 cells. The targeted nanomedicine efficiently depressed the progression of metastatic bone tumors and significantly inhibited the tumor-associated osteolysis in a model of bone tumors. This study provided an insight into the development of nanomedicine for metastatic bone tumors.