Abstract
Current therapeutic strategies for the treatment of bone metastases are often limited by the lack of selectivity, severe systemic toxicity and suboptimal efficacy. Nanomedicine meditated chemo-photodynamic therapy provides a promising therapeutic opportunity for enhanced cancer therapy. Herein, we constructed an alendronate (ALN)-functionalized bone-seeking nanoagent (BTZ@ZnPc-ALN) to co-deliver the proteasome inhibitor bortezomib (BTZ) and the photosensitizer Zinc phthalocyanine (ZnPc) for synergistic chemo-photodynamic therapy of bone metastases. Results showed that BTZ@ZnPc-ALN possessed favorable bone affinity both in vitro and in vivo and could release drug in a pH-responsive manner. Under irradiation, BTZ@ZnPc-ALN could generate reactive oxygen species (ROS) to cause mitochondrial damage, and increase the cytosolic Ca2+ levels and the expression of GRP78 protein to induce excessive endoplasmic reticulum (ER) stress, thereby synergistically inhibiting cell proliferation. More importantly, BTZ@ZnPc-ALN could prolong blood circulation time and preferentially navigate to the bone affected site. As a result, tumor growth was significantly inhibited by bone targeted chemo-photodynamic therapy, with tumor volume cut down by 85% compared with PBS group and bone remained undamaged. Besides, the systemic toxicity of BTZ was significantly reduced. Therefore, the versatile nanoagent is expected to be a promising nanoplatform to concern multiple intracellular stress for remarkable synergistic chemo-photodynamic therapy of bone metastases.