A light-triggered self-reinforced nanoagent for targeted chemo-photodynamic therapy of breast cancer bone metastases via ER stress and mitochondria mediated apoptotic pathways

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.