Bone-targeted oxidative stress nanoamplifier for synergetic chemo/chemodynamic therapy of bone metastases through increasing generation and reducing elimination of ROS

Abstract

The treatment of bone metastases remains an enormous challenge in clinical application. Strategies utilizing reactive oxygen species (ROS) to induce cell death show great potential for enhanced cancer therapy. Thus, for the first time, a versatile alendronate (ALN)-functionalized and cinnamaldehyde (CA)-loaded nanoscale coordination polymer (denoted as CA/ALN@FcB) based on 1,1′-ferrocenedicarboxylicacid (Fc) and L-buthionine-sulfoximine (BSO) was properly fabricated as an oxidative stress nanoamplifier for synergetic chemo/chemodynamic therapy of bone metastases. With appropriate size and strong bone affinity of ALN, CA/ALN@FcB can preferentially accumulate in the bone metastatic site. In this nanoamplifier, CA can act as the ROS generator to produce ROS to damage cancer cells and boost intracellular hydrogen peroxide (H2O2) level, which can be converted into hydroxyl radical (•OH) with the catalysis of Fc via Fenton reaction. Simultaneously, glutathione (GSH) depletion mediated by BSO can inhibit ROS elimination to maintain H2O2 level and •OH amount, ultimately leading to superior antitumor effect. Both in vitro and in vivo results demonstrated the self-enhanced synergetic chemo/chemodynamic therapy of CA/ALN@FcB. Such a nanoamplifier can generate and maintain sufficient ROS without the introduced external light triggering, exactly addressing the dilemma posed by fewer light penetration as well as the uncertain location of bone metastases. This study not only provides a novel strategy to achieve excellent cancer therapy by boosting ROS generation and simultaneously inhibiting ROS elimination, but also creates the precedent for the application of chemodynamic therapy for bone metastases treatment.