Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200011, People's Republic of China.
State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences , Shanghai 200050, People's Republic of China.
ACS Nano. 2017 Jul 25;11(7):7259-7273. doi: 10.1021/acsnano.7b03197. Epub 2017 Jul 13.
The early detection and thus treatment of breast cancer bone metastasis remain a big challenge clinically. As the most abundant cells within bone tissue, osteocytes have been found to manipulate the activity of early cancer bone metastasis by its crosstalk with cancer cells and osteoclasts. However, conventional bone-targeting nanomedicine has limited bone-lesion specificity and ignores the vital role of osteocytes during breast cancer bone metastasis. Also, it lacks detailed insight into the therapeutic mechanisms, which hinders the following translational practice. Previously, we have shown that a combination of zoledronic acid (ZA) and plumbagin (PL) synergistically alleviates cancer-induced bone destruction. Herein, we further develop a pH-responsive bone-targeting drug delivery system, i.e., the ZA-anchored bimodal mesoporous slica covered gadolinium(III) upconversion nanoparticles loaded with PL, to detect and treat bone metastasis sensitively and specifically at an early stage. This multifunctional nanosystem can target osteocytes to release PL as controlled by pH, decreasing osteocytic RANKL expression synergistically through the structural simulation of adenosine phosphate, which competitively inhibits the phosphorylation of osteocytic protein kinase-a, cAMP-response element binding protein, extracellular regulated protein kinase, and c-Jun N-terminal kinase. More importantly, by establishing a breast cancer bone metastasis mice model via intracardiac injection, we show that tumoriogenesis and osteoclastogenesis can both be attenuated significantly. We thereby realize the effective theranostics of tiny bone metastasis in breast cancer bone metastasis. Our work highlights the significance of theranostic nanomedicine and osteocyte-targeting therapy in the treatment of early bone metastasis, which could be applied in achieving efficient theranostic effects for other bone diseases.
早期检测和治疗乳腺癌骨转移仍然是临床上的一大挑战。骨细胞作为骨组织中最丰富的细胞，已被发现通过与癌细胞和破骨细胞的相互作用来调控早期癌症骨转移的活性。然而，传统的骨靶向纳米医学对骨病变的特异性有限，并且在乳腺癌骨转移过程中忽略了骨细胞的重要作用。此外，它缺乏对治疗机制的详细了解，这阻碍了后续的转化实践。此前，我们已经表明，唑来膦酸（ZA）和白花丹醌（PL）的联合使用可以协同缓解癌症引起的骨破坏。在此，我们进一步开发了一种 pH 响应性骨靶向药物传递系统，即 ZA 锚定的双模态介孔硅覆盖的钆（III）上转换纳米粒子负载 PL，以在早期阶段敏感和特异性地检测和治疗骨转移。这种多功能纳米系统可以靶向骨细胞，通过 pH 控制释放 PL，通过模拟腺苷磷酸盐的结构协同降低破骨细胞 RANKL 的表达，竞争性抑制破骨细胞蛋白激酶-a、cAMP 反应元件结合蛋白、细胞外调节蛋白激酶和 c-Jun N-末端激酶的磷酸化。更重要的是，通过通过心脏内注射建立乳腺癌骨转移小鼠模型，我们表明肿瘤发生和破骨细胞形成都可以显著减弱。因此，我们实现了乳腺癌骨转移中微小骨转移的有效治疗。我们的工作强调了治疗性纳米医学和骨细胞靶向治疗在治疗早期骨转移中的重要性，这可应用于实现其他骨疾病的高效治疗效果。
