Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People's Republic of China.
The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People's Republic of China.
Drug Des Devel Ther. 2021 Oct 28;15:4455-4468. doi: 10.2147/DDDT.S333999. eCollection 2021.
Bone metastases are common in malignant tumors, especially for the advanced cancers. Chemotherapy is an important treatment in clinic, but the application is limited due to the severe adverse reactions. We try to design bone-targeted drug delivery systems (DDS) for the delivery of chemotherapeutic drugs in bone metastatic carcinoma.
We added alendronate (Aln) to metal organic framework (MOF) to synthesize a new bone-targeted DDS named Aln-MOF. Doxorubicin (DOX) as a classic anti-cancer drug was encapsulated. The material characterization, drug release and bone affinity were detected. In vitro experiment, the cell toxicity was detected by cck-8 test and cellular uptake were detected by laser scanning confocal microscope and flow cytometry. In vivo experiment, the pharmacokinetics of DDS in the blood was analyzed by fluorescence spectrophotometer and the biodistribution was detected by a multi-mode optical in vivo imaging system. The anti-tumor effects of MOF and Aln-MOF were evaluated by monitoring the tumor volume and weight during the animal experiment. In addition, the toxicity of DDS to different organs was determined by HE staining.
Aln-MOF showed good stability, no cytotoxicity and better bone affinity than MOF. Both MOF and Aln-MOF could release DOX, and the release rate at pH = 5.5 was faster than the rate at pH = 7.4. The cellular uptake of Aln-MOF and MOF showed no difference. Aln-MOF had a long retention time in blood, which is beneficial for the enrichment of Aln-MOF in tumor sites. Aln-MOF mainly concentrated at bone metastases in mice. MOF and Aln-MOF could effectively delay tumor progression, and the effect of Aln-MOFDOX was more obvious (P < 0.05).
Our study confirmed that Aln-MOF has good stability, bone targeting and biosafety. Aln-MOF could release DOX and effectively kill tumor cells of bone metastases. Aln-MOF has a promising prospect in the treatment of bone metastasis.
骨转移是恶性肿瘤的常见现象，尤其是晚期癌症。化疗是临床上的重要治疗方法，但由于严重的不良反应，其应用受到限制。我们尝试设计用于骨转移性癌中化疗药物传递的骨靶向药物传递系统 (DDS)。
我们将阿仑膦酸钠 (Aln) 添加到金属有机骨架 (MOF) 中，合成了一种新的骨靶向 DDS，命名为 Aln-MOF。阿霉素 (DOX) 作为一种经典的抗癌药物被包裹在内。对材料特性、药物释放和骨亲和力进行了检测。在体外实验中，通过 CCK-8 试验检测细胞毒性，通过激光共聚焦显微镜和流式细胞术检测细胞摄取。在体内实验中，通过荧光分光光度计分析 DDS 在血液中的药代动力学，通过多模式活体成像系统检测其生物分布。通过监测动物实验过程中肿瘤体积和重量来评估 MOF 和 Aln-MOF 的抗肿瘤效果。此外，通过 HE 染色确定 DDS 对不同器官的毒性。
Aln-MOF 表现出良好的稳定性、无细胞毒性和优于 MOF 的骨亲和力。MOF 和 Aln-MOF 均可释放 DOX，在 pH = 5.5 时的释放率快于在 pH = 7.4 时的释放率。Aln-MOF 和 MOF 的细胞摄取没有差异。Aln-MOF 在血液中的保留时间较长，有利于 Aln-MOF 在肿瘤部位的富集。Aln-MOF 在小鼠中主要集中在骨转移部位。MOF 和 Aln-MOF 均可有效延缓肿瘤进展，Aln-MOFDOX 的效果更为明显 (P < 0.05)。
我们的研究证实 Aln-MOF 具有良好的稳定性、骨靶向性和生物安全性。Aln-MOF 可以释放 DOX，并有效杀死骨转移肿瘤细胞。Aln-MOF 在治疗骨转移方面具有广阔的应用前景。
