Enhancement of Cancer Chemotherapeutic Efficacy via Bone-Targeted Drug Delivery Carrier in Bone Metastases

PURPOSE: 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. MATERIAL AND METHODS: 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(DOX) and Aln-MOF(DOX) 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. RESULTS: Aln-MOF showed good stability, no cytotoxicity and better bone affinity than MOF. Both MOF(DOX) and Aln-MOF(DOX) 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(DOX) and Aln-MOF(DOX) could effectively delay tumor progression, and the effect of Aln-MOFDOX was more obvious (P < 0.05). CONCLUSION: Our study confirmed that Aln-MOF has good stability, bone targeting and biosafety. Aln-MOF(DOX) could release DOX and effectively kill tumor cells of bone metastases. Aln-MOF(DOX) has a promising prospect in the treatment of bone metastasis.