Vijayaraghavalu Sivakumar, Gao Yue, Rahman Mohammed Tanjimur, Rozic Richard, Sharifi Nima, Midura Ronald J, Labhasetwar Vinod
Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Genitourinary Malignancies Research Center, Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Biomaterials. 2020 Jan;227:119558. doi: 10.1016/j.biomaterials.2019.119558. Epub 2019 Oct 18.
Advanced-stage cancers often metastasize to bone, and is the major cause of cancer-related morbidity and mortality. Due to poor biodistribution of intravenously administered anticancer drugs within the bone, chemotherapy is not optimally effective in treating bone metastasis. Additionally, overexpression of receptor activator of nuclear factor κB ligand (RANKL) in the bone microenvironment drives the vicious, destructive cycle of progression of bone metastasis and bone resorption. We hypothesized that the combination treatment - with docetaxel (TXT), an anticancer drug encapsulated in sustained release biodegradable nanoparticles (TXT-NPs) that are designed to localize in bone marrow, and denosumab monoclonal antibody (DNmb), which binds to RANKL - could be more effective than either treatment alone. We tested our hypothesis in intraosseous prostate cancer (PC-3) cell-induced osteolytic mouse model of bone metastasis with treatments given intravenously. The results demonstrated better efficacy with TXT-NPs than with TXT-CrEL or saline control in inhibiting progression of metastasis and improving survival. TXT-NPs showed ~3-fold higher drug levels in metastasized bone tissue at 1 wk post-administration than TXT-CrEL, thus explaining their efficacy. However, the combination treatment (TXT-NPs + DNmb) given simultaneously was significantly more effective in inhibiting metastatic progression; it caused early tumor regression and improved survival, and caused no body weight loss or tumor relapse, even when the treatment was discontinued, whereas TXT-NPs or DNmb alone treatments showed tumor relapse after an initial regression. Micro-CT analysis of the bone from the combination treatment showed no bone loss and normal bone mineral content, bone density, and bone volume fraction, whereas TXT-NPs or DNmb alone treatments showed bone loss. Confirming the above results, histochemical analysis of the bone from the combination treatment demonstrated normal bone morphology, and osteoblast and osteoclast cell activities. In conclusion, TXT-NPs and DNmb in combination, because of their complementary roles in breaking the cross talk between cancer cells and bone cells, was significantly effective in treating bone metastasis.
晚期癌症常转移至骨骼，这是癌症相关发病和死亡的主要原因。由于静脉注射的抗癌药物在骨骼内的生物分布不佳，化疗在治疗骨转移方面并非最佳有效。此外，骨微环境中核因子κB受体活化因子配体（RANKL）的过表达驱动了骨转移进展和骨吸收的恶性、破坏性循环。我们假设联合治疗——使用多西他赛（TXT），一种封装在设计定位于骨髓的缓释可生物降解纳米颗粒（TXT-NPs）中的抗癌药物，以及与RANKL结合的地诺单抗单克隆抗体（DNmb）——可能比单独任何一种治疗更有效。我们在静脉给药治疗的骨内前列腺癌（PC-3）细胞诱导的骨转移溶骨性小鼠模型中检验了我们的假设。结果表明，与TXT-CrEL或生理盐水对照相比，TXT-NPs在抑制转移进展和提高生存率方面疗效更好。给药后1周，TXT-NPs在转移骨组织中的药物水平比TXT-CrEL高约3倍，从而解释了其疗效。然而，同时给予联合治疗（TXT-NPs + DNmb）在抑制转移进展方面显著更有效；它导致肿瘤早期消退并提高了生存率，且即使停止治疗也不会导致体重减轻或肿瘤复发，而单独使用TXT-NPs或DNmb治疗在初始消退后会出现肿瘤复发。联合治疗组骨骼的显微CT分析显示无骨质流失，骨矿物质含量、骨密度和骨体积分数正常，而单独使用TXT-NPs或DNmb治疗则显示有骨质流失。联合治疗组骨骼的组织化学分析证实了上述结果，显示骨形态正常，成骨细胞和破骨细胞活性正常。总之，TXT-NPs和DNmb联合使用，由于它们在打破癌细胞与骨细胞之间相互作用的互补作用，在治疗骨转移方面显著有效。
