Paclitaxel-Fe(3)O(4) nanoparticles inhibit growth of CD138(−) CD34(−) tumor stem-like cells in multiple myeloma-bearing mice

BACKGROUND: There is growing evidence that CD138(−) CD34(−) cells may actually be tumor stem cells responsible for initiation and relapse of multiple myeloma. However, effective drugs targeted at CD138(−) CD34(−) tumor stem cells are yet to be developed. The purpose of this study was to investigate the inhibitory effect of paclitaxel-loaded Fe(3)O(4) nanoparticles (PTX-NPs) on CD138(−) CD34(−) tumor stem cells in multiple myeloma-bearing mice. METHODS: CD138(−) CD34(−) cells were isolated from a human U266 multiple myeloma cell line using an immune magnetic bead sorting method and then subcutaneously injected into mice with nonobese diabetic/severe combined immunodeficiency to develop a multiple myeloma-bearing mouse model. The mice were treated with Fe(3)O(4) nanoparticles 2 mg/kg, paclitaxel 4.8 mg/kg, and PTX-NPs 0.64 mg/kg for 2 weeks. Tumor growth, pathological changes, serum and urinary interleukin-6 levels, and molecular expression of caspase-3, caspase-8, and caspase-9 were evaluated. RESULTS: CD138(−) CD34(−) cells were found to have tumor stem cell characteristics. All the mice developed tumors in 40 days after injection of 1 × 10(6) CD138(−) CD34(−) tumor stem cells. Tumor growth in mice treated with PTX-NPs was significantly inhibited compared with the controls (P < 0.005), and the groups that received nanoparticles alone (P < 0.005) or paclitaxel alone (P < 0.05). In addition, the PTX-NPs markedly inhibited interleukin-6 secretion, increased caspase-8, caspase-9, and caspase-3 expression, and induced apoptosis of tumor cells in the treated mice. CONCLUSION: PTX-NPs proved to be a potent anticancer treatment strategy that may contribute to targeted therapy for multiple myeloma tumor stem cells in future clinical trials.