title: PEGylated long-circulating liposomes deliver homoharringtonine to suppress multiple myeloma cancer stem cells.
abstract: The goal of this investigation was to evaluate the inhibiting effect of high proportion polyethyleneglycol of long-circulating homoharringtonine liposomes on RPMI8226 multiple myeloma cancer stem cells. The CD138-CD34-multiple myeloma cancer stem cells isolated from RPMI8226 cell line using magnetic activated cell sorting system were, respectively, incubated with the optimized formulation of polyethyleneglycol of long-circulating homoharringtonine liposomes and the homoharringtonine in vitro, and the multiple myeloma cancer stem cell proliferation, colony formation, and cell cycle were analyzed. The inhibition of the multiple myeloma CD138-CD34-cancer stem cell growth was investigated in non-obese-diabetic/severe-combined-immunodeficiency mice that were implanted with multiple myeloma RPMI 8226 cancer stem cells and treated with the LCL-HHT-H-PEG. The results showed that the polyethyleneglycol of long-circulating homoharringtonine liposomes significantly inhibited MM cancer stem cell proliferation, colony formation, and induced cancer stem cell apoptosis in vitro as well as MM cancer stem cell growth in non-obese-diabetic/severe-combined-immunodeficiency mice compared with the homoharringtonine. In addition, the mouse bone mineral density and the red blood cell count were significantly increased in polyethyleneglycol of long-circulating homoharringtonine liposomes group. In conclusion, the data demonstrated that the developed polyethyleneglycol of long-circulating homoharringtonine liposomes formulation may serve as an efficient therapeutic drug for suppressing CD138-CD34-multiple myeloma cancer stem cell growth by inducing cancer stem cell apoptosis in non-obese-diabetic/severe-combined-immunodeficiency mouse model. Impact statement Multiple myeloma (MM) remains largely incurable until now. One of the main reasons is that there are cancer stem cells (CSCs) in MM, which are responsible for MM's drug resistance and relapse. In this study, we wanted to extend our previous investigation22that whether we developed the LCL-HHT-H-PEG formulation have an inhibitory effect on MM CD138-CD34-CSCs in MM CSC engrafted NOD/SCID mouse model. Our data from the present study have demonstrated the therapeutic effect of LCL-HHT-H-PEG on MM-bearing mouse model. The study represents the first attempt to demonstrate that the LCL-HHT-H-PEG formulation is available for treatment MM patients in clinic. Therefore, this finding is important and deserves publication in Experimental Biology and Medicine.
authors.affiliation: 1 Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.affiliation: 1 Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Shi
authors.affiliation: 2 School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China Miao Li and Fangfang Shi contributed equally to the work.
authors.forename: Xiong
authors.initials: X
authors.lastname: Fei
authors.affiliation: 1 Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China.
authors.forename: Songyan
authors.initials: S
authors.lastname: Wu
authors.affiliation: 1 Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: 1 Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Pan
authors.affiliation: 2 School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China Miao Li and Fangfang Shi contributed equally to the work.
authors.forename: Shouhua
authors.initials: S
authors.lastname: Luo
authors.affiliation: 2 School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China Miao Li and Fangfang Shi contributed equally to the work.
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
authors.affiliation: 1 Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Dou
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D006248:Harringtonines / Q000494:pharmacology*; D000077863:Homoharringtonine; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D006248:Harringtonines; D008081:Liposomes; D000077863:Homoharringtonine
keywords: Multiple myeloma; cancer stem cells; homoharringtonine; long-circulating liposomes; polyethyleneglycol