细胞的命运:间充质干细胞的药代动力学
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摘要
细胞药物已成为药物研发中最新的领域之一。由于细胞药物具有增殖和自主趋化的能力,其体内药学特征与传统的小分子和大分子药物差异很大。目前,虽然细胞药物已经开始走向临床,但是对于细胞类药物进入体内之后的命运变化普遍缺乏认识。如果能够借助药代动力学理论,预测不同细胞药物的体内分布、代谢/排泄规律,进而在细胞药物进入机体之后的动态分布和细胞疗效之间建立关系,将有效提高细胞药物的临床疗效,降低风险,减少药物的相互作用。在该文中,我们以间充质干细胞(mesenchymal stem cell,MSC)为例,整理了现有的一些研究成果,试图对细胞药物的药代动力学和其药效、毒效的关系进行归纳,为今后进一步探索细胞药物在体内的命运奠定基础。
Recently, cellular drugs have become one of the hottest areas in drug development. Cellular drugs are quite different from the traditional small molecules and macromolecular drugs, because of their proliferation and chemotactic abilities. With the help of pharmacokinetic theories, it would be feasible to describe and predict the fate of cell drug, characterize their distribution, metabolism, and elimination in the body. That will improve the clinical efficacy and safety of the cellular drugs, reduce the risk of drug-drug interactions. In this paper, we take mesenchymal stem cell(MSC) as an example, trying to clarify the relationship between the pharmacokinetics and the efficacy/toxicity(PK/PD/TD) of cell drugs according to published literatures.
Recently, cellular drugs have become one of the hottest areas in drug development. Cellular drugs are quite different from the traditional small molecules and macromolecular drugs, because of their proliferation and chemotactic abilities. With the help of pharmacokinetic theories, it would be feasible to describe and predict the fate of cell drug, characterize their distribution, metabolism, and elimination in the body. That will improve the clinical efficacy and safety of the cellular drugs, reduce the risk of drug-drug interactions. In this paper, we take mesenchymal stem cell(MSC) as an example, trying to clarify the relationship between the pharmacokinetics and the efficacy/toxicity(PK/PD/TD) of cell drugs according to published literatures.
引文
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3 Wang L,Wang L,Cong X,Liu G,Zhou J,Bai B,et al.Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis:safety and efficacy.Stem Cells Dev2013;22(24):3192-202.
4 Emadedin M,Ghorbani Liastani M,Fazeli R,Mohseni F,Moghadasali R,Mardpour S,et al.Long-term follow-up of intraarticular injection of autologous mesenchymal stem cells in patients with knee,ankle,or hip osteoarthritis.Arch Iran Med2015;18(6):336-44.
5 Koh YG,Kwon OR,Kim YS,Choi YJ,Tak DH.Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone:2-year follow-up of a prospective randomized trial.Arthroscopy 2016;32(1):97-109.
6 Lee JS,Hong JM,Moon GJ,Lee PH,Ahn YH,Bang OY.A longterm follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke.Stem Cells 2010;28(6):1099-106.
7 Lai RC,Arslan F,Lee MM,Sze NS,Choo A,Chen TS,et al.Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury.Stem Cell Res 2010;4(3):214-22.
8 Mazzini L,Ferrero I,Luparello V,Rustichelli D,Gunetti M,Mareschi K,et al.Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis:A phase I clinical trial.Exp Neurol2010;223(1):229-37.
9 Marsh SE,Blurton-Jones M.Neural stem cell therapy for neurodegenerative disorders:The role of neurotrophic support.Neurochem Int 2017;106(Suppl C):94-100.
10 Becker AJ,McCulloch CE,Till JE.Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells.Nature 1963;197:452-4.
11 Friedenstein AJ,Deriglasova UF,Kulagina NN,Panasuk AF,Rudakowa SF,Luria EA,et al.Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method.Exp Hematol 1974;2(2):83-92.
12 Friedenstein AJ,Gorskaja JF,Kulagina NN.Fibroblast precursors in normal and irradiated mouse hematopoietic organs.Exp Hematol 1976;4(5):267-74.
13 Caplan AI.Mesenchymal stem cells.J Orthop Res 1991;9(5):641-50.
14 Lazarus HM,Haynesworth SE,Gerson SL,Rosenthal NS,Caplan AI.Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells(mesenchymal progenitor cells):implications for therapeutic use.Bone Marrow Transp 1995;16(4):557-64.
15 Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,et al.Multilineage potential of adult human mesenchymal stem cells.Science 1999;284(5411):143-7.
16 Quarto R,Mastrogiacomo M,Cancedda R,Kutepov SM,Mukhachev V,Lavroukov A,et al.Repair of large bone defects with the use of autologous bone marrow stromal cells.N Engl JMed 2001;344(5):385-6.
17 Bartholomew A,Sturgeon C,Siatskas M,Ferrer K,McIntosh K,Patil S,et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol 2002;30(1):42-8.
18 Glennie S,Soeiro I,Dyson PJ,Lam EW,Dazzi F.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.Blood 2005;105(7):2821-7.
19 Devine SM,Cobbs C,Jennings M,Bartholomew A,Hoffman R.Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates.Blood2003;101(8):2999-3001.
20 Zhang W,Ge W,Li C,You S,Liao L,Han Q,et al.Effects of mesenchymal stem cells on differentiation,maturation,and function of human monocyte-derived dendritic cells.Stem Cells Dev 2004;13(3):263-71.
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