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非酒精性脂肪性肝病的联合疗法和递送策略

王燕梅, 杨磊, 辛晓斐, 尹莉芳

王燕梅, 杨磊, 辛晓斐, 尹莉芳. 非酒精性脂肪性肝病的联合疗法和递送策略[J]. 中国药科大学学报, 2022, 53(4): 423-432. DOI: 10.11665/j.issn.1000-5048.20220405
引用本文: 王燕梅, 杨磊, 辛晓斐, 尹莉芳. 非酒精性脂肪性肝病的联合疗法和递送策略[J]. 中国药科大学学报, 2022, 53(4): 423-432. DOI: 10.11665/j.issn.1000-5048.20220405
WANG Yanmei, YANG Lei, XIN Xiaofei, YIN Lifang. Combination therapy and drug delivery strategies for treatment of non-alcoholic fatty liver disease[J]. Journal of China Pharmaceutical University, 2022, 53(4): 423-432. DOI: 10.11665/j.issn.1000-5048.20220405
Citation: WANG Yanmei, YANG Lei, XIN Xiaofei, YIN Lifang. Combination therapy and drug delivery strategies for treatment of non-alcoholic fatty liver disease[J]. Journal of China Pharmaceutical University, 2022, 53(4): 423-432. DOI: 10.11665/j.issn.1000-5048.20220405

非酒精性脂肪性肝病的联合疗法和递送策略

基金项目: 国家自然科学基金资助项目(No.81871477)

Combination therapy and drug delivery strategies for treatment of non-alcoholic fatty liver disease

Funds: This study was supported by the National Natural Science Foundation of China (No.81871477)
  • 摘要: 非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是与代谢功能障碍密切相关的一系列慢性肝病,其发病机制复杂,至今仅有一款PPAR-α/γ双重激动剂Saroglitazar上市,用于治疗非肝硬化非酒精性脂肪性肝炎。针对NAFLD发病机制中的相同或不同靶点和信号通路开发的联合治疗策略能有望实现药物与药物间的协同作用,小分子药物联用、RNAi联合疗法和化学基因疗法是目前极富前景的联合治疗策略。此外,设计安全、有效和特异性的药物递送系统能改善小分子药物与基因药物的成药性,并促进其临床转化和产业化。因此,本文介绍了小分子药物联用、基于RNAi的核酸药物联用和小分子与核酸药物联用的最新研发现状及其递送方式,以期为NAFLD的治疗提供新的思路与方法。
    Abstract: Non-alcoholic fatty liver disease (NAFLD) is a series of chronic liver diseases strongly associated with the metabolic disorder with an increasing rate of worldwide prevalence.Due to its complicated pathogenesis, only Saroglitazar has been approved by Indian Drug Controller General (DCGI) as a PPAR-α/γ dual agonist to treat non-cirrhotic non-alcoholic steatohepatitis.Combination therapy, which can target same or different signaling pathways of NAFLD pathogenesis, has been developed to achieve synergistic therapeutic efficacy.Currently, small-molecule drug combination, RNAi combination therapy, and chemogene therapy are proposed as promising strategies in NAFLD treatment.In addition, designing a smart, safe and effective drug delivery system is key to realizing the druggability, clinical translation and industrialization of small molecule drugs and gene drugs.This review summarizes the research status and delivery system of small-molecule drug combination, RNAi combination therapy, and chemogene therapy, in the hope of providing some novel insight for the treatment of NAFLD.
  • [1] . J Hepatol,2019,70(3):531-544.
    [2] Guo YT,Chen J,Liu N,et al. Association of circulating TXNIP levels with fatty liver in newly diagnosed type 2 diabetes mellitus[J]. Diabetes Metab Syndr Obes,2022,15:225-233.
    [3] Sodum N,Kumar G,Bojja SL,et al. Epigenetics in NAFLD/NASH:targets and therapy[J]. Pharmacol Res,2021,167:105484.
    [4] Rives C,Fougerat A,Ellero-Simatos S,et al. Oxidative stress in NAFLD:role of nutrients and food contaminants[J]. Biomolecules,2020,10(12):1702.
    [5] Safari Z,Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD)[J]. Cell Mol Life Sci,2019,76(8):1541-1558.
    [6] Ahrari A,Najafzadehvarzi H,Taravati A,et al. The inhibitory effect of PLGA-encapsulated berberine on hepatotoxicity and α-smooth muscle actin (α-SMA) gene expression[J]. Life Sci,2021,284:119884.
    [7] Juanola O,Martínez-López S,Francés R,et al. Non-alcoholic fatty liver disease:metabolic,genetic,epigenetic and environmental risk factors[J]. Int J Environ Res Public Health,2021,18(10):5227.
    [8] Prikhodko VA,Bezborodkina NN,Okovityi SV. Pharmacotherapy for non-alcoholic fatty liver disease:emerging targets and drug candidates[J]. Biomedicines,2022,10(2):274.
    [9] Dufour JF,Caussy C,Loomba R. Combination therapy for non-alcoholic steatohepatitis:rationale,opportunities and challenges[J]. Gut,2020,69(10):1877-1884.
    [10] B?ttger R,Pauli G,Chao PH,et al. Lipid-based nanoparticle technologies for liver targeting[J]. Adv Drug Deliv Rev,2020,154/155:79-101.
    [11] Peng W,Cheng SM,Bao ZH,et al. Advances in the research of nanodrug delivery system for targeted treatment of liver fibrosis[J]. Biomed Pharmacother,2021,137:111342.
    [12] Tacke F. Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis[J]. Expert Opin Investig Drugs,2018,27(3):301-311.
    [13] Radun R,Trauner M. Role of FXR in bile acid and metabolic homeostasis in NASH:pathogenetic concepts and therapeutic opportunities[J]. Semin Liver Dis,2021,41(4):461-475.
    [14] Kumar V,Xin XF,Ma JY,et al. Therapeutic targets,novel drugs,and delivery systems for diabetes associated NAFLD and liver fibrosis[J]. Adv Drug Deliv Rev,2021,176:113888.
    [15] Ratziu V,Sanyal A,Harrison SA,et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis:final analysis of the phase 2b CENTAUR study[J]. Hepatology,2020,72(3):892-905.
    [16] Pedrosa M,Seyedkazemi S,Francque S,et al. A randomized,double-blind,multicenter,phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis:study design of the TANDEM trial[J]. Contemp Clin Trials,2020,88:105889.
    [17] Griggs LA,Hassan NT,Malik RS,et al. Fibronectin fibrils regulate TGF-β1-induced epithelial-mesenchymal transition[J]. Matrix Biol,2017,60/61:157-175.
    [18] Kumar V,Dong YX,Kumar V,et al. The use of micelles to deliver potential hedgehog pathway inhibitor for the treatment of liver fibrosis[J]. Theranostics,2019,9(25):7537-7555.
    [19] Kumar V,Mundra V,Mahato RI. Nanomedicines of hedgehog inhibitor and PPAR-γ agonist for treating liver fibrosis[J]. Pharm Res,2014,31(5):1158-1169.
    [20] Romualdo GR,da Silva TC,de Albuquerque Landi MF,et al. Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease[J]. Environ Toxicol,2021,36(2):168-176.
    [21] Ma R,Chen J,Liang YL,et al. Sorafenib:a potential therapeutic drug for hepatic fibrosis and its outcomes[J]. Biomed Pharmacother,2017,88:459-468.
    [22] Chen Y,Liu YC,Sung YC,et al. Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors[J]. Sci Rep,2017,7:44123.
    [23] Sung YC,Liu YC,Chao PH,et al. Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development[J]. Theranostics,2018,8(4):894-905.
    [24] Shafie F,Nabavizadeh F,Shafie Ardestani M,et al. Sorafenib-loaded PAMAM dendrimer attenuates liver fibrosis and its complications in bile-duct-ligated rats[J]. Can J Physiol Pharmacol,2019,97(8):691-698.
    [25] Keating GM. Sorafenib:a review in hepatocellular carcinoma[J]. Target Oncol,2017,12(2):243-253.
    [26] Qin LF,Qin JM,Zhen XM,et al. Curcumin protects against hepatic stellate cells activation and migration by inhibiting the CXCL12/CXCR4 biological axis in liver fibrosis:a study in vitro and in vivo[J]. Biomed Pharmacother,2018,101:599-607.
    [27] Lung YM,Man FY,Christian S,et al. ARO-HSD,an investigational RNAi therapeutic,demonstrates reduction in ALT and hepatic HSD17B13 mRNA and protein in patients with NASH or suspected NASH[R]. AASLD,2021. https://www.natap.org/2021/AASLD/AASLD_99.htm.
    [28] Cui H,Zhu XY,Li SY,et al. Liver-targeted delivery of oligonucleotides with N-acetylgalactosamine conjugation[J]. ACS Omega,2021,6(25):16259-16265.
    [29] Ji D,Wang QH,Zhao Q,et al. Co-delivery of miR-29b and germacrone based on cyclic RGD-modified nanoparticles for liver fibrosis therapy[J]. J Nanobiotechnology,2020,18(1):86.
    [30] Yu FJ,Chen BC,Dong PH,et al. HOTAIR epigenetically modulates PTEN expression via microRNA-29b:a novel mechanism in regulation of liver fibrosis[J]. Mol Ther,2017,25(1):205-217.
    [31] Zeng CX,Wang YL,Xie C,et al. Identification of a novel TGF-β-miR-122-fibronectin 1/serum response factor signaling cascade and its implication in hepatic fibrogenesis[J]. Oncotarget,2015,6(14):12224-12233.
    [32] Li J,Ghazwani M,Zhang YF,et al. miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression[J]. J Hepatol,2013,58(3):522-528.
    [33] Wu J,Huang JS,Kuang SC,et al. Synergistic microRNA therapy in liver fibrotic rat using MRI-visible nanocarrier targeting hepatic stellate cells[J]. Adv Sci (Weinh),2019,6(5):1801809.
    [34] Zhao Z,Li YK,Jain A,et al. Development of a peptide-modified siRNA nano complex for hepatic stellate cells[J]. Nanomedicine,2018,14(1):51-61.
    [35] Qiao JB,Fan QQ,Zhang CL,et al. Hyperbranched lipoid-based lipid nanoparticles for bidirectional regulation of collagen accumulation in liver fibrosis[J]. J Control Release,2020,321:629-640.
    [36] Boakye CHA,Patel K,Doddapaneni R,et al. Novel amphiphilic lipid augments the co-delivery of erlotinib and IL36 siRNA into the skin for psoriasis treatment[J]. J Control Release,2017,246:120-132.
    [37] Gong CN,Hu CL,Gu FF,et al. Co-delivery of autophagy inhibitor ATG7 siRNA and docetaxel for breast cancer treatment[J]. J Control Release,2017,266:272-286.
    [38] Zhang BF,Xing L,Cui PF,et al. Mitochondria apoptosis pathway synergistically activated by hierarchical targeted nanoparticles co-delivering siRNA and lonidamine[J]. Biomaterials,2015,61:178-189.
    [39] Shrestha B,Wang LJ,Brey EM,et al. Smart nanoparticles for chemo-based combinational therapy[J]. Pharmaceutics,2021,13(6):853.
    [40] Salvoza N,Giraudi PJ,Tiribelli C,et al. Natural compounds for counteracting nonalcoholic fatty liver disease (NAFLD):advantages and limitations of the suggested candidates[J]. Int J Mol Sci,2022,23(5):2764.
    [41] Jia JD,Bauer M,Cho JJ,et al. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen α1(I) and TIMP-1[J]. J Hepatol,2001,35(3):392-398.
    [42] Song IS,Nam SJ,Jeon JH,et al. Enhanced bioavailability and efficacy of silymarin solid dispersion in rats with acetaminophen-induced hepatotoxicity[J]. Pharmaceutics,2021,13(5):628.
    [43] Qiao JB,Fan QQ,Xing L,et al. Vitamin A-decorated biocompatible micelles for chemogene therapy of liver fibrosis[J]. J Control Release,2018,283:113-125.
    [44] Jung Y,Brown KD,Witek RP,et al. Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans[J]. Gastroenterology,2008,134(5):1532-1543.
    [45] Kumar V,Mondal G,Dutta R,et al. Co-delivery of small molecule hedgehog inhibitor and miRNA for treating liver fibrosis[J]. Biomaterials,2016,76:144-156.
    [46] Han J,He YP,Zhao H,et al. Hypoxia inducible factor-1 promotes liver fibrosis in nonalcoholic fatty liver disease by activating PTEN/p65 signaling pathway[J]. J Cell Biochem,2019,120(9):14735-14744.
    [47] Hong F,Tuyama A,Lee TF,et al. Hepatic stellate cells express functional CXCR4:role in stromal cell-derived factor-1alpha-mediated stellate cell activation[J]. Hepatology,2009,49(6):2055-2067.
    [48] Liu CH,Chan KM,Chiang T,et al. Dual-functional nanoparticles targeting CXCR4 and delivering antiangiogenic siRNA ameliorate liver fibrosis[J]. Mol Pharm,2016,13(7):2253-2262.
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出版历程
  • 收稿日期:  2022-01-03
  • 修回日期:  2022-06-06
  • 刊出日期:  2022-08-24

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