阿霉素负载的直链烷基修饰氧化石墨烯经导管动脉化疗栓塞治疗肝癌
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摘要
【目的】研究阿霉素负载的直链烷基修饰的氧化石墨烯(DOX@GO-C18)作为药物载体经导管动脉化疗栓塞(TACE)治疗肝癌的安全性和有效性。【方法】制备并表征DOX@GO-C18。采用雄性新西兰大白兔建立VX2肝癌模型并以动态增强CT扫描明确肿瘤情况。在数字减影血管造影(DSA)引导下,以股动脉入路选择性插管至肝段动脉,通过微导管注射DOX@GO-C18的碘油分散液对肿瘤行TACE治疗。术前及术后第1、3、5、7和14天取外周静脉血液样本行肝功能检查,术后第14天行动态增强CT扫描并对肿瘤行HE染色、油红染色及DAPI荧光染色。【结果】DOX@GO-C18能稳定分散在碘油中。肝癌病灶在治疗前后的最大直径无明显变化,肿瘤血供明显减少。采用RECIST1.1标准进行评价,目标病灶治疗反应均为疾病稳定。病理学检查可见DOX@GO-C18伴随碘油主要沉积于肿瘤内,并释放DOX,肿瘤出现坏死。血清学检查显示术后出现一过性肝酶学异常,在2周内可恢复至正常水平。【结论】本研究初步证明DOX@GO-C18可作为一种应用于肝癌的TACE治疗的有效药物载体,其安全性可控。
【Objective】To investigate the safety and benefit of doxorubicin loaded hydrophobic linear alkyl modified graphene oxide(DOX@GO-C18)served as vectors in transcatheter arterial chemoembolization(TACE).【Methods】Doxorubicin loaded hydrophobic linear alkyl modified graphene oxide was manufactured and characterized. VX2 liver carcinoma was established in rabbits and the hepatic lesions were treated with TACE using DOX@GO-C18 which was dissolved in lipiodol. Pre-and post-CT scans were performed to evaluate the treatment response. Liver function was assessed via blood samples drawn on day 0(preoperative),1,3,7,and day 14. The animals were sacrificed on day 14 and tissue samples collected to stain for pathology(hematoxylin-eosin staining),lipiodol(oil red O staining)and DOX(fluorescent).【Results】The dispersion of DOX@GO-C18 in lipiodol was highly stable. Pre-and post-CT scan revealed that the diameter of the VX2 lesions barely varied and enhancements were decreased after the treatment. Target lesions gained stable disease(SD)as the treatment response based on Response Evaluation Criteria in Solid Tumors 1.1(RECIST 1.1).Histological examination revealed that DOX@GO-C18 was located within the tumor tissue along with the lipiodol. The release of DOX may contribute to the necrosis in tumor.【Conclusions】DOX@GO-C18[CC2]may proved to be a safe and effective vectors in TACE treatment for liver carcinoma.
【Objective】To investigate the safety and benefit of doxorubicin loaded hydrophobic linear alkyl modified graphene oxide(DOX@GO-C18)served as vectors in transcatheter arterial chemoembolization(TACE).【Methods】Doxorubicin loaded hydrophobic linear alkyl modified graphene oxide was manufactured and characterized. VX2 liver carcinoma was established in rabbits and the hepatic lesions were treated with TACE using DOX@GO-C18 which was dissolved in lipiodol. Pre-and post-CT scans were performed to evaluate the treatment response. Liver function was assessed via blood samples drawn on day 0(preoperative),1,3,7,and day 14. The animals were sacrificed on day 14 and tissue samples collected to stain for pathology(hematoxylin-eosin staining),lipiodol(oil red O staining)and DOX(fluorescent).【Results】The dispersion of DOX@GO-C18 in lipiodol was highly stable. Pre-and post-CT scan revealed that the diameter of the VX2 lesions barely varied and enhancements were decreased after the treatment. Target lesions gained stable disease(SD)as the treatment response based on Response Evaluation Criteria in Solid Tumors 1.1(RECIST 1.1).Histological examination revealed that DOX@GO-C18 was located within the tumor tissue along with the lipiodol. The release of DOX may contribute to the necrosis in tumor.【Conclusions】DOX@GO-C18[CC2]may proved to be a safe and effective vectors in TACE treatment for liver carcinoma.
引文
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[2]万源,陈斌,李楠,等.载药微球栓塞联合甲磺酸阿帕替尼治疗中晚期原发性肝癌的近期疗效分析[J].中山大学学报(医学版),2019,40(3):437-444.Wan Y,Chen B,Li N,et al.Short-Term Clinical Response of DEB-TACE Combined with Apatinib on Patients with Intermediate-advanced Hepatocellular Carcinoma[J].J Sun Yat-sen Univ(Med Sci),2019,40(3):437-444.
[3]Galle PR,Forner A,Llovet JM,et al.EASL Clinical Practice Guidelines:Management of hepatocellular carcinoma[J].J Hepatol,2018,69(1),182-236.
[4]Idée JM,Guiu B.Use of Lipiodol as a drug-delivery system for transcatheter arterial chemoembolization of hepatocellular carcinoma:a review[J].Crit Rev Oncol Hematol,2013,88(3),530-549.
[5]Liu J,Cui L,Losic D.Graphene and graphene oxide as new nanocarriers for drug delivery applications[J].Acta Biomater,2013,9(12):9243-9257.
[6]Hu H,Allan CCK,Li J,et al.Multifunctional organically modified graphene with super-hydrophobicity[J].nano res,2014,7(3):418-433.
[7]姜云,林润,张弢.直链烷基修饰的疏水氧化石墨烯的制备与表征[J].功能材料,2017,48(10),10013-10016.Jiang Y,Lin R,Zhang T.Synthesis and characterizations of linear alkyl modified hydrophobic graphene oxide[J].J Funct Mater,2017,48(10),10013-10016.
[8]Zhao H,Ding R,Zhao X,et al.Graphene-based nanomaterials for drug and/or gene delivery,bioimaging,and tissue engineering[J].Drug Discov Today,2017,22(9),1302-1317.
[9]戴海涛,黄勇慧,林润,等.磷酰胆碱修饰的氧化石墨烯经导管动脉化疗栓塞治疗肝癌[J].中山大学学报(医学版),2018,39(1):18-25.Dai HT,Huang YH,Lin R,et al.Phosphorylcholine oligomer-grafted graphene oxide for the transcatheter arterial chemoembolization of liver cancer[J].J Sun Yat-sen Univ(Med Sci),2018,39(1):18-25.
[10]Lencioni R,Llovet JM.Modified RECIST(mRE-CIST)assessment for hepatocellular carcinoma[J].Semin liver Dis,2010,30(1):52-60.
[11]Forner A,Reig M,Bruix J.Hepatocellular carcinoma[J].Lancet,2018,391(10127),1301-1314.
[12]Kan Z,Wright K,Wallace S.Ethiodized oil emulsions in hepatic microcirculation:in vivo microscopy in animal models[J].Acad Radiol,1997,4(4):275-282.
[13]Forner A,Gilabert M,Bruix J,et al.Treatment of intermediate-stage hepatocellular carcinoma[J].Nat Rev Clin Oncol,2014,11(9):525-535.
[14]Favoulet P,Cercueil JP,Faure P,et al.Increased cytotoxicity and stability of Lipiodol-pirarubicin emulsion compared to classical doxorubicin-Lipiodol:potential advantage for chemoembolization of unresectable hepatocellular carcinoma[J].Anticancer Drugs,2001,12(10):801-806.
[15]Bruix J,Reig M,Sherman M.Evidence-based diagnosis,staging,and treatment of patients with hepatocellular carcinoma[J].Gastroenterology,2016,150(4):835-853.
[16]Orecchioni M,Cabizza R,Bianco A,et al.Graphene as cancer theranostic tool:progress and future challenges[J].Theranostics,2015,5(7):710-723.
[17]You P,Yang Y,Wang M,et al.Graphene oxidebased nanocarriers for cancer imaging and drug delivery[J].Curr Pharm Des,2015,21(22):3215-3222.
[18]Ema M,Gamo M,Honda K.A review of toxicity studies on graphene-based nanomaterials in laboratory animals[J].Regul Toxicol Pharmacol,2017,85:7-24.
[19]Jin Y,Wang J,Ke H,et al.Graphene oxide modified PLA microcapsules containing gold nanoparticles for ultrasonic/CT bimodal imaging guided photothermal tumor therapy[J].Biomaterials,2013,34(20):4794-4802.
[20]Zhou F,Chen L,An Q,et al.Novel hydrogel material as a potential embolic agent in embolization treatments[J].Sci Rep,2016,6,32145.
[21]Song JE,Kim DY.Conventional vs drug-eluting beads transarterial chemoembolization for hepatocellular carcinoma[J].World J Hepatol,2017,9(18):808-814.
[22]Gholamrezanezhad A,Mirpour S,Geschwind JF,et al.Evaluation of 70-150-mum doxorubicin-eluting beads for transcatheter arterial chemoembolization in the rabbit liver VX2 tumour model[J].Eur Radiol,2016,26(10):3474-3482.
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