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Low-Molecular-Weight Fucoidan Promotes Therapeutic

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Low-Molecular-WeightFucoidanPromotesTherapeutic

RevascularizationinaRatModelofCriticalHindlimbIschemia

CHARLES-EDOUARDLUYT,ANNEMEDDAHI-PELL´E,BENOITHO-TIN-NOE,SYLVIACOLLIEC-JOUAULT,

JEANGUEZENNEC,LILIANELOUEDEC,HERV´EPRATS,MARIE-PAULEJACOB,MARYOSBORNE-PELLEGRIN,

DIDIERLETOURNEUR,andJEAN-BAPTISTEMICHEL

InstitutNationaldelaSante´etdelaRechercheMe´dicaleU460,CHUX.Bichat,Paris,France(C.E.L.,A.M.P.,B.H.T.N.,L.L.,MP.J.,M.O.P.,

J.B.M.);DirectiondesRessourcesVivantesValorisationProducts,InstitutFranc¸aisdeRecherchepourl’exploitationdelaMer,Nantes,France

(S.C.J.,J.G.);InstitutNationaldelaSante´etdelaRechercheMe´dicaleERIT-M0204,CHUX.Bichat,Paris,France(D.L.);andInstitutNational

delaSante´etdelaRechercheMe´dicaleU397,Rangueil,Toulouse,France(H.P.)

ReceivedOctober28,2002;acceptedDecember5,2002

ABSTRACT

Thetherapeuticpotentialoflow-molecular-weight(LMW)fu-

coidan,asulfatedpolysaccharideextractedfrombrownsea-

weeddevoidofdirectantithrombineffect,wasinvestigatedin

vitroandinamodelofcriticalhindlimbischemiainrat.Invitro

resultsshowedthatLMWfucoidanenhancedfibroblastgrowth

factor(FGF)-2-induced[3H]thymidineincorporationincultured

ratsmoothmusclecells.IntravenousinjectioninratsofLMW

fucoidansignificantlyincreasedthestromal-derivedfactor

(SDF)-1levelfrom1.2Ϯ0.1to6.5Ϯ0.35ng/mlinplasma.The

therapeuticeffectofLMWfucoidan(5mg/kg/day),FGF-2(1

␮g/kg/day),andLMWfucoidancombinedwithFGF-2wasas-

sessed14daysafterinductionofischemiaby1)clinicaleval-

uationofclaudication,2)tissuebloodflowanalysis,3)histoen-

zymologyofmusclemetabolicactivity,and4)quantificationof

capillarydensity.BothLMWfucoidanandFGF-2similarlyim-provedresidualmusclebloodflow(62.5Ϯ6.5and64.5Ϯ

4.5%,respectively)comparedwiththecontrolgroup(42Ϯ

3.5%,pϽ0.0001).ThecombinationofFGF-2andLMW

fucoidanshowedfurthersignificantimprovementintissue

bloodflow(90.5Ϯ3%,pϽ0.0001).Theseresultswere

confirmedbyphosphorylaseactivity,showingmuscleregen-

erationinratstreatedwiththecombinationofFGF-2and

LMWfucoidan.Capillarydensitycountincreasedfrom9.6Ϯ

0.7capillaries/musclesectioninuntreatedischemiccontrols

to14.3Ϯ0.9withLMWfucoidan,14.5Ϯ0.9withFGF-2,and

19.1Ϯ0.9incombination(pϽ0.001).Thus,LMWfucoidan

potentiatesFGF-2activity,mobilizesSDF-1,andfacilitates

angiogenesisinaratmodel.Thisnaturalcompoundcouldbe

ofinterestasanalternativeforconventionaltreatmentin

criticalischemia.

Inrecentyears,therapeuticangiogenesishasbeenpro-

posedinthetreatmentofchronicischemia.Inanimals,it

wasshownthatbasicfibroblastgrowthfactor(FGF-2)

(Gospodarowicz,1974;Maciagetal.,1984),whichismito-

genicforvascularendothelialcells,fibroblasts,and

smoothmusclecells,caninduceangiogenesisinvivo

(Yanagisawa-Miwaetal.,1992;LefaucheurandSebille,

1995;Sellkeetal.,1996;Yangetal.,1996;Shouetal.,

1997).FGF-2bindstoheparansulfatesthatstabilizeitby

protectingitfromproteolyticcleavageandenhanceits

bioavailability(Aviezeretal.,1994;Roghanietal.,1994;

Pellegrini,2001).Tissueheparansulfatestherebyserveas

coreceptorsforgrowthfactors.

Fucoidansarevegetalsulfatedpolysaccharidesextracted

frombrownalgae.High-molecular-weight(HMW)fucoidansareknowntobindgrowthfactors,suchasFGFs,andprotect

themfromproteolysis(Belfordetal.,1993).HMWfucoidans

canreleasetheglycosaminoglycan-boundstromal-derived

factor-1(SDF-1)fromitstissuestoragesites.SDF-1mobi-

lizesmedullaryprogenitors(FrenetteandWeiss,2000;

Sweeneyetal.,2000,2002),whichcouldparticipateinan-

giogenesiswithvascularendothelialgrowthfactorandFGF

(Salvuccietal.,2002).Therefore,wesupposedthatfucoidans

wouldhavetherapeuticpotentialincriticalmuscleischemia.

Afractionoflow-molecular-weight(LMW)fucoidan(7Ϯ

2kDa)wasobtainedbyradicaldepolymerizationofHMW

extractsfrombrownseaweed(Nardellaetal.,1996)and

wasdevoidofanydirectantithrombineffect(Haroun-Bou-

hedjaetal.,2000).Inthisstudy,wehavetestedtheability

ofLMWfucoidantopotentiatetheeffectofFGF-2invitro

andtomobilizeSDF-1invivoandhaveassessedthein

vivotherapeuticeffectusingaratmodelofcriticalhind-

limbischemiapreviouslydevelopedinourlaboratory(Luyt

etal.,

2000).Article,publicationdate,andcitationinformationcanbefoundat

http://jpet.aspetjournals.org.

DOI:10.1124/jpet.102.046144.

ABBREVIATIONS:FGF-2,fibroblastgrowthfactor2;HMW,high-molecular-weight;SDF-1,stromal-derivedfactor-1;LMW,low-molecular-

weight;SMC,smoothmusclecell;EDL,extensorumdigitorumlongus.0022-3565/03/3051-24–30$7.00

THEJOURNALOFPHARMACOLOGYANDEXPERIMENTALTHERAPEUTICSVol.305,No.1

Copyright©2003byTheAmericanSocietyforPharmacologyandExperimentalTherapeutics46144/1047564JPET305:24–30,2003PrintedinU.S.A.

24

合集下载

胃癌靶向治疗的曙光——Claudin18.2

胃癌靶向治疗的曙光——Claudin18.2

肿瘤防治研究2023年第50卷第10期 Cancer Res Prev Treat,2023,Vol.50,No.10·1022·

doi:10.3971/j.issn.1000-8578.2023.23.0164

胃癌靶向治疗的曙光——Claudin18.2

李澔1，叶显辉2，周俊杰1，李晓芬1

Dawn of Targeted Therapy Using Claudin18.2 for Gastric Cancer

LI Hao1, YE Xianhui2, ZHOU Junjie1, LI Xiaofen1 

1. Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China

Hospital, Sichuan University, Chengdu 610041, China; 2. Colorectal Cancer Center, West

China Hospital, Sichuan University, Chengdu 610041, China

CorrespondingAuthor:LIXiaofen,E-mail:***************

Abstract: In recent years, significant advancements in molecular biology have paved the way for novel 

targeted therapeutic strategies for gastric cancer treatment. Claudin18, which is an important structural protein 

involved in tight junctions between cells, and its subtype Claudin18.2 (CLDN18.2), which is specifically 

药物涂层球囊治疗下肢动脉硬化闭塞

药物涂层球囊治疗下肢动脉硬化闭塞

- 10 -Chinese and Foreign Medical Research Vol.20, No.30 October, 2022论 著 Lunzhu 《中外医学研究》第20卷 第30期（总第542期）2022年10月

*基金项目：安徽省蚌埠医学院自然重点项目（2020byzd088）①蚌埠医学院第一附属医院　安徽　蚌埠　233004药物涂层球囊治疗下肢动脉硬化闭塞症短期效果分析*

蔡瑶①　余朝文①　官泽宇① 【摘要】　目的：观察紫杉醇药物涂层球囊治疗下肢动脉硬化闭塞症的短期效果。方法：选取蚌埠医学院第一附属医院血管外科2018年1月-2020年9月104例初发症状性下肢动脉硬化闭塞症的患者，根据治疗方法分为试验组和对照组，每组52例。试验组给予紫杉醇药物涂层球囊进行血管成形术，对照组给予血管裸金属支架植入术。对手术前后不同阶段两组Rutherford分级、患肢踝肱指数（ABI）、跛行距离、一期通畅率、再狭窄率和不良事件的发生进行分析。结果：两组术前、术后6个月Rutherford分级比较，差异均无统计学意义（P>0.05）；但术后6个月，两组Rutherford分级较术前均改善，差异均有统计学意义（P<0.05）。两组术前、术后1周及术后1个月间歇性跛行距离比较，差异均无统计学意义（P>0.05）；两组手术前后不同时间点间歇性跛行距离组内比较，差异均有统计学意义（P<0.05）。两组术前、术后1周及术后1个月ABI比较，差异均无统计学意义（P>0.05）；但试验组术后6个月ABI高于对照组（P<0.05）；两组手术前后不同时间点ABI组内比较，差异均有统计学意义（P<0.05）。两组术后6个月一期通畅率比较，差异无统计学意义（P>0.05）；两组术后6个月再狭窄率比较，差异有统计学意义（P<0.05）。在随访过程中，两组各有1例患者死亡，直接原因为急性心脑血管意外；两组均未发生截肢。结论：紫杉醇药物涂层球囊治疗下肢动脉硬化闭塞症的短期效果与裸金属支架相当，但术后6个月ABI的值更高、再狭窄率更低。 【关键词】　下肢动脉硬化闭塞症　药物涂层球囊　短期疗效 doi：10.14033/ki.cfmr.2022.30.003 文献标识码　A 文章编号　1674-6805（2022）30-0010-05 Analysis of Short-term Efficacy of Drug-coated Balloon in the Treatment of Lower Extremity Arteriosclerosis Obliterans/CAI Yao, YU Chaowen, GUAN Zeyu. //Chinese and Foreign Medical Research, 2022, 20(30): 10-14 [Abstract]　Objective: To investigate the short-term efficacy of Paclitaxel drug-coated balloon in the treatment of lower extremity arteriosclerosis obliterans. Method: A total of 104 patients with initial symptomatic lower extremity arteriosclerosis obliterans in the First Affiliated Hospital of Bengbu Medical College from January 2018 to September 2020 were selected and divided into the experimental group and the control group according to treatment method, 52 cases in each group. The experimental group was given Paclitaxel drug-coated balloon dilatation and the control group was given vascular bare-metal stent implantation. The Rutherford grade, ankle-humeral index (ABI), intermittent claudication distance, primary patency rate, restenosis rate and incidence of adverse events were compared between two groups in different stages before and after surgery. Result: The differences between two groups in Rutherford grading before and 6 months after surgery were not statistically significant (P>0.05); however, the Rutherford grading of two groups at 6 months after surgery were improved compared with those before surgery, the differences were statistically significant (P<0.05). The differences between two groups in intermittent claudication distance before, 1 week and 1 month after surgery were not statistically significant (P>0.05); there were statistically significant differences in the distance of intermittent claudication between the two groups at different time points before and after operation (P<0.05). The differences between two groups in ABI before, 1 week and 1 month after surgery were not statistically significant (P>0.05); but ABI in the experiment group at 6 months after surgery was higher than that in the control group (P<0.05); there were statistically significant differences in ABI between the two groups at different time points before and after operation (P<0.05). The difference between two groups in first-stage patency at 6 months after surgery was not statistically significant (P>0.05); the difference between two groups in restenosis rate at 6 months after surgery were statistically significant (P<0.05). During follow-up, 1 patient died in each group, and the direct cause was acute cardio-cerebrovascular accident, no amputation occurred in two group. Conclusion: The short-term effect of Paclitaxel drug-coated balloon dilatation is comparable to that of bare-metal stent, but ABI is higher and restenosis rate is lower after 6 months. [Key words]　Lower extremity arteriosclerosis obliterans　Drug-coated balloon　Short-term efficacy First-author’s address: The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China

双倍剂量质子泵抑制剂联合阿莫西林疗法补救治疗幽门螺杆菌感染的疗效及安全性分析

双倍剂量质子泵抑制剂联合阿莫西林疗法补救治疗幽门螺杆菌感染的疗效及安全性分析

现代消化及介入诊疗　２０２２年第２７卷第４期ＭｏｄｅｒｎＤｉｇｅｓｔｉｏｎ＆Ｉｎｔｅｒｖｅｎｔｉｏｎ２０２２牞Ｖｏｌ．２７牞Ｎｏ．４　［１６］付蕾，李潜，卢创新，等．尿酸联合ＣＡ１９９检测对结直肠癌ＴＮＭ分期和预后判断的价值［Ｊ］．肿瘤，２０２０，４０（７）：４９６５０２．［１７］钱香，王宏，任真，等．ＮＬＲ与ＦＩＢ和ＣＥＡ及ＣＡ１９９在结直肠癌中的应用价值［Ｊ］．中华预防医学杂志，２０２１，５５（４）：４９９５０５．［１８］ＧａｏＹ，ＷａｎｇＪ，ＺｈｏｕＹ，ｅｔａｌ．ＥｖａｌｕａｔｉｏｎｏｆＳｅｒｕｍＣＥＡ，ＣＡ１９９，ＣＡ７２４，ＣＡ１２５ａｎｄＦｅｒｒｉｔｉｎａｓＤｉａｇｎｏｓｔｉｃＭａｒｋｅｒｓａｎｄＦａｃｔｏｒｓｏｆＣｌｉｎｉｃａｌＰａｒａｍｅｔｅｒｓｆｏｒＣｏｌｏｒｅｃｔａｌＣａｎｃｅｒ［Ｊ］．ＳｃｉＲｅｐ，２０１８，８（１）：２７３２２７４１．［１９］胡志方，檀心广，刘燕．结直肠癌患者炎症因子相关评分对患者临床结局的预测价值分析［Ｊ］．现代消化及介入诊疗，２０２０，２５（６）：７４９７５３．［２０］ＲｏｇｏｖｓｋｉｉＶ．ＭｏｄｕｌａｔｉｏｎｏｆＩｎｆｌａｍｍａｔｉｏｎＩｎｄｕｃｅｄＴｏｌｅｒａｎｃｅｉｎＣａｎｃｅｒ［Ｊ］．ＦｒｏｎｔＩｍｍｕｎｏｌ，２０２０，１１：１１８０．［２１］王俊，周凯．术前血清白蛋白检测对结直肠癌患者根治术后预后的评估价值［Ｊ］．山东医药，２０１７，５７（３７）：９４９６．［２２］ＣｕｉＪ，ＹｕＭ，ＺｈａｎｇＮ，ｅｔａｌ．Ｐｒｏｇｎｏｓｔｉｃｓｃｏｒｅｓｂａｓｅｄｏｎｔｈｅｐｒｅｏｐｅｒａｔｉｖｅｐｌａｓｍａｆｉｂｒｉｎｏｇｅｎａｎｄｓｅｒｕｍａｌｂｕｍｉｎｌｅｖｅｌａｓａｐｒｏｇｎｏｓｔｉｃｆａｃｔｏｒｉｎｐａｔｉｅｎｔｓｗｉｔｈｕｐｐｅｒｕｒｉｎａｒｙｔｒａｃｔｕｒｏｔｈｅｌｉａｌｃａｒｃｉｎｏｍａ［Ｊ］．Ｏｎｃｏｔａｒｇｅｔ，２０１７，８（４０）：６８９６４６８９７３．［２３］ＦａｎＳ，ＰｅｎｇＨＸ，ＧａｏＱＦ，ｅｔａｌ．ＰｒｅｏｐｅｒａｔｉｖｅｃｉｒｃｕｌａｔｉｎｇＦＰＲａｎｄＣＣＦｓｃｏｒｅａｒｅｐｒｏｍｉｓｉｎｇｂｉｏｍａｒｋｅｒｓｆｏｒｐｒｅｄｉｃｔｉｎｇｃｌｉｎｉｃａｌｏｕｔｃｏｍｅｏｆｓｔａｇｅⅡ－Ⅲｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒｐａｔｉｅｎｔｓ［Ｊ］．ＣａｎｃｅｒＭａｎａｇＲｅｓ，２０１８，１０：２１５１２１６１．［２４］周航亮，陈鲜宝，崔莹珊，等．ＦＰＲ在Ⅰ～Ⅲ期结直肠癌患者术后辅助化疗疗效判断和预后评估中的价值［Ｊ］．检验医学，２０２０，３５（１０）：５９６４．［２５］廖存，马辉，阮国添，等．４３５例结直肠癌患者术前血清前白蛋白水平与肿瘤的临床病理特征的关系研究［Ｊ］．结直肠肛门外科，２０１９，２５（３）：２８４２８８［２６］ＤｉｎｇＰ，ＺｈｅｎｇＣ，ＣａｏＧ，ｅｔａｌ．ＣｏｍｂｉｎａｔｉｏｎｏｆｐｒｅｏｐｅｒａｔｉｖｅｐｌａｓｍａｆｉｂｒｉｎｏｇｅｎａｎｄＡＪＣＣｓｔａｇｉｎｇｉｍｐｒｏｖｅｓｔｈｅａｃｃｕｒａｃｙｏｆｓｕｒｖｉｖａｌｐｒｅｄｉｃｔｉｏｎｆｏｒｐａｔｉｅｎｔｓｗｉｔｈｓｔａｇｅⅠ－Ⅱｇａｓｔｒｉｃｃａｎｃｅｒａｆｔｅｒｃｕｒａｔｉｖｅｇａｓｔｒｅｃｔｏｍｙ［Ｊ］．ＣａｎｃｅｒＭｅｄ，２０１９，８（６）：２９１９２９２９．［２７］ＳｏｎＨＪ，ＰａｒｋＪＷ，ＣｈａｎｇＨＪ，ｅｔａｌ．ＰｒｅｏｐｅｒａｔｉｖｅＰｌａｓｍａＨｙｐｅｒｆｉｂｒｉｎｏｇｅｎｅｍｉａｉｓＰｒｅｄｉｃｔｉｖｅｏｆＰｏｏｒＰｒｏｇｎｏｓｉｓｉｎＰａｔｉｅｎｔｓｗｉｔｈＮｏｎｍｅｔａｓｔａｔｉｃＣｏｌｏｎＣａｎｃｅｒ［Ｊ］．ＡｎｎＳｕｒｇＯｎｃｏｌ，２０１３，２０（９）：２９０８２９１３．（收稿日期：２０２１１２２５）（本文编辑：巩兰波）

氟化透明质酸光敏剂负载聚多巴胺纳米粒子用于乏氧肿瘤的光动力与光热协同治疗

氟化透明质酸光敏剂负载聚多巴胺纳米粒子用于乏氧肿瘤的光动力与光热协同治疗

氟化透明质酸光敏剂负载聚多巴胺纳米粒子用于乏氧肿瘤的光动力与光热协同治疗

田君;张伟安

【摘 要】光动力疗法(PDT)是光敏剂通过光激活产生的单线态氧(1O2)来杀死癌细胞.光动力疗法的3个关键因素主要有:光、光敏剂与组织氧.在PDT治疗过程中,氧气消耗和实体瘤中固有的缺氧微环境可能进一步导致供氧不足,阻碍光动力疗效,而光热疗法(PTT)不受乏氧环境的影响,且具有无创性、低毒性等优点.将全氟化碳(PFCs)和光敏剂(Pba)接枝到透明质酸(HA)链中,然后负载聚多巴胺纳米粒子(PDANPs),设计出了一种新型的靶向自供氧光动力与光热协同治疗体系.由于PDANPs优良的光热转换性能、PFC较高的氧亲和力和HA的肿瘤靶向性,使得该协同疗法的抗肿瘤作用显著提高,细胞毒性实验以及细胞摄取实验证明了其增强的光热与光动力治疗效果.

【期刊名称】《华东理工大学学报（自然科学版）》

【年(卷),期】2019(045)002

【总页数】8页(P285-292)

【关键词】自供氧;全氟化碳;聚多巴胺;光动力治疗;光热治疗

【作 者】田君;张伟安

【作者单位】华东理工大学化学与分子工程学院,上海 200237;华东理工大学化学与分子工程学院,上海 200237

【正文语种】中 文 【中图分类】O69

由于发病率和死亡率的增加，癌症已成为全球范围内死亡的主要原因之一。到目前为止，已经开展了许多用于癌症治疗的技术，例如基因治疗、放射疗法、化学疗法、光动力疗法（PDT）、光热疗法（PTT）和协同疗法[1-2]。其中，PDT是通过光敏剂（PS）在光激活情况下产生活性氧（ROS）杀死癌细胞的一种治疗方法，在过去40年中已被广泛地应用于许多局部和表面的癌症治疗[3]。PDT涉及3个主要因素，一个是能够收集光并进行光动力学反应的PS，一个是为PS提供能量的适当光源，以及由激发的PS转移能量产生ROS所需的组织内氧气[4-5]。

然而，PDT的有效性受到肿瘤供氧不足这一微环境的限制[6-7]。实体肿瘤通常由于快速增殖的特性和混乱不规则的血管系统导致其需氧量远超过血液氧气供应量，而使部分肿瘤处于缺氧微环境中[8]。由于肿瘤区低氧气水平，因此乏氧肿瘤区可能被排除在多种治疗方法之外，不可避免地会导致肿瘤复发和转移[9]。针对PDT的这一问题，国内外众多学者进行了许多研究。Wang等[10]报告了一种基于血红蛋白（Hb）氧气载体体系，即通过化学作用将血红蛋白与三嵌段共聚物共轭结合，通过自组装行为得到将第二代光敏剂酞菁锌（ZnPc）包封在中间的胶束。研究者评估了共轭后Hb的氧结合能力和抗氧化活性，从而补偿ROS产生过程中的氧需求量。更重要的是，与无Hb的ZnPc胶束相比，含有Hb的ZnPc胶束体系在HeLa细胞中体外实验中能够产生更多的单线态氧（1O2）且具有更大的细胞光毒性。Cheng等[11]利用全氟化碳（PFCs）作为PS和氧气的载体，研究出了新型的氧自给的PDT（Oxy-PDT），近红外吸收波长为808 nm，并且它们与全氟化碳均匀分散在脂质单层中，在表面修饰聚乙二醇（PEG，MW=2 000）。这个体系不依赖于乏氧微环境、氧耗或血管损伤，并且体外实验和体内实验显示出比传统PDT更好的治疗功效。此外，PFCs的1O2寿命远远长于水中的1O2，从而导致了持久的光动力效果。Zheng等[12]报道了一种基于卟啉脂质体的体系，将卟啉接枝到脂质链中，通过组装形成卟啉体的结构，研究发现，在正常氧气含量情况下，该体系可体现协同的光动力与光热效用，而在乏氧情况下，光热可替代光动力起到很好的治疗作用。PTT因其对正常组织的无创性、低毒性以及高效的治疗效果而倍受关注[13]，而且不受乏氧微环境的影响。光热剂在NIR区具有强吸光度，能够有效地将光能转化为热能，从而导致肿瘤区域过热（高于42 ℃）并杀死肿瘤细胞。理想的光热剂具有高的光热转换效率和光稳定性且不会对正常组织产生毒副作用等优点[14]。各种具有优异PTT效果的光热材料被广泛探讨，包括无机纳米材料[15-16]和聚合物纳米粒子[17-18]。尽管大多数光热剂在肿瘤治疗中显示出很大的应用前景，但诸如光稳定性差、光热转化效率不足以及循环时间短等一些性质阻碍了其在癌症治疗中的进一步应用。聚多巴胺纳米材料由于具有优异的生物相容性和生物降解性，已被作为生物医学应用的优异材料[19]，现今PDANPs常被用作PTT剂，是由于其独特的强光吸收和高的光热转换效率[20-22]，另外，由于PDANPs的能量转移和电子转移性能，它也可以用作荧光猝灭剂[23]。