Carbonnanoparticlessuspensioninjectionforthedeliveryofdoxorubicin:Comparableefficacyandreducedtoxicity
作者：唐小海等
本文发表于：《MaterialsScienceengineering》年
单位：四川大学生物治疗国家重点实验室（成都，中国）
Abstract摘要
Drugdeliverysystemsfordoxorubicin(DOX)haveattractedtremendousinterestnowadaysfortheimprovedefficacyand/orreducedtoxicity.Duetothearomaticstructuresandhydrophobicdomains,carbonnanoparticlesuspensioninjection(CNSI),aclinicalappliedreagentforlymphnodemapping,stronglyadsorbsDOXandholdsgreatpotentialincancertherapy.Herein,weevaluatedthetherapeuticeffectsofCNSI-DOXtoestablishitsdeliveryapplicationsforcancerdrugs.CNSIadsorbedDOXfromsolutionquicklyafterthemixing,andthereleaseofDOXfromCNSIfollowedapH-dependentway.CNSI-DOXandfreeDOXhadnearlyidenticalinhibitiveeffectsoncancercells,whilethevehicleCNSIwasnontoxic.CNSI-DOXlargelyprolongedthelifespanofascitestumorbearingmiceaftertheintraperitoneallyinjectionandtheascitesweightsshowedsignificantdecreases.CNSI-DOXalsoinhibitedthegrowthofsubcutaneousxenograftsfollowingthesameadministrationroute.ThetherapeuticefficacyofCNSI-DOXwassimilartothatoffreeDOXinascitestumormodel,butslightlylowerinsubcutaneousxenograftsmodel.TheadvantageofusingCNSIwasmajorlyreflectedbythereducedtoxicityofDOXaccordingtothebodyweightchanges,serumbiochemicalindicatorsandhistopathologicalobservations.TheLD50(medianlethaldose)valueofCNSI-DOXwas43.8mg/kgbodyweight,nearlythreetimesofthatoffreeDOX(15.2mg/kgbodyweight).OurresultssuggestedthatCNSImightbeusedforDOXdeliverythrough“offlabel”thepatientsimmediately.
阿霉素（DOX）的药物传递系统现已引起了人们对改善功效和/或降低毒性的极大兴趣。纳米炭混悬注射液（CNSI），具有芳香结构和疏水结构，临床上用于淋巴结定位，其能强烈吸附DOX并在癌症治疗中具有巨大潜力。在此，我们评估了CNSI-DOX对癌症药物的传递应用的治疗效果。CNSI在混合后迅速从溶液中吸附DOX，并且从CNSI中释放DOX遵循pH依赖性方式。CNSI-DOX和游离DOX对癌细胞具有几乎相同的抑制作用，而载体CNSI是无毒的。CNSI-DOX在腹腔注射后大大延长了腹水瘤小鼠的寿命，腹水重量显着下降。CNSI-DOX也在相同的给药途径下抑制皮下异种移植物的生长。CNSI-DOX的治疗效果与腹水瘤模型中的游离DOX相似，但在皮下异种移植模型中略低。根据体重变化，血清生化指标和组织病理学观察，DOX的毒性降低，这反映出了使用CNSI的优势。CNSI-DOX的LD50（半数致死量）值为43.8mg/kg体重，几乎是游离DOX（15.2mg/kg体重）的三倍。我们的研究结果表明，CNSI可通过“超说明书”使用来对患者进行DOX传递。
Keywords关键词
CarbonnanoparticlessuspensioninjectionDoxorubicin;Doxorubicin;Toxicity;Drugdelivery;Tumor
纳米炭－阿霉素混悬注射液;阿霉素;毒性;药物输送;肿瘤
1
Introduction概述
Doxorubicin(DOX)isananthracyclineanticancerdrugforthetherapyofbothsolidandhematologicmalignancies[1,2].However,itsclinicaluseislargelylimitedbyitsbonemarrowtoxicity,astrointestinaltoxicity,andcardiotoxicity[3,5].Therefore,themajorissueinDOXtherapyistoreduceitstoxicityandmaintainitsefficacysimultaneously.Typically,therearetwomainstrategiesforthispurpose.First,theantioxidantscouldeliminatethereactiveradicalsgeneratingduringtheDOXtreatmentandprotectthepatientsfromcardiotoxicity[6,8].Second,thedrugdeliverysystem(DDS)couldenhancethetumoruptakeandreducethenon-specificaccumulationofDOXtoreduceitstoxicityandimproveitsefficacy[9–12].Forthispathway,diversevehicleswerereportedworldwide,suchasliposomes[13],polymercarriers[14],andinorganicnanomaterials[15].
阿霉素（DOX）是一种用于治疗实体和恶性血液病的蒽环类抗癌药物[1,2]。然而，其临床应用在很大程度上受其骨髓、胃肠道和心脏毒性的限制[3,5]。因此，DOX治疗的主要问题是降低其毒性并同时保持其疗效。通常，主要有两种策略。首先考虑抗氧化剂可以消除DOX治疗过程中产生的活性自由基，保护患者免受心脏毒性[6,8]。其次，药物传递系统（DDS）可以增强肿瘤摄取，减少DOX的非特异性积累，降低其毒性，提高其疗效[9-12]。对于该途径，全世界报道了多种载体，例如脂质体[13]、聚合物载体[14]和无机纳米材料[15]。
Inrecentdecades,carbonnanomaterialshaveattractedgreatinterestinDOXtherapyforboththeanti-oxidationandthedelivery.Forinstance,fullerenolwasfoundtobegoodantioxidantandprotectedthebodyfromtheDOXtoxicity[16].Ontheotherhand,DOXhaslargearomaticringsinthestructureandispartiallyhydrophobic,whichstronglybindstocarbonnanomaterialsthroughπ-πinteractionandhydrophobicinteraction[17].AnothermeritofusingcarbonnanomaterialsasdeliveryvehiclescouldbethatDOXshowspH-dependentreleaseoncarbonnanomaterials[17].MoreDOXmoleculesdetachfromcarbonsurfaceatacidicpHvalues,thuswouldhopefullybe
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