预览加载中，请您耐心等待几秒...

肿瘤靶向治疗.pdf

预览
1/9
2/9
3/9
4/9
5/9
6/9
7/9
8/9
9/9

在线预览结束，喜欢就下载吧，查找使用更方便

下载提示 文本预览

如果您无法下载资料，请参考说明：

1、部分资料下载需要金币，请确保您的账户上有足够的金币

2、已购买过的文档，再次下载不重复扣费

3、资料包下载后请先用软件解压，在使用对应软件打开

ARTICLE SelectiveTumorCellTargetingUsing Low-Affinity,MultivalentInteractions CobyB.Carlson†,‡,PatriciaMowery‡,RobertM.Owen†,EmilyC.Dykhuizen†,and LauraL.Kiessling†,‡,§,* †DepartmentofChemistry,1101UniversityAvenue,UniversityofWisconsin–Madison,Madison,Wisconsin53706, ‡DepartmentofBiochemistry,433BabcockDrive,UniversityofWisconsin–Madison,Madison,Wisconsin53706,and §UniversityofWisconsinComprehensiveCancerCenter,Madison,Wisconsin53706 nehundredyearshavepassedsincePaul Ehrlichcoinedtheterm“magicbullet”tode-ABSTRACTThisreporthighlightstheadvantagesoflow-affinity,multivalentin- Oscribeachemotherapeuticthatseeksoutandteractionstorecognizeonecelltypeoveranother.Ourgoalwastodeviseastrat- killsdisease-causingcellswhileleavingnormalonesegytomediateselectivekillingoftumorcells,whichareoftendistinguishedfrom unaffected(1).Thisvisionaryconceptremainsaninspi-normalcellsbytheirhigherlevelsofparticularcellsurfacereceptors.Totest rationformanytargeteddrugstrategies.Indeed,numer-whethermultivalentinteractionscouldleadtohighlyspecificcelltargeting,we ousanticancerdrugsrelyonthehigh-affinitymono-usedachemicallysynthesizedsmall-moleculeligandcomposedoftwodistinctmo- Ϸ–9 valentinteractionbetweenacell-bindingagent(e.g.,tifs:(1)anArg-Gly-Asp(RGD)peptidomimeticthatbindstightly(Kd10M)to ␣␤␣␣ monoclonalantibodyorfragmentthereof)andatumor-v3integrinsand(2)thegalactosyl-(1–3)galactose(-Galepitope),whichisrec- associatedantigentodirectacytotoxicmoietyselec-ognizedbyhumananti-␣-galactosylantibodies(anti-Gal).Importantly,anti-Gal tivelytothetumor(2).Despitethepotentialadvantagesbindingrequiresamultivalentpresentationofcarbohydrateresidues;anti-Galan- Ϸ–5 ofthisstrategy,thismodeofcellrecognitionisabiotic.tibodiesinteractweaklywiththemonovalentoligosaccharide(Kd10M)but Ϸ–11␣ Onecriticalconsequenceofsuchnon-naturalrecogni-bindtightly(Kd10M)tomultivalentdisplaysof-Galepitopes.Suchadis- tionisthatitoftenlackstherequiredselectivity.Thus,playisgeneratedwhenthebifunctionalconjugatedecoratesacellpossessin