TW201619606A - 用於羰基之偵測及定量之方法及裝置 - Google Patents
用於羰基之偵測及定量之方法及裝置 Download PDFInfo
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- TW201619606A TW201619606A TW104120993A TW104120993A TW201619606A TW 201619606 A TW201619606 A TW 201619606A TW 104120993 A TW104120993 A TW 104120993A TW 104120993 A TW104120993 A TW 104120993A TW 201619606 A TW201619606 A TW 201619606A
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Abstract
螢光發色團諸如苯二胺衍生物可經歷氧化偶合及聚合以形成光學、色度學及螢光多聚體及聚合物。在有利環境條件下含羰基部分諸如醛及酮之存在可起始、催化、加速及調節此反應，其繼而提供用於偵測及定量此等部分之機制。經選擇苯二胺衍生物可用於通過量測反應及相關光譜轉變來偵測及定量醛及酮。特定而言，本文描述間苯二胺(mPDA)及相關化合物用於醛偵測及定量之用途。本方法提供一種不使用分離步驟之監測醛及酮含量之便利方式。該方法可應用於動力學及準終點偵測檢定形式。
Description
本申請案主張於2015年5月4日頒布之美國臨時申請案第62/156,441號、於2015年4月20日頒布之美國臨時申請案第62/149,988號、及於2014年6月27日頒布之美國臨時申請案第62/018,448號之權益，其等均以全文引用的方式併入本文中。
本發明係關於羰基偵測及定量之領域，及特定而言偵測及定量在生物樣品中之含羰基部分之濃度。
偵測含羰基部分係已知，但是精確偵測在生物樣品中特定低濃度之特定含羰基部分仍不清楚。已知羰基用於在高溫下引發鄰苯二胺及對苯二胺聚合以產生隨後用於製備產物之固體聚合物，但苯二胺衍生物用於偵測在一些生物樣品中之含羰基部分之方法仍不清楚。此外，量測在溶液中螢光物質之螢光以測定相應於該物質之分子存在以及定量在給定樣品中此等分子濃度係已知。進一步分析在生物樣品中之羰基係已知，例如參見於2003年11月6日公告之美國公開案第2003/0208133號及於2011年1月6日公告之美國公開案第2011/003395號，其等均以全文引用的方式併入本文中。
本發明一實施例係關於一種偵測在生物樣品中之含羰基部分之方法，該方法包括將苯二胺衍生物添加至含水鹽溶液以由此形成苯二胺溶液；將來自該生物樣品之含羰基部分添加至該苯二胺溶液以由此形成螢光溶液；及從該螢光溶液偵測螢光。
本發明另一實施例係關於一種含有醇、鹽、表面活性劑、苯二胺衍生物及含羰基部分之溶液。
本發明又一實施例係關於含有間苯二胺衍生物與含羰基部分產物之大體上無沉澱物溶液。
本發明另一實施例係關於一種偵測及量測在生物樣品中之含羰基部分濃度之方法，該方法包括：a)從該生物樣品分離含羰基部分；b)將該含羰基部分添加至含有苯二胺衍生物之水溶液以形成螢光溶液；及c)量測從該螢光溶液發射之預定波長的螢光。
本發明另一實施例係關於一種偵測及量測在人類呼吸樣品中醛濃度之方法，該方法包括：a.將來自人類呼吸樣品之醛捕捉至氧化矽上；b.在微酸性條件下於醇中形成包括鹽、緩衝劑、表面活性劑之溶液；c.將苯二胺衍生物添加至步驟b溶液；d.將捕捉之醛洗脫至步驟c溶液；e.測定步驟c溶液之螢光訊號；f.測定步驟d溶液之螢光訊號；g.從來自步驟f之螢光訊號中減去來自步驟e之螢光訊號；及h.比較來自步驟g之所得螢光訊號之淨值與已知醛的標準螢光以測定該螢光溶液中之醛濃度。
本發明另一實施例係關於一種裝置，包括；a)具有基板之呼吸室，該基板支撐來自動物呼吸之含羰基部分；及b)具有包括醇、鹽、表面活性劑、及緩衝劑之水溶液的流體室。
本發明又一實施例係關於一種用於偵測及定量在生物樣品中之含羰基部分濃度之裝置，該裝置包括具有其中結合活性反應性捕捉劑之基板。
本發明另一實施例係關於一種偵測在生物樣品中之含羰基部分之方法，該方法包括以下步驟：提供具有其中結合活性反應性捕捉劑之基板、將來該自生物樣品之含羰基部分捕捉於該基板上、及形成包括經塗色含羰基部分之溶液。
本發明另一實施例係關於一種偵測在生物樣品中之含羰基部分之方法，該方法包括以下步驟：a.提供基板；b.將活性反應性捕捉劑結合至該基板；c.將含羰基部分捕捉於該基板上；及d.從該基板將活性反應性捕捉劑及含羰基部分洗脫至溶液由此形成經塗色含羰基部分。
本發明另一實施例係關於一種偵測在生物樣品中之含羰基部分之方法，該方法包括將螢光發色團添加至含水鹽溶液以由此形成螢光發色團溶液；將來自生物樣品之含羰基部分添加至該螢光發色團溶液以由此形成螢光溶液；及從該螢光溶液偵測螢光。
圖1A顯示具有降低表面活性劑相依性之替代苯二胺衍生物。
圖1B顯示替代苯二胺衍生物。
圖1C顯示合成在圖1B中顯示之替代苯二胺衍生物之途徑。
圖1D顯示圖1B中顯示之替代苯二胺衍生物對醛引發間苯二胺聚
合FRET回應之例圖。
圖1E顯示描繪在1μM己醛存在時在圖1B中顯示之替代苯二胺衍生物的螢光增長之圖表。
圖2顯示描繪mPDA與1-己醛反應之發射光譜隨時間變化之圖表。
圖3顯示描繪隨mPDA與作為含羰基部分之1-己醛反應時間的推移之螢光增長之圖表。
圖4A顯示描繪隨與1-己醛反應時間推移隨著十二烷硫酸鈉(「SDS」)濃度從0.01至0.4%(w/v)之螢光增長之圖表。
圖4B顯示描繪在SDS濃度於0.2% SDS時與空白試樣對比之隨著與1-己醛反應時間推移的螢光增長之圖表。
圖4C顯示描繪在SDS濃度於0.4% SDS時與空白試樣對比之隨著與1-己醛反應時間推移的螢光增長之圖表。
圖5顯示展示隨著1-己醛濃度之螢光之圖表。
圖6顯示描繪隨著醛鏈長之相對螢光之圖表。
圖7顯示描繪經選擇小型芳胺相對螢光之圖表。
以下描述及附圖係解說性及並不解釋為限制。本文描述眾多特定細節以提供徹底理解本揭示。然而，在特定實例中，未描述熟知或習知細節以避免模糊該描述。參考此說明書，「一實施例」或「實施例」意指關於該實施例描述之特定特性、結構、或特徵係包含於本揭示至少一實施例。參考在本揭示一或另一實施例可係(但是並不必然)參考相同實施例；及，此等參考意指至少實施例之一，既非獨立亦非與其他實施例相互排斥之替代實施例。
在本揭示文中及在使用各個術語之特定內容中，用於此說明書之術語一般具有其在此項技術中常規含義。在本說明書下文或別處討
論用於描述本揭示之特定術語以為從業人員提供有關此揭示描述之額外導引。方便起見，可強調特定術語，例如使用斜體及/或引號標記。使用強調對術語範圍及含義並無影響；在相同內容中不論其是否強調，術語範圍及含義相同。
因此，替代語言或同義詞可用於任何一或數個本文討論之術語。不論本文是否詳細闡述或討論術語，不會賦予其任何特殊意義。提供特定術語同義詞。敘述一或數個同義詞不排除其他使用之同義詞。在包括任何本文討論術語實例之說明書中任何處使用之實例僅係解說性，並非意在進一步限制本揭示或任何例證術語之範圍及含義。
本發明係關於一種用於偵測、定量及檢定較佳地在生物樣品中，及較佳地在生物樣品中為低濃度的包括醛之含羰基部分(「CCM」)之方法及裝置。在此方面，CCM定義為包括一或數種不同含羰基部分。
如本文使用，「生物樣品」指在其廣泛含義，及包括固體及液體或任何獲自自然之生物樣品，包括個體、體液、細胞株、組織培養、或任何其他來源。如所指明，生物樣品包括體液或氣體，諸如呼吸、血液、精液、淋巴液、血清、血漿、尿、滑液、脊髓液、痰、膿、汗液，以及獲自環境之液體樣品諸如植物萃取物、池塘水等等。固體樣品可包括動物或植物身體部分，包括但不限於毛髮、指甲、樹葉等等。用於本發明一實施例之較佳生物樣品係人類呼吸。
CCM係具有至少一羰基之化合物。羰基係在廣泛化學化合物中出現之二價基團>C=0。該基團由雙鍵接至氧原子之碳原子組成。可在三種主要類有機化合物中最為頻繁的觀察到該羰基官能團：醛、酮、及羧酸。如本文使用，「醛」具有其常規化學含義及本發明方法用於偵測在生物樣品中之醛濃度。特定而言，本發明用於偵測各種醛形式，包括不作限於1-己醛、丙二醛、4-羥基壬烯醛(4-
hydroxynonenal)、乙醛、1-丙醛、2-甲基丙醛、2,2-二甲基丙醛，1-丁醛及1-戊醛。
由基板捕捉之CCM量可變化，但是通常對於由200mg之50至270目(300至50μm)粒子組成且床直徑為12.5mm之基板來說，一般而言，其應等於在呼氣進如呼吸測醉器之管後在人類呼吸中的量。較佳地其應係75至0.1ppb(400至4皮莫耳)及更佳為20ppb至0.01ppb(80至0.4皮莫耳)。
本發明應服從「混合&讀取」及「實時」檢定格式以以偵測CCM。本發明可應用於偵測溶液中之CMM。本發明可藉由添加初級捕捉(如下文描述在基板上)及釋放(如下文描述從負載基板洗脫)過程而應用於偵測氣相中之痕量CCM。較佳地在該過程一步驟中，將氣相CCM(例如來自人類呼吸之醛)捕捉於基板上。
本發明之基板最好係由固體(但並不一定剛性)材料形成。該固體基板可由各種材料形成，諸如薄膜、紙、不織網、針織物、編織織物、發泡體、玻璃，等等。例如，用於形成固體基板之材料可包括(但不限於)天然、合成、或以合成方法改質之天然材料，諸如多醣(例如，纖維素材料諸如紙及纖維素衍生物諸如乙酸纖維素及硝化纖維素)；聚醚碸；聚乙烯；耐綸；聚偏二氟乙烯(PVDF)；聚酯；聚丙烯；氧化矽；無機材料，諸如去活化氧化鋁、矽藻土、MgSO4、或其他在多孔基質中均勻分散之無機微細材料，與聚合物諸如氯乙烯、氯乙烯丙烯共聚物，及氯乙烯-乙酸乙烯酯共聚物；布，天然(例如，棉)及合成(例如，耐綸或嫘縈)；多孔凝膠，諸如氧化矽凝膠、瓊脂糖、聚葡糖、及明膠；聚合薄膜，諸如聚丙烯醯胺等等。較佳地該基板係視情況在玻璃料之間隔開之氧化矽固相基質。選擇基板尺寸使得由該基板捕捉可量測量之CCM。該尺寸可變化，但一般而言其係約2mL，較佳為約1mL及更佳為約0.25mL。
該基板通常由50至60埃孔之粒子床組成，具有50至270目(300至50μm)，及質量75至300mg，較佳為60至120目(250至125μm)質量100至200mg及更佳為50至120目(210至125μm)質量125至175mg。
在該過程另一步驟中，將螢光發色團諸如苯二胺衍生物添加至洗脫溶液以形成苯二胺溶液。可用於本發明之苯二胺衍生物包括但不限於包括不作限制之間苯二胺(「mPDA」)及其衍生物之眾多苯二胺衍生物，及在圖1A與圖1B中顯示之彼等，mPDA對於用以偵測包括不作限制1-己醛之醛而言較佳。儘管特定p-PDA或o-PDA衍生物可用於本發明方法，其不可用於偵測1-己醛，原因係其產生不能用於下文討論之基於光學偵測之渾濁膠狀懸浮液。
其他苯二胺衍生物包括以下或其混合物：
其中R1、R2、R3、R4各者分別選自由以下組成之群：H、烷基、經取代烷基、烷氧基、經取代烷氧基、醯基、醯基胺基、醯氧基、胺基、經取代胺基、胺基羰基、胺基硫羰基、胺基羰基胺、胺基硫羰基胺基、胺基羰氧基、胺基磺醯基、胺基磺醯氧基、胺基磺醯基胺基、甲脒基、羧基、羧基酯、(羧基酯)胺基、(羧基酯)氧基、氰基、鹵基、羥基、SO3-、磺醯基、經取代磺醯基、磺醯氧基、硫代醯基、硫醇基(thioal)、烷硫基、經取代烷硫基、醯基、經取代芳基、雜芳基、經取代雜芳基、環烷基、經取代環烷基、雜環、及經取代雜環。
參考圖1B，顯示mPDA-橘，即，4-[2-[4-(二乙胺基)苯基-乙烯
基]-1-[1-(3,5-二亞胺基苯甲醯胺)-戊基胺基-5-氧基己基]吡啶鎓。該mPDA衍生物mPDA-橘利用a)對環境變化之敏感性及b)調節mPDA-醛引發聚合之表面活性劑相依性之可能。用於合成mPDA-橘之方案在圖1C中闡明。基本方案係通過烷基醯胺鍵聯劑將mPDA結合至苯乙烯基吡啶鎓部分。
隨著分子結合至醛引發之mPDA聚合物，mPDA-橘顯示量子產率提高。此外，苯乙烯基吡啶鎓部分之激發及發射性質提供來自mPDA聚合物之FRET(福斯特(Forster)能量轉移)產生訊號。該苯乙烯基吡啶鎓部分顯示於470nm處最大之寬激發及於570nm處最大之發射。激發分析圖與mPDA聚合物之發射分析圖具有充分重疊以提供基於FRET之訊號產生。將藉由於mPDA聚合物(405nm)處之激發及於570nm處苯乙烯基吡啶鎓部分發射之發射表明基於FRET之訊號產生。在圖1D中顯示mPDA-橘對於mPDA之醛引發聚合的FRET回應之例圖。
由於聚合物引發需要高濃度苯乙烯基吡啶鎓之淬火，因此單獨mPDA-橘之直接醛引發聚合不會產生回應訊號。預期僅當mPDA-橘含於mPDA與mPDA-橘之混合物中時才會得到回應。實際上，僅當mPDA-橘以大幅度稀釋莫耳比mPDA/mPDA-橘為1,000：1至10,000：1摻雜入mPDA時才觀察到醛回應。在圖1E中闡明該對醛之回應。當於405nm激發及當將1μM己醛添加至該系統時觀察到mPDA-橘於570nm之發射增長。當於470至490nm直接激發mPDA-橘苯乙烯基吡啶鎓部分時未觀察到發射增長。該回應係在背景值上約3X，參見圖1E，此處條件係7mM mPDA，5μM mPDA-橘(莫耳比15,000：1)，90mM NaCl，15%乙醇，0.1%SDS，50mM pH2.5之檸檬酸鹽。該激發係於405nm及發射於575至585nm。如可觀察到，在缺乏醛時該背景水平維持相當穩定及自誘發導致mPDA-橘結合最少出現。儘管與單一mPDA為15X相比，mPDA-橘回應為遠遠較低之3X，該衍生物具有數
個優點：1)由在激發與發射間大斯托克斯(Stokes)位移提供之提升波長鑑別及2)經加強之基線穩定性。
一般而言，在苯二胺溶液中苯二胺衍生物濃度範圍從0.5mM至25mM。對於mPDA而言，在苯二胺溶液中mPDA濃度範圍一般從0.5至21mM，較佳為2至10mM，及對於諸如1-己醛之醛而言最佳5mM。儘管有上述，對於mPDA-橘而言，必須將其稀釋為低莫耳比mPDA，較佳為1000至10,000。
一般而言，洗脫溶液包括鹽、緩衝劑、表面活性劑、及有機溶劑。鹽濃度之範圍可從5mM至200mM及較佳為20mM至80mM；緩衝劑濃度之範圍可從25mM至200mM及較佳為40mM至60mM；及表面活性劑濃度之範圍可從0.05%(1.7mM)至0.4%(13.9mM)，及較佳為0.15%(5.2mM)至0.25%(8.7mM)。最佳使用0.2%或6.96mM。鹽可係任何對螢光溶液無負面影響及控制洗脫溶液中之鹽溶效應之鹽，及可包括NaCl、LiCl、KCl、硫酸鹽與磷酸鹽、及其混合物，較佳係NaCl。
採用緩衝劑使洗脫溶液維持微酸性及較佳地於pH2與4.5間，更佳為2.5。該緩衝劑可係硼酸鹽緩衝劑、磷酸鹽緩衝劑、檸檬酸鹽緩衝劑，有機緩衝劑諸如HEPES(1-哌嗪乙烷磺酸)或亦TRIS(三(羥甲基)胺基乙烷)緩衝劑，較佳係使用檸檬酸鹽緩衝劑以偵測醛。
該表面活性劑可包括癸基硫酸鈉、十二烷基硫酸鈉(「SDS」)、十四烷基硫酸鈉及Standapol ES-1，其中包括SDS之C10、C12及C14形式之SDS係較佳。亦可使用Trition X-100、Ninate 11、Georpon 71、Tetraonic 1357、Cremapor-el、Chemal la-9、Silwet L7900、Surfynly468、表面活性劑10G及Tween 80，但是其不具有與較佳洗脫溶液、CCM 1-己醛及mPDA之良好效果。
在缺乏SDS時，如下文討論之聚合及醛回應受到嚴重抑制。
mPDA係高水溶性及SDS之存在可提供將mPDA組織及定位至基質之支架以促進聚合反應。
該溶劑可包括EtOH、MeOH、丙醇、及異丙醇之水溶液，15%EtOH係較佳。
鹽濃度與苯二胺濃度之莫耳比係重要。一般而言該比例應從0.03至0.5變化。對於CCM 1-己醛而言，已發現0.165之mPDA對NaCl的莫耳比可提供最優回應。
實踐本發明方法之溫度較佳地從15至35℃變化，25至30℃係更佳。
對於醛諸如1-己醛而言，洗脫溶液之一較佳實施例包括33mM NaCl、50mM檸檬酸鹽、pH2.5、15%EtOH、及0.2%SDS。其他較佳洗脫溶液包括50mM檸檬酸鹽、pH2.5、15%丙醇及0.4%癸基硫酸鈉。
使用含有苯二胺衍生物之洗脫溶液時，將CCM洗脫至苯二胺溶液以形成螢光溶液。CCM與mPDA反應形成螢光物質，藉由量測由在螢光溶液中螢光物質發射之螢光來偵測其在螢光溶液中之存在。
藉由監測訊號提升(終點)及/或隨著給定mPDA濃度之醛濃度而變化之訊號改變速率(動力學)來定量醛含量，及比較此數據與呼吸之羰基群樣品。實務上必須濾除不同於所選擇羰基之羰基的影響。具有兩種一般檢定格式或偵測模式。一般而言其係以終點及動力學方式描述。在終點檢定中，培養該系統一段時間及讀取訊號。在該點訊號反應系統中分析物之數量。對於陽性檢定而言，分析物濃度越高，訊號提升越多。在動力學檢定中，監測速率變化一段設定時期。速率變化係與分析物之量相關。較佳地在本發明中採用終點檢定。
可在包括慣用掃描光譜儀、板讀取器或基於LED/二極體之光譜儀之典型螢光光譜儀上進行檢定量測，接著進行標準檢定實踐。出於闡明之目的，藉由將共2mL反應溶液與醛混合至標準螢光光析管及
使用LED/二極體光譜儀於特定時間切面以模擬終點測定來量測強度增加而獲得在圖2中顯示之數據。所使用之LED/二極體光譜儀係由具有LED源之Ocean Optics Jazz光譜儀與經由光纖耦合至Qpod-e(Quantum Northwest)溫度控制螢光樣品架之二極體偵測組成。通過紫LED(電壓：3.3V，電流：0.03A)產生405nm激發。使用具有設為495至505nm帶通及250msec整合發射之ILX-5118二極體偵測來偵測該訊號。如大部分基於螢光之檢定，最優設定取決於所使用之光譜儀之通量及雜散光排斥特徵及各個儀器必須憑經驗決定。
在一較佳實施例中，苯二胺衍生物在溶液中與CCM反應以產生螢光發射或螢光物質。據信苯二胺衍生物氧化偶合至CCM及苯二胺衍生物聚合為二聚體、三聚體、低聚物及/或聚合物。儘管由CCM存在調節聚合及具有劑量回應，並不確定CCM是否實際上變成部分該生長聚合物。
可將使用CCM聚合苯二胺衍生物之過程描述為分散聚合。聚苯二胺已經用於構建奈米結構及不同形狀、管、球等等之膠狀分散液。然而，若該聚合產生大高分子量結構，則在溶液中出現在本發明中不利於光學偵測之沉澱。由此必須選擇用於本發明方法之成分以避免在螢光溶液中具有抑制CCM偵測及定量之元素。
本發明採用CCM調節(起始、催化及加速)苯二胺衍生物之氧化偶合及聚合之能力來偵測及定量在生物樣品中的含痕量醛、酮及羰基之分析物。苯二胺氧化偶合及聚合產生發色及螢光物質。在mPDA及醛之情況下，聚合物或多聚體之形成產生於405nm寬吸光帶及於505nm相關發射帶。已在<350nm之UV區域中發現單體吸光。由此，聚合物之產生後可合宜地接著慣用吸光或螢光光譜法。在這方面，應瞭解該吸光及發射帶可根據CCM及選擇之苯二胺衍生物變化，但是此等可用於實踐本發明之帶均為本發明一部分。
例如，參考圖2，顯示在1μM 1-己醛存在下隨著時間之mPDA反應的發射光譜。螢光溶液條件係：1μM 1-己醛、5.4mM mPDA、33mM NaCl、50mM檸檬酸鹽(pH 2.5)、15% EtOH、及0.1% SDS。該發射隨時間而顯著增加。
參考圖3，觀察到具有或不具有醛(「空白試樣」)之反應及回應。螢光溶液條件係：1μM 1-己醛、5.4mM mPDA、33mM NaCl、50mM檸檬酸鹽(pH 2.5)、15% EtOH、及0.1% SDS。發射增加程度及增加速率取決於在苯二胺溶液中醛濃度。醛濃度越高，觀察到越大及越迅速訊號增加。在缺乏醛時，該「空白試樣」經歷表明在該檢測條件下緩慢mPDA聚合之緩慢漸小訊號提升。推測該聚合係由於存在諸如鐵之痕量氧化劑、反應性氧物質及其他引發劑之故。在添加CCM時，在空白試樣或背景觀察到顯著訊號增強。特別注意變化速率易於追蹤。由此，該偵測系統適合動力學及終點檢定設計及偵測模態。可於特定時間點，例如，15分鐘(時間切面)或藉由監測與醛相關之斜率定量該回應。動力速率足夠緩慢，不需要迅速及高精度之反應物添加。藉由CCM諸如醛調節聚合反應及其用作CCM定量分析感應器係另一在本說明書中描述之新穎發現及應用。其他替代包括標識、塗色或標記CCM以供隨後分析。
參考圖4A、4B及4C，顯示CCM引發之與苯二胺衍生物的聚合反應對環境條件及反應系統組分諸如SDS濃度敏感。在此等圖中螢光溶液條件係：1μM 1-己醛、5.4mM mPDA，33mM NaCl，50mM檸檬酸鹽(pH 2.5)，及15% EtOH。例如，該反應及醛檢定效能取決於鹽含量、mPDA含量、表面活性劑、pH及溫度。由於該反應涉及單體至聚合物之「準相」轉化，不足之mPDA濃度產生有限訊號變化之緩慢反應。相比之下，大量mPDA導致非常迅速反應及形成限制光學偵測之不可溶沉澱物。此外，大量過量導致增加之背景或「空白試樣」訊
號。
參考圖4A，訊號隨著SDS濃度而增加。在0.4% SDS濃度時，該訊號增加接近於0.2%觀察到訊號之3倍。
圖4B及4C分別顯示醛回應與0.2% SDS及0.4% SDS空白試樣之比較。SDS濃度增加亦導致「空白試樣」或背景訊號之增加。藉由SDS濃度調節訊號及背景且不能藉由單獨監測訊號回應來測定最優化之SDS濃度。因此必須最優化SDS濃度以提供訊號及背景訊號產生之間的最佳鑑別。對於特定實施例而言，最優SDS濃度位於狹窄濃度帶內，且小偏差可導致增加變化性及限制檢定敏感性。
參考圖5，顯示具有經背景校正之隨著1-己醛濃度變化的mPDA之螢光回應。觀察到從0.1至1μM 1-己醛之線性回應。該等數據點係三次重複樣品之平均值。在將醛添加至苯二胺溶液後20分鐘量測該訊號。在此等條件下(10.8mM mPDA、65.5mM NaCl、50mM檸檬酸鹽(pH 2.5)、0.2% SDS於25℃)，可達到0.1μM之溶液偵測極限(LOD)。
參考圖6中圖表，mPDA對隨著鏈長變化之脂肪族醛顯示差別回應。該圖表反映在醛添加後20分鐘及以下條件下的螢光訊號：5.4mM mPDA，33mM NaCl，50mM檸檬酸鹽(pH 2.5)，15% EtOH，及0.1% SDS。於20分鐘時量測該訊號及此時間切面充當假終點分析方法。對於脂肪族醛而言，該相對回應隨脂肪族鏈長增加。乙醯醛之回應僅係針對1-己醛所觀察到回應之12%。相比之下，癸基(C10)醛之回應與1-己醛相比高出30%。
芳香二胺之性質亦為使用本發明方法之重要考量。O-PDA係高反應性及經歷快速一般氧化。o-PDA之高反應性妨礙其在本發明較佳實施例中作為醛感應器之用途。參考圖7，顯示二胺之子集合的相對螢光回應及闡明位置及電子效應二者對醛螢光回應之影響。傳統芳香供電子效應及吸電子效應應調節苯二胺衍生物對聚合之反應性及感受
性。在較佳條件(甚至當暴露於過量醛時)下硝基苯二胺及萘苯二胺均未觀察到醛回應中。已發現醛偵測係基於反應聚合之調節。若選擇之分子係高反應性及易於引發以聚合，則一般氧化劑會促進反應過程及會限制其作為感應器之能力。另一方面，若該分子「過於」穩定，該聚合過程變得受抑制及不能由醛充分促進及需要更強氧化劑以產生回應。
本發明亦包括一種用於使用本發明方法之裝置。該裝置包括較佳地由塑膠製成之呼吸室及在呼吸室中具有基板。該基板係由上文討論之材料及較佳為氧化矽製成。該基板支撐來自動物呼吸之含羰基部分，例如醛。該裝置亦包括流體室。該流體室包含包括醇(例如，15%EtOH)、鹽(例如，NaCl)、表面活性劑(例如，SDS)，及緩衝劑(例如，檸檬酸鹽)之水溶液。該溶液亦可包括苯二胺衍生物諸如mPDA。
以下實例闡明一種使用本發明測定人類呼吸樣品是否含有可量測醛濃度及在呼吸中醛濃度之途徑。採用上文討論之方法論，進行一系列螢光量測以提供已知含於人類呼吸樣品(群)中各種特定醛及其混合物之標準，及此等各種標準及其混合物之濃度的標準。使用此等標準，測定在人類呼吸樣品中特定醛或醛混合物之存在及此等特定醛或醛混合物濃度。一般而言在一實施例中，步驟如下：a.將來自人類呼吸樣品之醛捕捉至氧化矽上；b.在微酸性條件下於醇中形成包括鹽、緩衝劑、表面活性劑之溶液；c.將苯二胺衍生物添加至步驟b溶液；d.將捕捉之醛洗脫至步驟c溶液；e.測定步驟c溶液之螢光訊號；f.測定步驟d溶液之螢光訊號；g.從來自步驟f之螢光訊號中減去來自步驟e之螢光訊號；及h.比較來自步驟g之螢光訊號與已知醛標準螢光(校準曲線，即，經由檢定對已知濃度回應)之淨值以測定在螢光溶液中的醛濃度。簡
而言之，此係「y」軸值之比較以提供「x」軸值，或者，已知y及標準函數y=f(x)解出x。
在本發明另一實施例中，可使用共價連接至包括(非限制)螢光肼或胺氧基化合物之CCM(該「劑」)的活性反應性捕捉劑來預負載基板。一些胺氧基化合物實例係如下：具有較佳係5或者6之單一異構體之胺氧基5(6)四甲基玫瑰紅(胺氧基5(6)TAMRA)；及具有較佳係5或者6單一異構體之胺氧基5(6)羰基螢光素(胺氧基5(6)FAM)，例如胺氧基-C5-5-FAM。其他包括胺氧基-7-胺基-3-乙醯基-4甲基香豆素-6-磺酸；5-胺氧基乙酸玫瑰紅B；及二硝基苯肼。在前述實例中，反應性基團指明不具有鏈接基團，其可係熟悉此項技術者熟知。除前述之外，本發明包括肼或醯肼變型。較佳地該劑係一些極性。
例如，對於由200mg 50至270網目(300至50μm)粒子組成且具有12.5mm之床直徑之基板而言，該劑之量可係5.5mg至0.1mg，及較佳為2.5mg至0.4mg。
在本發明又一實施例中，使用雙溶液方法論。在基板負載CCM後，將CCM洗脫至一般而言包括30%乙醇及較佳有50mM檸檬酸鹽、30% pH 2.5之乙醇的「沖洗」溶液。將該劑添加至沖洗溶液由此產生塗色之CCM。此溶液隨後經過另一基板，較佳地氧化矽玻璃料堆疊，以捕捉塗色之CCM。隨後使用包括高於50%乙腈及較佳為90%乙醇之第二「沖洗」溶液從其中捕捉有塗色之CCM之基板洗脫該塗色之CCM。此第二實施例優點之一係不必須基線讀數以移除雜訊。
除非本文另有清晰需要，貫穿描述及申請專利範圍，詞語「包括」、「包括」及等等解釋為相容意義，而不是排斥或絕對含義；即，「包含，但不限於」意義。此外，術語「此處」、「上文」、「下文」及相似含義詞語，當用於本申請案時應指此整體申請案而不是此申請案任何特定部分。在本文容許處，在上文實施方式中使用單數或複數之
詞語亦可分別包括複數或單數。關於二或數個項目列表中之詞語「或」，涵蓋全部該詞語下文解釋：任何在列表中項目、全部在列表中項目、及任何在列表中項目之組合。
本揭示上文實施方式並非意在為全面性或將該教示限制為上文揭示之精確形式。當在上文出於闡明目的描述揭示之特定實施例及實例時，各種等效修改係可能在本揭示範疇內，如彼等熟悉相關技術者應瞭解。例如，當方法以給定順序呈現時，替代實施例可以不同順序進行該方法，及可刪除，移動，添加、細分、組合、及/或修改一些方法步驟以提供替代或子組合。本文指出之進一步任何特定數字僅實例：替代實施例可採用不同值或範圍。
此等及其他變化可根據上文實施方式而構成本揭示。當上文實施方式描述本揭示特定實施例及描述詳細最佳模式時，不論以上在文中多詳細出現，可以眾多方式實踐該教示。系統詳情可以其實施詳情大幅度變化，同時仍包含於本文揭示主旨中。如上文指出，當描述本揭示特定特徵或態樣時使用之特定術語不應意指該術語於本文中重新定義而限制於與術語相關之本揭示的任何特定特性、特徵或態樣。一般而言，在以下技術方案中使用之術語不應解釋為將該揭示限制於在本說明書中揭示的特定實施例，除非上文實施方式部分明確定義此等術語。因此，本揭示實際範疇不僅包含揭示之實施例，亦包含在技術方案中實踐或實施本揭示之全部等效途徑。
因此，儘管已經顯示及描述本發明示範實施例，應瞭解全部本文使用術語係描述性而非限制，及可由一般技術者在不脫離本發明精神及範疇下產生眾多變化、修改、及取代。
Claims (56)
- 一種偵測生物樣品中之含羰基部分之方法，該方法包括將苯二胺衍生物添加至含水鹽溶液以由此形成苯二胺溶液；將來自該生物樣品之含羰基部分添加至該苯二胺溶液以由此形成螢光溶液；及從該螢光溶液偵測螢光。
- 如請求項1之方法，其中該含羰基部分係選自由下列組成之群：醛、酮、羧酸及其混合物。
- 如請求項2之方法，其中該醛係脂肪族。
- 如請求項1之方法，其中該生物樣品係人類呼吸。
- 如請求項1之方法，其中該苯二胺衍生物係選自由間苯二胺衍生物及其混合物組成之群。
- 如請求項1之方法，其中該螢光具有於505nm處之可量測發射帶。
- 如請求項1之方法，其中藉由在溶液中之含羰基部分聚合該苯二胺衍生物以形成螢光物質。
- 如請求項1之方法，其中該螢光溶液係維持在低於約35℃。
- 如請求項1之方法，其中該含水鹽溶液包括醇、鹽、表面活性劑及緩衝劑。
- 如請求項9之方法，其中該緩衝劑係檸檬酸鹽。
- 如請求項9之方法，其中該醇係選自由以下組成之群：R-OH(其中R係直鏈或支鏈脂肪族基團)、及其混合物。
- 如請求項10之方法，其中該醇係乙醇。
- 如請求項9之方法，其中該鹽係NaCl。
- 如請求項9之方法，其中該表面活性劑係十二烷基硫酸鈉。
- 如請求項7之方法，其中該螢光溶液中不具有在量測時會實質上 干擾該等螢光物質之量測的沉澱物。
- 如請求項1之方法，其中峰值螢光位準係與特定含羰基部分有關。
- 如請求項1之方法，其中該偵測之螢光係對應於該生物樣品中之含羰基部分之濃度。
- 如請求項1之方法，其中該水溶液係微酸性。
- 如請求項1之方法，其中該水溶液之pH範圍係從2至4.5。
- 如請求項1之方法，其中該溶液係處於pH 2.5。
- 如請求項9之方法，其中該苯二胺衍生物對該鹽之莫耳比範圍係從0.03至0.5。
- 如請求項1之方法，其中從氧化矽洗脫該含羰基部分。
- 如請求項1之方法，其中該苯二胺衍生物係放置在安瓿中。
- 如請求項22之方法，其中該氧化矽係放置在流體室中。
- 如請求項1之方法，其中該含羰基部分係含C1至C12羰基之有機分子。
- 一種溶液，其含有醇、鹽、表面活性劑、苯二胺衍生物及含羰基部分。
- 一種大體上無沉澱物之溶液，其含有間苯二胺衍生物與含羰基部分之產物。
- 一種偵測及量測生物樣品中之含羰基部分濃度之方法，該方法包括a)從該生物樣品分離含羰基部分；b)將該含羰基部分添加至含有苯二胺衍生物之水溶液以形成螢光溶液；及c)量測從該螢光溶液發射之預定波長的螢光。
- 如請求項28之方法，其中該生物樣品係呼吸樣品。
- 如請求項28之方法，其中該螢光溶液產生於405nm處之寬吸光帶及於505nm處之相關發射帶。
- 如請求項28之方法，其中該水溶液含有表面活性劑，且隨時間推移之螢光位準隨表面活性劑濃度而變化。
- 如請求項28之方法，其中使用螢光量測測定該生物樣品中之該含羰基部分之濃度。
- 一種偵測及量測人類呼吸樣品中之醛濃度之方法，該方法包括：a.將來自人類呼吸樣品之醛捕捉至氧化矽上；b.在微酸性條件下於醇中形成包括鹽、緩衝劑、表面活性劑之溶液；c.將苯二胺衍生物添加至步驟b之溶液；d.將經捕捉之醛洗脫至步驟c之溶液中；e.測定步驟c溶液之螢光訊號；f.測定步驟d溶液之螢光訊號；g.從來自步驟f之螢光訊號中減去來自步驟e之螢光訊號；及h.比較來自步驟g之所得螢光訊號之淨值與已知醛的標準螢光以測定該螢光溶液中之醛濃度。
- 如請求項33之方法，其中該醛係醛混合物。
- 如請求項33之方法，其中於505nm處量測該螢光。
- 一種裝置，包括：a)具有基板之呼吸室，該基板支撐來自動物呼吸之含羰基部分；及b)具有包括醇、鹽、表面活性劑、及緩衝劑之水溶液之流體室。
- 如請求項36之裝置，其中該溶液包括苯二胺衍生物。
- 如請求項36之裝置，其中該苯二胺衍生物係間苯二胺。
- 如請求項36之裝置，其中該含羰基部分係至少一種醛。
- 如請求項36之裝置，其中該基板係氧化矽。
- 一種用於偵測及定量生物樣品中之含羰基部分濃度之裝置，該裝置包括具有其中結合活性反應性捕捉劑之基板。
- 如請求項41之裝置，其中該苯二胺衍生物係間苯二胺。
- 一種用於偵測生物樣品中之含羰基部分之方法，該方法包括以下步驟：提供具有其中結合活性反應性捕捉劑之基板，將來自該生物樣品之含羰基部分捕捉於該基板上，及形成包括經塗色含羰基部分之溶液。
- 一種用於偵測生物樣品中之含羰基部分之方法，該方法包括以下步驟：a.提供基板；b.將活性反應性捕捉劑結合至該基板；c.將含羰基部分捕捉於該基板上；及d.從該基板將該等活性反應性捕捉劑及含羰基部分洗脫至溶液中，由此形成經塗色含羰基部分。
- 如請求項44之方法，其中該生物樣品係呼吸及該活性反應性捕捉劑係螢光肼或胺氧基化合物。
- 如請求項44之方法，其進一步包括在另一基板上捕捉該等經塗色之含羰基部分及將此等經捕捉經塗色之含羰基部分洗脫至另一溶液中以供隨後分析。
- 如請求項1、28或33中任一項之方法，其中該苯二胺衍生物包括4-[2-[4-(二乙胺基)苯基-乙烯基]-1-[1-(3,5-二亞胺基苯甲醯胺)-戊基胺基-5-氧基己基]吡啶鎓。
- 如請求項37之裝置，其中該苯二胺衍生物包括4-[2-[4-(二乙胺基) 苯基-乙烯基]-1-[1-(3,5-二亞胺基苯甲醯胺)-戊基胺基-5-氧基己基]吡啶鎓。
- 如請求項26之溶液，其中該苯二胺衍生物包括4-[2-[4-(二乙胺基)苯基-乙烯基]-1-[1-(3,5-二亞胺基苯甲醯胺)-戊基胺基-5-氧基己基]吡啶鎓。
- 如請求項27之溶液，其中該苯二胺衍生物包括4-[2-[4-(二乙胺基)苯基-乙烯基]-1-[1-(3,5-二亞胺基苯甲醯胺)-戊基胺基-5-氧基己基]吡啶鎓。
- 如請求項1、28或33中任一項之方法，其中該苯二胺衍生物包括以下任一者或混合物：
- 如請求項37之裝置，其中該苯二胺衍生物包括以下任一者或混合物：
- 如請求項26之溶液，其中該苯二胺衍生物包括以下任一者或混合物：
- 如請求項27之溶液，其中該苯二胺衍生物包括以下任一者或混合物：
- 一種偵測生物樣品中之含羰基部分之方法，該方法包括將螢光 發色團添加至含水鹽溶液以由此形成螢光發色團溶液；將來自該生物樣品之含羰基部分添加至該螢光發色團溶液以由此形成螢光溶液；及從該螢光溶液偵測螢光。
- 如請求項55之方法，其中該螢光發色團係苯二胺衍生物。
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- 2015-06-29 WO PCT/US2015/038391 patent/WO2015200924A1/en active Application Filing
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- 2015-06-29 WO PCT/US2015/038389 patent/WO2015200922A1/en active Application Filing
- 2015-06-29 TW TW104120999A patent/TW201607510A/zh unknown
- 2015-06-29 SI SI201530815T patent/SI3160361T1/sl unknown
- 2015-06-29 CN CN201580039856.2A patent/CN106537122A/zh active Pending
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- 2015-06-29 CA CA2953537A patent/CA2953537A1/en not_active Abandoned
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