傅 強(qiáng)，羅智敏，郭鵬琦

(西安交通大學(xué)醫(yī)學(xué)部藥學(xué)院藥物分析學(xué)系，陜西西安 710061)

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分子印跡技術(shù)及其在藥物分離與分析中的應(yīng)用

傅 強(qiáng)，羅智敏，郭鵬琦

(西安交通大學(xué)醫(yī)學(xué)部藥學(xué)院藥物分析學(xué)系，陜西西安 710061)

復(fù)雜體系微量藥物和藥物相關(guān)物質(zhì)的分離與分析是藥學(xué)研究領(lǐng)域的共性問(wèn)題。建立高靈敏度、高選擇性、高速度、自動(dòng)化、連續(xù)化、智能化的分析技術(shù)是藥物分析學(xué)科發(fā)展的重要方向。新方法的建立對(duì)于進(jìn)一步了解生命過(guò)程和藥物的作用、保障藥品質(zhì)量、提高藥品療效發(fā)揮了積極的推動(dòng)作用。近年來(lái)發(fā)展起來(lái)的分子印跡技術(shù)具有構(gòu)效預(yù)定性、識(shí)別特異性、長(zhǎng)期穩(wěn)定性和廣泛適用性等特點(diǎn)，得到研究者的廣泛關(guān)注。本文簡(jiǎn)述分子印跡技術(shù)的原理和制備方法，綜述了分子印跡技術(shù)在手性藥物分析、體內(nèi)藥物分析、中藥活性成分和生物大分子的分離與分析等中的應(yīng)用，并對(duì)其面臨的問(wèn)題及應(yīng)用前景進(jìn)行了展望。

分子印跡技術(shù)；藥物分離；藥物分析

藥物與生命體的相互作用，本質(zhì)上是物質(zhì)間的相互作用。靈敏度高、特異性強(qiáng)的分析技術(shù)對(duì)于進(jìn)一步了解生命過(guò)程和藥物的作用、保障藥品質(zhì)量、提高藥品療效發(fā)揮了積極的推動(dòng)作用。分子印跡技術(shù)(molecular imprinting technology, MIT)是一種高選擇性、特異性的分離和分析技術(shù)，這種技術(shù)的思想源于抗原-抗體專(zhuān)一性識(shí)別?；诜肿幼R(shí)別的聚合物材料——分子印跡聚合物具有構(gòu)效預(yù)定性、識(shí)別特異性、長(zhǎng)期穩(wěn)定性和廣泛適用性等特點(diǎn)，且具有抗惡劣環(huán)境能力強(qiáng)、穩(wěn)定性好、使用壽命長(zhǎng)等優(yōu)點(diǎn)，使得MIT在諸多領(lǐng)域均展現(xiàn)了良好的應(yīng)用前景。

1 原理與聚合物制備

1.1 基本原理 分子印跡的概念是由POLYAKOV 1931年提出，MOSBACH研究組在Nature上發(fā)表了茶堿和安定分子印跡聚合物的報(bào)道，引起了人們對(duì)MIT的極大關(guān)注，使得MIT得到了迅速的發(fā)展[1-2]。

MIT是一個(gè)為目標(biāo)分子合成人工抗體的過(guò)程。分子印跡聚合物(molecularly imprinted polymers, MIPs)的合成過(guò)程是以目標(biāo)分子為模板(template)，將具有結(jié)構(gòu)互補(bǔ)的功能單體(functional monomers)與模板分子結(jié)合后，使用交聯(lián)劑(cross linker)聚合在一起，然后將目標(biāo)分子去除，便會(huì)留下一系列大小、形狀與目標(biāo)分子相匹配的結(jié)合位點(diǎn)。MIPs不僅具有類(lèi)似天然抗體識(shí)別的特異性、高選擇性和高結(jié)合能力等特點(diǎn)，還具有更好的穩(wěn)定性、制備過(guò)程簡(jiǎn)單并可重復(fù)使用等優(yōu)點(diǎn)[3]。

1.2 MIPs的制備 MIPs的制備過(guò)程如圖1所示。根據(jù)模板分子與功能單體相互作用的原理不同，傳統(tǒng)MIPs的制備方法主要包括預(yù)組裝法、自組裝法、結(jié)合法和金屬螯合法[1]。

圖1 MIPs制備過(guò)程示意圖Fig.1 The preparation process of molecularly imprinted polymers

然而，傳統(tǒng)的MIPs制備方法均為不可控的自由基聚合法，這就導(dǎo)致MIPs存在非特異性的結(jié)合位點(diǎn)、結(jié)合位點(diǎn)分布不均一以及聚合層厚度不均一等問(wèn)題。為了克服這些缺點(diǎn)，近幾年研究人員將可控活性自由基聚合法引入到MIT中，該法通過(guò)控制溶液中參與反應(yīng)的自由基的鈍化，從而控制整個(gè)反應(yīng)的速度和進(jìn)程[4]?？煽鼗钚宰杂苫酆戏ㄖ饕ㄒ韵聨追N：

1.2.1 可逆加成-斷裂鏈轉(zhuǎn)移聚合法(reversible addition fragmentation chain transfer polymerization, RAFT) 該法制備過(guò)程中需要有可逆加成序列的存在，通過(guò)控制該序列中活躍鏈和休眠鏈間雙硫酯鍵的轉(zhuǎn)移來(lái)控制聚合的進(jìn)程。該法所得聚合物的分子量分布、分子大小和分子結(jié)構(gòu)都可以實(shí)現(xiàn)有效控制[5]。

1.2.2 引發(fā)-轉(zhuǎn)移-終止聚合法(initiation and transfer termination polymerization, ITTP) 該法是利用二硫代氨基甲酸鹽分裂成初始化的烷基以及穩(wěn)定的第二種自由基過(guò)程來(lái)制備。由于第二種自由基無(wú)法引發(fā)新的聚合鏈，當(dāng)向該反應(yīng)供給熱量或者減少紫外輻射時(shí)兩種自由基會(huì)重組而停止鏈增長(zhǎng)，之后再進(jìn)行下一次引發(fā)聚合，因此會(huì)在一定程度上實(shí)現(xiàn)了在線控制[6]。

1.2.3 原子轉(zhuǎn)移自由基聚合法(atom transfer radical polymerization, ATRP) 該法是通過(guò)可逆的氧化還原反應(yīng)產(chǎn)生多種活性基團(tuán)，經(jīng)金屬離子/配體復(fù)合物所催化，該催化劑則可以被從休眠態(tài)到活化態(tài)所轉(zhuǎn)移的鹵素原子所氧化，從而使復(fù)合物到達(dá)一個(gè)高氧化狀態(tài)[7]。

1.2.4 氮氧自由基聚合法(nitroxide mediated polymerization, NMP) 該法是一個(gè)熱可逆終止反應(yīng)，烷氧基胺C-ON鍵的均裂會(huì)促使該反應(yīng)的發(fā)生，從而烷基和氮氧自由基被激活，可以通過(guò)控制自由基產(chǎn)生的量來(lái)控制整個(gè)反應(yīng)的進(jìn)程[8]。

2 MIPs在藥物分離與分析中的應(yīng)用

與常規(guī)的分離或分析用的色譜固定相比較，MIPs的突出特點(diǎn)是對(duì)目標(biāo)分子具有高度的選擇性，同時(shí)還具有良好的物理化學(xué)穩(wěn)定性，能夠耐受高溫、高壓、酸堿、有機(jī)溶劑等，容易保存、制備簡(jiǎn)單、易于實(shí)現(xiàn)規(guī)?；苽洌蚨玫奖容^廣泛的應(yīng)用。MIPs在藥物分離與分析中主要被應(yīng)用于手性藥物分析、體內(nèi)藥物分析、中藥活性成分分離與分析以及藥物雜質(zhì)分離與分析等幾個(gè)方面。

2.1 手性藥物分析 手性藥物(chiral drug)的拆分一直是制藥工業(yè)、臨床藥物分析和環(huán)境檢測(cè)領(lǐng)域的研究熱點(diǎn)。目前世界臨床使用的合成藥物中，手性藥物占40%，且87%以上的手性藥物是以外消旋體的形式出售[9]。隨著對(duì)手性藥物研究的不斷深入，人們已經(jīng)發(fā)現(xiàn)手性藥物的藥效學(xué)、藥動(dòng)學(xué)和毒理學(xué)可表現(xiàn)出質(zhì)和量的區(qū)別，這就對(duì)分離手性藥物的技術(shù)提出了新的要求。盡管目前已有手性合成、酶拆分以及其它的分離技術(shù)，但MIPs在分離對(duì)映體方面有獨(dú)到之處，而且MIPs作為色譜固定相進(jìn)行手性拆分也是MIPs早期的研究重點(diǎn)。目前已成功分離的手性藥物見(jiàn)表1。

表1 MIPs用于對(duì)手性藥物的分析Tab.1 The application of MIPs for the analysis of chiral drugs

盡管MIPs作為手性固定相已經(jīng)研究二十余年，但其仍未投入商業(yè)使用，原因可能是由于MIPs手性固定相僅能針對(duì)特定手性藥物進(jìn)行分離，廣譜適用性較差；另外，缺乏高純度的光學(xué)異構(gòu)體作為模板，也限制了其應(yīng)用。

2.2 體內(nèi)藥物分析 體液成份復(fù)雜，干擾物質(zhì)多，而待測(cè)藥物濃度一般都很低。如何方便、快捷地對(duì)樣品進(jìn)行預(yù)處理，將少量的目標(biāo)藥物從大量復(fù)雜的生物基質(zhì)中分離出來(lái)，以便準(zhǔn)確定性、定量，是體內(nèi)藥物分析面臨的首要問(wèn)題[28]。近年來(lái)，隨著藥物分析技術(shù)的不斷提高，生物樣品預(yù)處理技術(shù)得到迅速發(fā)展，并克服了傳統(tǒng)萃取方式回收率低、繁瑣費(fèi)時(shí)、溶劑毒性大、易乳化等不足。其中，固相萃取技術(shù)(solid phase extraction, SPE)因其對(duì)目標(biāo)物具有回收率高、有機(jī)溶劑用量少、無(wú)相分離操作、能處理微量樣品以及易于自動(dòng)化等優(yōu)點(diǎn)而被廣泛和普遍應(yīng)用的樣品前處理方法[29]。然而，由于常規(guī)固相萃取吸附材料(如硅膠或C18材料等)與目標(biāo)分析物之間的作用是非特異性的，常常因萃取介質(zhì)對(duì)目標(biāo)物的選擇性較差的原因，在吸附目標(biāo)物的同時(shí)也引入了部分基質(zhì)和干擾物，使得對(duì)目標(biāo)物的分析受到干擾[30]。而分子印跡固相萃取是以MIPs為萃取介質(zhì)的固相萃取技術(shù)，MIPs具有從復(fù)雜樣品中特異地吸附目標(biāo)分子的能力，這一性質(zhì)使得MIPs非常適合作為SPE萃取介質(zhì)實(shí)現(xiàn)對(duì)復(fù)雜樣品中的目標(biāo)物選擇性的分離和富集[31]。

自1994年SELLERGREN等[32]以戊咪為模板分子制備了MIPs并將其作為固相萃取吸附劑用于對(duì)尿液中戊咪的分離后，將MIPs與SPE結(jié)合用于對(duì)體內(nèi)藥物分析的研究呈現(xiàn)出迅速發(fā)展。分子印跡-固相萃取(molecularly imprinted-solid phase extraction, MISPE)可用于對(duì)各種復(fù)雜樣品中目標(biāo)物的分離、純化和濃縮，涉及到的生物樣品包括各種體液、組織和排泄物等[33]，被檢測(cè)過(guò)化合物多為藥物及其代謝物、毒物或其他有害物質(zhì)等(表2)。

2.3 環(huán)境樣品中藥物的分離與分析 鑒于環(huán)境樣品中目標(biāo)物的濃度低、組分復(fù)雜且易變化，因而其檢測(cè)對(duì)技術(shù)的要求越來(lái)越高。MIPs用作固相萃取劑可克服環(huán)境樣品體系復(fù)雜的預(yù)處理手續(xù)，為這些樣品的采集、富集和分析提供極大的方便，尤其在痕量分析中發(fā)揮重要作用，毫摩爾水平下的痕量物質(zhì)經(jīng)這一方法預(yù)富集處理后，在色譜中則易于檢出(表3)。隨著MIT的不斷深入和應(yīng)用領(lǐng)域的不斷拓展，MIT在環(huán)境領(lǐng)域定會(huì)有更廣闊的應(yīng)用前景。

2.4 中藥活性成分的分離與分析 中藥是一個(gè)復(fù)雜的、結(jié)構(gòu)多樣性的天然組合化學(xué)庫(kù)，其所含的化合物結(jié)構(gòu)類(lèi)型多樣、量懸殊且許多成分未知，導(dǎo)致對(duì)中藥活性成分分離和分析的難度較大[76]。目前分離和分析中藥活性成分主要依賴(lài)于硅膠柱色譜(silica gel column chromatography)、大孔吸附樹(shù)脂柱色譜(macroporous adsorption resin column chromatography)、聚酰胺柱色譜(polyamide column chromatography)、凝膠柱色譜(gel column choromatography)、高速逆流色譜(high-speed countercurrent chromatography)、制備型高效液相色譜(preparative high performance liquid chromatography)等技術(shù)，為了更好地對(duì)活性成分進(jìn)行分離和分析，常需經(jīng)多種溶劑萃取和反復(fù)柱色譜，不僅溶劑消耗量大、環(huán)境污染嚴(yán)重，而且效率和收率也低[77]?；贛IT制備的MIPs具有親和性強(qiáng)和選擇性高、抗惡劣環(huán)境能力強(qiáng)、穩(wěn)定性好、使用壽命長(zhǎng)、應(yīng)用范圍廣等特點(diǎn)[78]，而且MIPs具有其他分離材料所不具備的特異性和選擇性，MIT將在中藥目標(biāo)成分的分離和分析中具有廣闊的應(yīng)用前景。目前用MIT研究的中藥成分有黃酮類(lèi)、多元酚類(lèi)、生物堿類(lèi)、甾體類(lèi)、香豆素類(lèi)和木脂素類(lèi)等(表4)，均取得了良好的效果。

表2 MIPs用于對(duì)體內(nèi)樣品中目標(biāo)物的分析Tab.2 The application of MIPs for the analysis of targets in biological samples

表3 MIPs用于對(duì)環(huán)境樣品中藥物的分離與分析Tab.3 The application of MIPs for the analysis of different types of drugs

表4 MIPs用于中藥活性成分的分離與分析Tab.4 The application of MIPs for the separation and analysis of the active ingredients in traditional Chinese medicines

然而，MIPs在中藥活性成分分離與分析中的應(yīng)用也有一定的局限性：①有些模板十分昂貴或難于獲取，且模板需用量較大，導(dǎo)致成本過(guò)高；②目前制備相對(duì)分子質(zhì)量較大的目標(biāo)物的MIPs還有一定的困難，需進(jìn)一步開(kāi)發(fā)中藥活性成分的模板；③MIPs的吸附容量受外界條件影響較大、較不穩(wěn)定，因此對(duì)目標(biāo)物的回收率常出現(xiàn)波動(dòng)；④MIPs對(duì)模板的結(jié)構(gòu)類(lèi)似物也會(huì)有一定的交叉識(shí)別作用，因此吸附物很難保證是單一模板化合物，吸附后還需進(jìn)一步純化等。

2.5 藥物雜質(zhì)的分離與分析 藥物雜質(zhì)控制是藥品質(zhì)量研究中的一項(xiàng)重要內(nèi)容。藥物中的雜質(zhì)含量低、來(lái)源廣泛、結(jié)構(gòu)類(lèi)型多且與主成分類(lèi)似，必須選擇合適的分析技術(shù)進(jìn)行研究[110]。MIPs的高選擇性、高強(qiáng)度、高耐用性及可重復(fù)使用等諸多優(yōu)點(diǎn)使得MIT在藥物雜質(zhì)分離和分析中也顯示出良好的應(yīng)用前景。

NAJAFI等[111]采用MIPs-電位傳感器分析吡羅昔康中的雜質(zhì)2-氨基吡啶(2-AP)，結(jié)果顯示，該傳感器對(duì)2-AP有高度識(shí)別性；HASHEMI等[112-113]制備的MIPs分別用于從鹽酸苯海拉明原料藥和氟伏沙明原料藥中特異識(shí)別具有潛在遺傳毒性的雜質(zhì)；BALAMURUGAN等[114]合成了分子印跡液相色譜柱用于檢測(cè)偽麻黃堿硫酸鹽對(duì)映體雜質(zhì)，結(jié)果顯示，兩個(gè)對(duì)映體的分離度不低于2，拖尾因子小于3.5，分離效果良好；LUO等[115-116]采用表面分子印跡法制備了MIPs，該MIPs可以從青霉素原料藥中特異識(shí)別具潛在致敏性的青霉噻唑酸；DU等[117]采用溶膠凝膠法制備的MIPs可從氯唑西林鈉原料藥中特異識(shí)別氯唑西林噻唑酸雜質(zhì)；SZéKELY等[118]制備的MIPs結(jié)合有機(jī)溶劑納濾，可實(shí)現(xiàn)從藥物活性組分中對(duì)具有遺傳毒性的1,3-diisopropylurea的特異識(shí)別和分離。因此，MIT的不斷發(fā)展為藥物雜質(zhì)的分離和分析提供了新的方法。

2.6 生物大分子的分離與分析 以蛋白質(zhì)、DNA、多糖等生物大分子為模板的MIT是一個(gè)嶄新而且富有挑戰(zhàn)性的研究。MIT利用仿生原理進(jìn)行分子識(shí)別，它具有的高特異性、高親和性以及良好的穩(wěn)定性都為其在生物大分子的分析應(yīng)用奠定了基礎(chǔ)，已經(jīng)成功被印跡的生物大分子具體見(jiàn)表5。

表5 MIPs用于生物大分子的分離與分析Tab.5 The application of MIPs for the separation and analysis of biomacromolecules

目前，分子印跡作為一種新型的技術(shù)用于生物大分子印跡也有許多局限性[118,142]：①生物大分子和聚合物單體官能團(tuán)間的相互作用缺乏系統(tǒng)研究，在識(shí)別過(guò)程中是孔穴的三維空間結(jié)構(gòu)還是功能基團(tuán)或其他方面起主導(dǎo)作用還無(wú)共識(shí)；②目前還沒(méi)有令人滿(mǎn)意的聚合方法以得到高吸附量的MIPs，這就使得MIT遠(yuǎn)遠(yuǎn)不能滿(mǎn)足實(shí)際應(yīng)用的需要；③尚未找到合適的方法洗脫蛋白質(zhì)印跡分子，活性蛋白質(zhì)很難得到回收利用。

3 展 望

近年來(lái)，隨著MIT的不斷發(fā)展，其作為一種方便、有效、操作簡(jiǎn)單的分離技術(shù)，已經(jīng)被廣泛應(yīng)用于生物樣品預(yù)處理、體內(nèi)微量藥物和代謝產(chǎn)物的檢測(cè)、毒物和藥物濫用分析、食品中藥物的非法添加和殘留分析、原料藥及制劑中有關(guān)物質(zhì)的富集和檢查等方面；更由于MIT具有易于產(chǎn)業(yè)化等優(yōu)點(diǎn)，越來(lái)越受到廣大研究者的重視，在藥學(xué)領(lǐng)域中也發(fā)揮了越來(lái)越大的作用，并顯示出獨(dú)特的優(yōu)勢(shì)和良好的應(yīng)用前景。

然而，作為一種新型的分離、富集手段，MIT自身還存在一定的問(wèn)題：①M(fèi)IPs與目標(biāo)物識(shí)別的作用機(jī)制研究相對(duì)膚淺；②功能單體、交聯(lián)劑和聚合方法的選擇有很大局限性；③該技術(shù)在諸多的應(yīng)用研究較多，但目前商業(yè)化的步伐緩慢，如何加速M(fèi)IT的商業(yè)化是研究者需要關(guān)注的問(wèn)題；④MIPs分離和富集目標(biāo)物的過(guò)程易于受到外界諸多因素的影響，如何提高其重復(fù)性的問(wèn)題亟待解決；⑤盡管對(duì)生物大分子的印跡研究已取得了一定的進(jìn)展，但所采用的方法多數(shù)普適性較差，方法本身也不夠成熟，實(shí)驗(yàn)結(jié)果的重現(xiàn)性不好，制備過(guò)程較煩瑣，迄今研究過(guò)的對(duì)象也比較少；⑥由于聚合條件的限制，MIPs在水相條件下聚合以及在水相條件下應(yīng)用的研究相對(duì)滯后，而且其在水環(huán)境下的識(shí)別機(jī)制也不甚清楚。因此，MIT還需要隨著新型材料的應(yīng)用和新技術(shù)的推進(jìn)從而進(jìn)一步發(fā)展和完善。

盡管MIT具有上述種種局限性，但由于其具備很高的選擇性以及優(yōu)良的理化特性，其必然會(huì)隨著技術(shù)本身的不斷發(fā)展和應(yīng)用的逐漸增多，將在藥物的分離與分析領(lǐng)域發(fā)揮越來(lái)越大的作用。

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(編輯 卓選鵬)

Molecular imprinting technology and its application in separation and analysis of drugs

FU Qiang, LUO Zhi-min, GUO Peng-qi

(Department of Pharmaceutical Analysis, School of Pharmacy of Xi’an Jiaotong University Health Science Center, Xi’an 710061, China)

The separation and analysis of trace drugs and drug-related substances in complex systems is a common issue in the field of pharmaceutical research. Establishment of high-sensitivity, high-selectivity, high-speed, automatic, continuous, and intelligent analysis technology is an important direction for the development of pharmaceutical analysis. The establishment of the new method has played a positive role in promoting further understanding of life process and the role of drug effect, guaranteeing drug quality and improving drug efficacy. Molecular imprinting technology (MIT) has attracted wide concern among researchers in recent years because of its characteristics of predetermined structure-activity, recognition specificity, long-term stability and wide applicability. This articles briefly introduces the principles and preparation methods; and reviews the application of MIT in the separation and analysis of chiral drugs, drugsinvivo, the active ingredients of traditional Chinese medicines, and the biomacromolecules. Besides, the problems and future development are also discussed.

molecular imprinting technology; drug separation; pharmaceutical analysis

傅強(qiáng)，西安交通大學(xué)醫(yī)學(xué)部藥學(xué)院藥物分析學(xué)系教授，醫(yī)學(xué)博士，博士生導(dǎo)師，享受?chē)?guó)務(wù)院政府特殊津貼專(zhuān)家。主要從事藥物色譜分析、毒物分析及藥品質(zhì)量標(biāo)準(zhǔn)研究工作。近年來(lái)主持國(guó)家自然科學(xué)基金面上項(xiàng)目4項(xiàng)，發(fā)表研究論文156篇，授權(quán)發(fā)明專(zhuān)利7項(xiàng)，主編教材和著作16部。已指導(dǎo)畢業(yè)碩士研究生45名，博士研究生8名。主持的項(xiàng)目曾獲陜西省高等學(xué)?？茖W(xué)技術(shù)一等獎(jiǎng)、陜西省科學(xué)技術(shù)一等獎(jiǎng)、吳階平醫(yī)學(xué)研究獎(jiǎng)——保羅·楊森藥學(xué)研究獎(jiǎng)、西安交通大學(xué)教學(xué)名師獎(jiǎng)、王寬誠(chéng)育才獎(jiǎng)。兼任教育部高等學(xué)校藥學(xué)類(lèi)專(zhuān)業(yè)教學(xué)指導(dǎo)委員會(huì)委員(2013～2017)，中國(guó)高等醫(yī)學(xué)教育藥學(xué)教育研究會(huì)常務(wù)理事，中國(guó)藥學(xué)會(huì)藥物分析專(zhuān)業(yè)委員會(huì)委員(第7屆、第8屆)，中國(guó)藥學(xué)會(huì)藥學(xué)教育專(zhuān)業(yè)委員會(huì)委員(第1屆)，J PharmANal、藥物分析雜志、西安交通大學(xué)學(xué)報(bào)(醫(yī)學(xué)版)等雜志編委。

2016-09-06

2016-09-28

國(guó)家自然科學(xué)基金資助項(xiàng)目(No.81573391, 81603073)

Supported by the National Natural Science Foundation of China (No.81573391 and 81603073)

傅強(qiáng). E-mail: fuqiang@xjtu.edu.cn

R914.1

A

10.7652/jdyxb201606001

專(zhuān)家介紹

優(yōu)先出版：http://www.cnki.net/kcms/detail/61.1399.R.20161010.1506.002.html(2016-10-10)