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)

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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。新方法的建立對于進(jìn)一步了解生命過程和藥物的作用、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。近年來發(fā)展起來的分子印跡技術(shù)具有構(gòu)效預(yù)定性、識(shí)別特異性、長期穩(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，并對其面臨的問題及應(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)對于進(jìn)一步了解生命過程和藥物的作用、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-抗體專一性識(shí)別。基于分子識(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程。分子印跡聚合物(molecularly imprinted polymers, MIPs)的合成過程是以目標(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、制備過程簡單并可重復(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]。可控活性自由基聚合法主要包括以下幾種：

1.2.1 可逆加成-斷裂鏈轉(zhuǎn)移聚合法(reversible addition fragmentation chain transfer polymerization, RAFT) 該法制備過程中需要有可逆加成序列的存在，通過控制該序列中活躍鏈和休眠鏈間雙硫酯鍵的轉(zhuǎn)移來控制聚合的進(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程來制備。由于第二種自由基無法引發(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，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，可以通過控制自由基產(chǎn)生的量來控制整個(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表1。

表1 MIPs用于對手性藥物的分析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，而待測藥物濃度一般都很低。如何方便、快捷地對樣品進(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，以便準(zhǔn)確定性、定量，是體內(nèi)藥物分析面臨的首要問題[28]。近年來，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)因其對目標(biāo)物具有回收率高、有機(jī)溶劑用量少、無相分離操作、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尿液中戊咪的分離后，將MIPs與SPE結(jié)合用于對體內(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]，被檢測過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，因而其檢測對技術(shù)的要求越來越高。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，其所含的化合物結(jié)構(gòu)類型多樣、量懸殊且許多成分未知，導(dǎo)致對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于硅膠柱色譜(silica gel column chromatography)、大孔吸附樹脂柱色譜(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、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、多元酚類、生物堿類、甾體類、香豆素類和木脂素類等(表4)，均取得了良好的效果。

表2 MIPs用于對體內(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)致成本過高；②目前制備相對分子質(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，因此對目標(biāo)物的回收率常出現(xiàn)波動(dòng)；④MIPs對模板的結(jié)構(gòu)類似物也會(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、來源廣泛、結(jié)構(gòu)類型多且與主成分類似，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偽麻黃堿硫酸鹽對映體雜質(zhì)，結(jié)果顯示，兩個(gè)對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)作用還無共識(shí)；②目前還沒有令人滿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，隨著MIT的不斷發(fā)展，其作為一種方便、有效、操作簡單的分離技術(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、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)揮了越來越大的作用，并顯示出獨(dú)特的優(yōu)勢和良好的應(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題：①M(fèi)IPs與目標(biāo)物識(shí)別的作用機(jī)制研究相對膚淺；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)注的問題；④MIPs分離和富集目標(biāo)物的過程易于受到外界諸多因素的影響，如何提高其重復(fù)性的問題亟待解決；⑤盡管對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，制備過程較煩瑣，迄今研究過的對象也比較少；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)揮越來越大的作用。

[1] 傅強(qiáng)，曾愛國，杜瑋，等. 分子印跡技術(shù)與藥物分析[M]. 西安:西安交通大學(xué)出版社. 2014, 1-2.

[2] VLATAKIS G, ANDERSSON LI, MULLER R, et al. Drug assay using antibody mimics made by molecular imprinting[J]. Nature, 1993, 361(6413):645-647.

[3] SCHIRHAGL R. Bioapplications for molecularly imprinted polymers[J]. Anal Chem, 2013, 86(1):250-261.

[4] BOMPART M, HAUPT K. Molecularly imprinted polymers and controlled/living radical polymerization[J]. Aust J Chem, 2009, 62(52):751-761.

[5] HALHALLI MR, SCHILLINGER E, AURELIANO CSA, et al. Thin walled imprinted polymer beads featuring both uniform and accessible binding sites[J]. Chem Mater, 2012, 24(15):2909-2919.

[6] SALIAN VD, BYRNE ME. Living radical polymerization and molecular imprinting: Improving polymer morphology in imprinted polymers[J]. Macromol Mater Eng, 2013, 298(4):379-390.

[7] KIM YH, FORD WT, MOUREY TH. Branched poly(styrene-b-tert-butyl acrylate) and poly(styrene-b-acrylic acid) by ATRP from a dendritic poly(propylene imine) (NH2)64core[J]. J Polym Sci Pol Chem, 2007, 45(20):4623-4634.

[8] HAWKER CJ, BOSMAN AW, HARTH E. New polymer synthesis by nitroxide mediated living radical polymerizations[J]. Chem Rev, 2001, 33(15):3661-3688.

[9] 馬娟娟，王新龍，楊春杰. 分子印跡聚合物材料在手性藥物分離和藥物檢測中的應(yīng)用[J]. 化工時(shí)刊, 2004, 18(1):5-8.

[10] MAYES AG, MOSBACH K. Molecularly imprinted polymer beads: suspension polymerization using a liquid perfluorocarbon as the dispersing phase[J]. Anal Chem, 1996, 68(21):3769-3774.

[11] QU P, LEI J, OUYANG R, et al. Enantioseparation and amperometric detection of chiral compounds by in situ molecular imprinting on the microchannel wall[J]. Anal Chem, 2009, 81(23):9651-6.

[12] ZHU X, ZHU Q. Molecular imprinted Nylon-6 stir bar as a novel extraction technique for enantioseparation of amino acids[J]. J Appl Polym Sci, 2008, 109(4):2665-2670.

[13] MENG Z, ZHOU L, WANG J, et al. Molecule imprinting chiral stationary phase[J]. Biomed Chromatogr, 1999, 13(6):389-93.

[14] HUANGFU F, WANG B, SHAN J, et al. Enantioselective analysis of naproxen using chiral molecular imprinting polymers based thin-layer chromatography[J]. E-Polymers, 2013, 13(1):180-188.

[15] LEI, J, TAN T. Chiral separation of racemic drugs using molecular imprinting[J]. Prog Nat Sci, 2002, 12(12):900-903.

[16] 趙瀟，秦培勇. 布洛芬手性拆分分子印跡復(fù)合膜的制備與表征[J]. 北京化工大學(xué)學(xué)報(bào)(自然科學(xué)版), 2013, 40(1):5-9.

[17] FU Q, SANBE H, KAGAWA C, et al. Uniformly sized molecularly imprinted polymer for (S)-nilvadipine. Comparison of chiral recognition ability with HPLC chiral stationary phases based on a protein[J]. Anal Chem, 2003, 75(2):191-198.

[18] AMUT E, FU Q, FANG Q, et al. In situ polymerization preparation of chiral molecular imprinting polymers monolithic column for amlodipine and its recognition properties study[J]. J Polym Res, 2009, 17(3):401-409.

[19] FISCHER L, MUELLER R, EKBERG B, et al. Direct enantioseparation of. beta.-adrenergic blockers using a chiral stationary phase prepared by molecular imprinting[J]. J Am Chem Soc, 1991, 113(24):9358-9360.

[20] DUARTE M, BILLING J, YILMAZ E. Solvent-free synthesis of chiral molecularly imprinted polymers: Porosity control using a nano-sized solid porogen[J]. J Appl Polym Sci, 2016, 133(41):44104-44108.

[21] RAMSTROM O, YU C, MOSBACH K. Chiral recognition in adrenergic receptor binding mimics prepared by molecular imprinting[J]. J Mol Recognit, 1996, 9(5-6):691-696.

[22] HAGINAKA J, KAGAWA C. Uniformly sized molecularly imprinted polymer for d-chlorpheniramine: Evaluation of retention and molecular recognition properties in an aqueous mobile phase[J]. J Chromatogr A, 2001, 913(1-2):141-146.

[23] OU J, DONG J, TIAN T, et al. Enantioseparation of tetrahydropalmatine and Tr?ger’s base by molecularly imprinted monolith in capillary electrochromatography[J]. J Biochem Bioph Met, 2007, 70(1):71-76.

[24] OU J, TANG S, ZOU H. Chiral separation of 1,1’-bi-2-naphthol and its analogue on molecular imprinting monolithic columns by HPLC[J]. J Sep Sci, 2005, 28(17):2282-2287.

[25] SAJINI T, MATHEW B, THOMAS A. Fabrication and optimization of chiral receptor sites for D-MA using molecular imprinting technology[J]. Int J Educ Sci Res, 2015, 2(6):20-35.

[26] 歐俊杰，董靖，吳明火，等. 分子印跡整體柱在高效液相色譜和電色譜手性分離中的應(yīng)用[J]. 色譜, 2007, 25(2):129-134.

[27] LAHAV M, KHARITONOV AB, WILLNER I. Imprinting of chiral molecular recognition sites in thin TiO2, films associated with field-effect transistors: Novel functionalized devices for chiroselective and chirospecific analyses[J]. Chemistry, 2001, 7(18):3992-3997.

[28] 童珊珊，余江南，劉文英，等. 體內(nèi)藥物分析中的樣品預(yù)處理技術(shù)[J]. 藥學(xué)進(jìn)展, 2001, 25(1):24-27.

[29] CAMEL V. Solid phase extraction of trace elements[J]. Spectrochim Acta B, 2003, 58(7):1177-1233.

[30] 蔡亞岐，牟世芬. 分子印跡固相萃取及其應(yīng)用[J]. 分析測試學(xué)報(bào), 2005, 24(5):116-121.

[31] CHEONG WJ, YANG SH, ALI F. Molecular imprinted polymers for separation science: A review of reviews[J]. J Sep Sci, 2013, 36(3):609-628.

[32] SELLERGREN B. Direct drug determination by selective sample enrichment on an imprinted polymer[J]. Anal Chem, 1994, 66(9):1578-1582.

[33] TURIEL E, MARTIN-ESTEBAN A. Molecularly imprinted polymers for sample preparation: A review[J]. Anal Chim Acta, 2010, 668(668):87-99.

[34] LUO K, LIU M, FU Q, et al. Solid-phase extraction of S-(-)-amlodipine from plasma with a uniformly sized molecularly imprinted polymer[J]. J Appl Polym Sci, 2012, 125(5):3524-3531.

[35] FU Q, HE L, ZHANG Q, et al. Uniformly sized molecularly imprinted polymers for on-line concentration, purification, and measurement of nimodipine in plasma[J]. J Appl Polym Sci, 2009, 111(6):2830-2836.

[36] ZHANG Q, FU Q, AMUT E, et al. Preparation and evaluation of propranolol-imprinted monolithic stationary phase by in situ technique and application in analysis of propranolol in biological samples[J]. Anal Lett, 2009, 42(3):536-554.

[37] TABANDEH M, GHASSAMIPOUR S, AQABABA H, et al. Computational design and synthesis of molecular imprinted polymers for selective extraction of allopurinol from human plasma[J]. J Chromatogr B, 2012, 898(6):24-31.

[38] MA JB, QIU HW, RUI QH, et al. Fast determination of catecholamines in human plasma using carboxyl-functionalized magnetic-carbon nanotube molecularly imprinted polymer followed by liquid chromatography-tandem quadrupole mass spectrometry[J]. J Chromatogr A, 2015, 1429:86-96.

[39] LIU Z, BUCKNALL DG, ALLEN MG. Absorption performance of iodixanol-imprinted polymers in aqueous and blood plasma media[J]. Acta Biomater, 2010, 6(6):2003-2012.

[40] MOEIN MM, JAVANBAKHT M, AKBARI-ADERGANI B. Molecularly imprinted polymer cartridges coupled on-line with high performance liquid chromatography for simple and rapid analysis of human insulin in plasma and pharmaceutical formulations[J]. Talanta, 2014, 121:30-36.

[41] MURASE N, TANIGUCHI SI, TAKANO E, et al. A molecularly imprinted nanocavity-based fluorescence polarization assay platform for cortisol sensing[J]. J Mater Chem B, 2016, 4(10):1770-1777.

[42] LIANG C, PENG H, BAO X, et al. Study of a molecular imprinting polymer coated BAW bio-mimic sensor and its application to the determination of caffeine in human serum and urine[J]. Analyst, 1999, 124(12):1781-1785.

[43] JAFARI MT, REZAEI B, ZAKER B, et al. Ion mobility spectrometry as a detector for molecular imprinted polymer separation and metronidazole determination in pharmaceutical and human serum samples[J]. Anal Chem, 2009, 81(9):3585-3591.

[44] KHANSARI MR, BIKLOO S, SHAHREZA S. Determination of donepezil in serum samples using molecularly imprinted polymer nanoparticles followed by high-performance liquid chromatography with ultraviolet detection[J]. J Sep Sci, 2016, 39(5):1000-1008.

[45] SADEGHI S, MOTAHARIAN A. Voltammetric sensor based on carbon paste electrode modified with molecular imprinted polymer for determination of sulfadiazine in milk and human serum[J]. Mat Sci Eng C, 2013, 33(8):4884-4891.

[46] KHORRAMI AR, MEHRSERESHT S. Synthesis and evaluation of a selective molecularly imprinted polymer for the contraceptive drug levonorgestrel[J]. J Chromatogr B, 2008, 867(2):264-269.

[47] REZAEI B, JAFARI MT, KHADEMI R. Selective separation and determination of primidone in pharmaceutical and human serum samples using molecular imprinted polymer-electrospray ionization ion mobility spectrometry (MIP-ESI-IMS)[J]. Talanta, 2009, 79(3):669-675.

[48] SALEHI S, RASOUL-AMINI S, ADIB N, et al. Synthesis of molecular imprinted polymers for selective extraction of domperidone from human serum using high performance liquid chromatography with fluorescence detection[J]. J Chromatogr B, 2016, 1027:165-173.

[49] FAN W, HE M, YOU L, et al. Water-compatible graphene oxide/molecularly imprinted polymer coated stir bar sorptive extraction of propranolol from urine samples followed by high performance liquid chromatography-ultraviolet detection[J]. J Chromatogr A, 2016, 1443:1-9.

[50] REJTHAROVA M, REJTHAR L. Determination of chloramphenicol in urine, feed water, milk and honey samples using molecular imprinted polymer clean-up[J]. J Chromatogr A, 2009, 1216(46):8246-8253.

[51] SCORRANO S, LONGO L, VASAPOLLO G. Molecularly imprinted polymers for solid-phase extraction of 1-methyladenosine from human urine.[J]. Anal Chim Acta, 2010, 659(1-2):167-171.

[52] XIONG Y, ZHOU H, ZHANG Z, et al. Flow-injection chemiluminescence sensor for determination of isoniazid in urine sample based on molecularly imprinted polymer[J]. Spectrochim Acta A, 2007, 66(2):341-346.

[53] DOUE M, BICHON E, DERVILLY-PINEL G, et al. Molecularly imprinted polymer applied to the selective isolation of urinary steroid hormones: An efficient tool in the control of natural steroid hormones abuse in cattle[J]. J Chromatogr A, 2012, 1270(24):51-61.

[54] LAI J, CHEN F, SUN H, et al. Molecularly imprinted microspheres for the anticancer drug aminoglutethimide: Synthesis, characterization, and solid-phase extraction applications in human urine samples[J]. J Sep Sci, 2014, 37(9-10):1170-1176.

[55] GU X, HE H, WANG CZ, et al. Synthesis of surface nano-molecularly imprinted polymers for sensitive baicalin detection from biological samples[J]. RSC Adv, 2015, 5(52):41377-41384.

[56] LUO Y, HUANG P, FU Q, et al. Preparation of monolithic imprinted stationary phase for clenbuterol by in situ polymerization and application in biological samples pretreatment[J]. Chromatographia, 2011, 74(9-10):693-701.

[57] HU Y, LI Y, LIU R, et al. Magnetic molecularly imprinted polymer beads prepared by microwave heating for selective enrichment of β-agonists in pork and pig liver samples[J]. Talanta, 2011, 84(2):462-470.

[58] ANDREA P, MIROSLAV S, SILVIA S, et al. A solid binding matrix/molecularly imprinted polymer-based sensor system for the determination of clenbuterol in bovine liver using differential-pulse voltammetry[J]. Sensor Actuat B Chem, 2001, 76(1):286-294.

[59] FENG MX, WANG GN, YANG K, et al. Molecularly imprinted polymer-high performance liquid chromatography for the determination of tetracycline drugs in animal derived foods[J]. Food Control, 2016, 69:171-176.

[60] TANG Y, LAN J, XUE G, et al. Determination of clenbuterol in pork and potable water samples by molecularly imprinted polymer through the use of covalent imprinting method[J]. Food Chem, 2016, 190:952-959.

[61] DU W, LEI C, ZHANG S, et al. Determination of clenbuterol from pork samples using surface molecularly imprinted polymers as the selective sorbents for microextraction in packed syringe[J]. J Pharmaceu Biomed Anal, 2014, 91(91C):160-168.

[62] DU W, FU Q, ZHAO G, et al. Dummy-template molecularly imprinted solid phase extraction for selective analysis of ractopamine in pork[J]. Food Chem, 2013, 139(1-4):24-30.

[63] YANG J, HU Y, CAI JB, et al. Selective hair analysis of nicotine by molecular imprinted solid-phase extraction: An application for evaluating tobacco smoke exposure[J]. Food Chem Toxicol, 2007, 45(6):896-903.

[64] DIPL-CHEM JLU, HALL AJ, PRIV-DOZ MB, et al. A stoichiometric molecularly imprinted polymer for the class-selective recognition of antibiotics in aqueous media[J]. Angew Chem Int Edit, 2006, 45(31):5158-5161.

[65] YIN JF, MENG ZH, DU MJ, et al. Pseudo-template molecularly imprinted polymer for selective screening of trace β-lactam antibiotics in river and tap water[J]. J Chromatogr A, 2010, 1217(33):5420-5426.

[66] XU L, PAN J, DAI J, et al. Preparation of thermal-responsive magnetic molecularly imprinted polymers for selective removal of antibiotics from aqueous solution [J]. J Hazard Mater, 2012, 233-234(10):48-56.

[67] CHEN L, ZHANG X, XU Y, et al. Determination of fluoroquinolone antibiotics in environmental water samples based on magnetic molecularly imprinted polymer extraction followed by liquid chromatography-tandem mass spectrometry[J]. Anal Chim Acta, 2010, 662(1):31-38.

[68] NOIR ML, LEPEUPLE AS, GUIEYSSE B, et al. Selective removal of 17β -estradiol at trace concentration using a molecularly imprinted polymer[J]. Water Res, 2007, 41(12):2825-2831.

[69] RACHKOV A, MINOURA N. Recognition of oxytocin and oxytocin-related peptides in aqueous media using a molecularly imprinted polymer synthesized by the epitope approach[J]. J Chromatogr A, 2000, 889(1-2):111-118.

[70] RACHKOV A, HU M, BULGAREVICH E, et al. Molecularly imprinted polymers prepared in aqueous solution selective for [Sar1,Ala8]angiotensin II[J]. Anal Chim Acta, 2004, 504(1):191-197.

[71] KARLSSON JG, ANDERSSON LI, NICHOLLS IA. Probing the molecular basis for ligand-selective recognition in molecularly imprinted polymers selective for the local anaesthetic bupivacaine[J]. Anal Chim Acta, 2001, 435(1):57-64.

[72] KUGIMIYA A, TAKEUCHI T. Molecularly imprinted polymer-coated quartz crystal microbalance for detection of biological hormone[J]. Electroanalysis, 1999, 11(15):1158-1160.

[73] CHEN L, LIU J, ZENG Q, et al. Preparation of magnetic molecularly imprinted polymer for the separation of tetracycline antibiotics from egg and tissue samples[J]. J Chromatogr A, 2009, 1216(18):3710-3719.

[74] 劉蓉，鐘桐生，龍立平，等. 氯丙嗪分子印跡敏感膜傳感器的制備與應(yīng)用[J]. 應(yīng)用化學(xué), 2013, 30(11):1361-1365.

[75] SCHIRMER C, MEISEL H. Synthesis of a molecularly imprinted polymer for the selective solid-phase extraction of chloramphenicol from honey[J]. J Chromatogr A, 2006, 1132(1-2):325-328.

[76] LIU S, YI L, LIANG Y. Traditional Chinese medicine and separation science[J]. J Sep Sci, 2008, 31(11):2113-2137.

[77] 林喆，羅艷，原忠. 分子印跡技術(shù)在中藥活性成分分離純化中的應(yīng)用[J]. 中草藥, 2007, 38(3):457-460.

[78] WHITCOMBE MJ, KIRSCH N, NICHOLLS IA. Molecular imprinting science and technology: A survey of the literature for the years 2004-2011[J]. J Mol Recognit, 2014, 27(6): 297-401.

[79] XIE J, ZHU L, LUO H, et al. Direct extraction of specific pharmacophoric flavonoids from gingko leaves using a molecularly imprinted polymer for quercetin[J]. J Chromatogr A, 2001, 934(s1):1-11.

[80] YADA N, CHADIN K, BOYSEN RI, et al. Miniaturized molecularly imprinted polymer extraction method for the gas chromatographic analysis of flavonoids[J]. J Sep Sci, 2014, 37(8):1018-1025.

[81] SUN S, ZHANG M, LI Y, et al. A molecularly imprinted polymer with incorporated graphene oxide for electrochemical determination of quercetin[J]. Sensors, 2013, 13(5):5493-5506.

[82] DENDERZ N. Determination of some flavonoids by HPLC using quercetin-molecularly imprinted polymers[J]. J Liq Chromatogr R T, 2015, 38(6):702-708.

[83] STEIAKAKI MA, CHATZIDAKIS G, KEFALOPOULOS D, et al. An insight into the recognition mechanisms of Molecularly Imprinted Polymers (MIPs) for flavonoids quercetin, kaempferol and hydroxytyrosol[J]. Planta Med, 2008, 74(9):1152-1152.

[84] 程紹玲，楊迎花. 利用分子印跡技術(shù)分離葛根異黃酮[J]. 中成藥, 2006, 28(10):1484-1488.

[85] 雷啟福，鐘世安，向海艷，等. 兒茶素活性成分分子印跡聚合物的分子識(shí)別特性及固相萃取研究[J]. 分析化學(xué), 2005, 33(6):857-860.

[86] 向海艷，周春山，鐘世安，等. 白藜蘆醇分子印跡聚合物合成及其對中藥虎杖提取液活性成分的分離[J]. 應(yīng)用化學(xué), 2005, 22(7):739-743.

[87] HAGINAKA J, TABO H, ICHITANI M, et al. Uniformly-sized, molecularly imprinted polymers for (-)-epigallocatechin gallate, -epicatechin gallate and -gallocatechin gallate by multi-step swelling and polymerization method[J]. J Chromatogr A, 2007, 1156(1-2):45-50.

[88] LIN LQ, LI YC, FU Q, et al. Preparation of molecularly imprinted polymer for sinomenine and study on its molecular recognition mechanism[J]. Polymer, 2006, 47(11):3792-3798.

[89] LIN LQ, ZHANG J, FU Q, et al. Concentration and extraction of sinomenine from herb and plasma using a molecularly imprinted polymer as the stationary phase[J]. Anal Chim Acta, 2006, 561(1-2):178-182.

[90] FU Q, FANG Q, FENG B, et al. Matrine-imprinted monolithic stationary phase for extraction and purification of matrine from Sophorae flavescentis, Ait[J]. J Chromatogr B, 2011, 879(13-14):894-900.

[91] SAMBE H, HOSHINA K, MOADDEL R, et al. Uniformly-sized, molecularly imprinted polymers for nicotine by precipitation polymerization[J]. J Chromatogr A, 2006, 1134(1-2):88-94.

[92] XIE J, ZHU L, XU X. Affinitive separation and on-line identification of antitumor components from Peganum nigellastrum by coupling a chromatographic column of target analogue imprinted polymer with mass spectrometry[J]. Anal Chem, 2002, 74(10):2352-2360.

[93] LASAKOVA M, THIEBAUT D, JANDERA P, et al. Molecularly imprinted polymer for solid-phase extraction of ephedrine and analogs from human plasma[J]. J Sep Sci, 2009, 32(7):1036-1042.

[94] LOPEZ C, CLAUDE B, MORIN P, et al. Synthesis and study of a molecularly imprinted polymer for the specific extraction of indole alkaloids from Catharanthus roseus extracts[J]. Anal Chim Acta, 2011, 683(2):198-205.

[95] CHEN CY, WANG CH, CHEN AH. Recognition of molecularly imprinted polymers for a quaternary alkaloid of berberine[J]. Talanta, 2011, 84(4):1038-1046.

[96] ATLABACHEW M, TORTO N, CHANDRAVANSHI BS, et al. A (-)-norephedrine-based molecularly imprinted polymer for the solid-phase extraction of psychoactive phenylpropylamino alkaloids from Khat ( Catha edulis, Vahl. Endl.) chewing leaves[J]. Biomed Chromatogr, 2015, 30(7):1007-1015.

[97] ZENG S, SHE Y, JIAO B, et al. Molecularly imprinted polymer for selective extraction and simultaneous determination of four tropane alkaloids from Przewalskia tangutica Maxim. fruit extracts using LC-MS/MS[J]. Rsc Adv, 2015, 5(115):94997-95006.

[98] WANG Y, ZHANG Z, LI N. Separation of the alkaloids in Sophora flavescens Aiton by using a molecular imprinted polymer on a silica-gel surface[J]. Anal Methods, 2015, 7(10):183-188.

[99] LI P, MU C, WANG T, et al. Selective adsorption of tetrahydropalmatine by a molecularly imprinted polymer with modified rosin cross-linker[J]. S Afr J Chem, 2014, 67:67-70.

[100] HE JF, ZHU QH, DENG QY. Investigation of imprinting parameters and their recognition nature for quinine-molecularly imprinted polymers[J]. Spectrochim Acta A, 2007, 67(5):1297-1305.

[101] KUGIMIYA A, MATSUI J, ABE H, et al. Synthesis of castasterone selective polymers prepared by molecular imprinting[J]. Anal Chim Acta, 1998, 365(1-3):75-79.

[102] 韓永萍，林強(qiáng)，王昶. 懸浮法制備豆甾醇分子印跡聚合物微球[J]. 應(yīng)用化學(xué), 2008, 25(5):556-559.

[103] HU SG, LI L, HE XW. Solid-phase extraction of esculetin from the ash bark of Chinese traditional medicine by using molecularly imprinted polymers[J]. J Chromatogr A, 2005, 1062(1):31-37.

[104] WALSHE M, HOWARTH J, KELLY MT, et al. The preparation of a molecular imprinted polymer to 7-hydroxycoumarin and its use as a solid-phase extraction material[J]. J Pharmaceut Biomed, 1997, 16(2):319-325.

[105] 馬向霞，何錫文，張茉，等. 香豆素-3-羧酸分子印跡聚合物復(fù)合膜對底物的結(jié)合及滲透選擇性質(zhì)的研究[J]. 高等學(xué)?；瘜W(xué)學(xué)報(bào), 2006, 27(7):1237-1241.

[106] HROBONOVA K, LEHOTAY J, CIZMARIK J. Examination of the chemical composition of propolis IX. Solid phase extraction of coumarins from propolis by using molecularly imprinted polymer[J]. Lung India, 2013, 12(1):1-11.

[107] ZHU X, CAO Q, HOU N, et al. The preparation and the recognition property of molecularly imprinted polymer of podophyllotoxin[J]. Anal Chim Acta, 2006, 561(1):171-177.

[108] 許志鋒，劉嵐，鄧芹英. Alizarin-Cu(Ac)2配合物的分子烙印聚合物的制備和結(jié)合特性[J]. 應(yīng)用化學(xué), 2006, 23(8):826-829.

[109] 尹艷鳳，李倦生，姚運(yùn)先，等. 大黃素分子印跡整體柱的合成及性能表征[J]. 分析測試學(xué)報(bào), 2008, 27(7):758-761.

[110] 杜薇，鄒巧根，孫莉莉，等. 色譜及其聯(lián)用技術(shù)在藥物雜質(zhì)分析中的應(yīng)用[J]. 海峽藥學(xué), 2013, 25(5):1-5.

[111] NAJAFI M, MEHDIPOUR R. Molecularly imprinted polymer-based potentiometric sensor for 2-aminopyridine as a potential impurity in piroxicam[J]. Drug Test Anal, 2011, 3(2):132-137.

[112] HASHEMI-MOGHADDAM H, ALAEIAN MR. Synthesis of molecularly imprinted polymer for removal of effective impurity (benzhydrol) from diphenhydramine hydrochloride drug[J]. J Chin Chem Soc Taipei, 2014, 61(6):643-648.

[113] HASHEMI-MOGHADDAM H, SHAKERI M. Removal of potentioally genotoxic impurity from fluroxamine maleate crude drug by molecularly imprinted polymer[J]. Korean J Chem Eng, 2014, 31(10):1898-1902.

[114] BALAMURUGAN K, GOKULAKRISHNAN K. Preparation and evaluation of molecularly imprinted polymer liquid chromatography column for the determination of enantiomeric impurity of d-pseudo ephedrine sulfate -validated methods according to the ICH guidelines[J]. Saudi Pharmaceut J Spj Off Pub Saudi Pharmaceut Soc, 2010, 6(1):53-61.

[115] LUO Z, ZENG A, ZHENG P, et al. Preparation of surface molecularly imprinted polymers as the solid-phase extraction sorbents for the specific recognition of penicilloic acid in penicillin[J]. Anal Methods, 2014, 6(19):7865-7874.

[116] LUO Z, DU W, ZHENG P, et al. Molecularly imprinted polymer cartridges coupled to liquid chromatography for simple and selective analysis of penicilloic acid and penilloic acid in milk by matrix solid-phase dispersion[J]. Food Chem Toxicol, 2015, 83:164-173.

[117] DU K, LUO Z, GUO P, et al. Preparation and evaluation of a molecularly imprinted sol-gel material as the solid-phase extraction adsorbents for the specific recognition of cloxacilloic acid in cloxacillin[J]. J Sep Sci, 2015, 39(3):80-88.

[118] SZEKELY G, BANDARRA J, HEGGIE W, et al. A hybrid approach to reach stringent low genotoxic impurity contents in active pharmaceutical ingredients: Combining molecularly imprinted polymers and organic solvent nanofiltration for removal of 1,3-diisopropylurea[J]. Sep Purif Technol, 2012, 86(8):79-87.

[119] DING Z, BLIGH SWA, LEI T, et al. Molecularly imprinted polymer based on MWCNT-QDs as fluorescent biomimetic sensor for specific recognition of target protein[J]. Mat Sci Eng C-Mater, 2015, 48:469-479.

[120] LUO Z, DU W, GUO P, et al. A porous hybrid imprinted membrane for selectively anchoring target proteins from a complex matrix[J]. RSC Adv, 2015, 5(89):72610-72620.

[121] LUO Z, SHU H, GUO P, et al. Study of the allergenic benzypenicilloyl-HSA and its specific separation from human plasma by a pre-designed hybrid imprinted membrane[J]. RSC Adv, 2016, 6(19):15549-15557.

[122] KAN X, ZHAO Q, SHAO D, et al. Preparation and recognition properties of bovine hemoglobin magnetic molecularly imprinted polymers[J]. J Phys Chem B, 2010, 114(11):3999-4004.

[123] LI Y, YANG HH, YOU QH, et al. Protein recognition via surface molecularly imprinted polymer nanowires[J]. Anal Chem, 2006, 78(1):317-320.

[124] ZHANG W, HE XW, CHEN Y, et al. Composite of CdTe quantum dots and molecularly imprinted polymer as a sensing material for cytochrome c[J]. Biosens Bioelectro, 2011, 26(5):2553-2558.

[125] LIN HY, RICK J, CHOU TC. Optimizing the formulation of a myoglobin molecularly imprinted thin-film polymer-formed using a micro-contact imprinting method[J]. Biosens Bioelectro, 2007, 22(12):3293-3301.

[126] KUBO T, ARIMURA S, TOMINAGA Y, et al. Molecularly imprinted polymers for selective adsorption of lysozyme and cytochrome c using a PEG-based hydrogel: Selective recognition for different conformations due to pH conditions[J]. Macromolecules, 2015,48: 4081-4087.

[127] TIWARI MP, PRASAD BB. An insulin monitoring device based on hyphenation between molecularly imprinted micro-solid phase extraction and complementary molecularly imprinted polymer-sensor[J]. J Chromatogr A, 2014, 1337(7):22-31.

[128] BOSSI A, PILETSKY SA, PILETSKA EV, et al. Surface-grafted molecularly imprinted polymers for protein recognition[J]. Analy Chem, 2001, 73(21):5281-5286.

[129] TRETJAKOV A, SYRITSKI V, REUT J, et al. Surface molecularly imprinted polydopamine films for recognition of immunoglobulin G[J]. Microchim Acta, 2013, 180(15-16):1433-1442.

[130] EVTUGYN G, PORFIREVA A, IVANOV A, et al. Molecularly imprinted polymerized methylene green as a platform for electrochemical sensing of aptamer-thrombin interactions[J]. Electroanalysis, 2009, 21(11):1272-1277.

[131] KARIMIAN N, TURNER APF, TIWARI A. Electrochemical evaluation of troponin T imprinted polymer receptor[J]. Biosens Bioelectro, 2014, 59C(13):160-165.

[132] RAMANAVICIENE A, RAMANAVICIUS A. Molecularly imprinted polypyrrole-based synthetic receptor for direct detection of bovine leukemia virus glycoproteins[J]. Biosens Bioelectro, 2004, 20(6):1076-1082.

[133] JETZSCHMANN KJ, JAGERSZKI G, DECHTRIRAT D, et al. Biomimetic sensors: Vectorially imprinted hybrid nanofilm for acetylcholinesterase recognition [J]. Adv Funct Mater, 2015, 25(32):185-194.

[134] BOSSERDT M, ERDOSSY J, LAUTNER G, et al. Microelectrospotting as a new method for electrosynthesis of surface-imprinted polymer microarrays for protein recognition[J]. Biosens Bioelectro, 2015, 73:123-129.

[135] BOGNAR J, SZUCS J, DORKO Z, et al. Nanosphere lithography as a versatile method to generate surface-imprinted polymer films for selective protein recognition[J]. Adv Funct Mater, 2013, 23(37):4703-4709.

[136] DECHTRIRAT D, JETZSCHMANN KJ, STOCKLEIN WFM, et al. Protein rebinding to a surface-confined imprint[J]. Adv Funct Mater, 2012, 22(24):5231-5237.

[137] DECHTRIRAT D, GAJOVIC-EICHELMANN N, BIER FF, et al. Hybrid material for protein sensing based on electrosynthesized MIP on a mannose terminated self-assembled monolayer[J]. Adv Funct Mater, 2014, 24(15):2233-2239.

[138] CAI D, REN L, ZHAO H, et al. A molecular-imprint nanosensor for ultrasensitive detection of proteins[J]. Nat Nanotechnol, 2010, 5(8):597-601.

[139] FENG X, GAN N, ZHOU J, et al. A novel dual-template molecularly imprinted electrochemiluminescence immunosensor array using Ru(bpy)32+-Silica@Poly-L-lysine-Au composite nanoparticles as labels for near-simultaneous detection of tumor markers[J]. Electrochim Acta, 2014, 139(26):127-136.

[140] GAJOVIC-EICHELMANN N, EHRENTREICH-FORSTER E, BIER FF. Directed immobilization of nucleic acids at ultramicroelectrodes using a novel electro-deposited polymer[J]. Biosens Bioelectro, 2003, 19(19):417-422.

[141] DEORE B, FREUND MS. Saccharide imprinting of poly(aniline boronic acid) in the presence of fluoride[J]. Analyst, 2003, 128(6):803-806.

[142] BERGMANN NM, PEPPAS NA. Molecularly imprinted polymers with specific recognition for macromolecules and proteins[J]. Prog Polym Sci, 2008, 33(3):271-288.

(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，享受國務(wù)院政府特殊津貼專家。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。近年來主持國家自然科學(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)、王寬誠育才獎(jiǎng)。兼任教育部高等學(xué)校藥學(xué)類專業(yè)教學(xué)指導(dǎo)委員會(huì)委員(2013～2017)，中國高等醫(yī)學(xué)教育藥學(xué)教育研究會(huì)常務(wù)理事，中國藥學(xué)會(huì)藥物分析專業(yè)委員會(huì)委員(第7屆、第8屆)，中國藥學(xué)會(huì)藥學(xué)教育專業(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

專家介紹

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