TWI583953B - Highly sensitive lspr detection kit and the using method thereof - Google Patents
Highly sensitive lspr detection kit and the using method thereof Download PDFInfo
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本發明係關於一種LSPR生化感測套組及其應用方法。更特別地,本發明係關於一種利用於進行LSPR分析時將裸金粒子修飾於待測物上,以增強LSPR訊號的方法。 The invention relates to an LSPR biochemical sensing kit and an application method thereof. More particularly, the present invention relates to a method for modifying bare gold particles on a test object for enhancing LSPR signals when performing LSPR analysis.
侷域表面電漿子共振(Localized surface plasmon resonance;LSPR)的原理在於,當金屬奈米粒子製作於透明基板上時,受到入射光的激發,將使得金屬奈米粒子表面產生表面電漿共振,由於此共振的頻率與強度容易受到周遭環境的影響,而產生波長的位移或者訊號強度的改變等,故可利用局部介電常數的變化來進行分析物的偵測。因此只要有分析物鍵結在粒子附近,吾等便可以藉由光學儀器量到光學變化。可以想像,奈米粒子表面就像是微小型的探測器,在奈米尺度的範圍之內都可以量測到很高的光學變化訊號。 The principle of localized surface plasmon resonance (LSPR) is that when metal nanoparticles are fabricated on a transparent substrate, excitation by incident light will cause surface plasma resonance on the surface of the metal nanoparticles. Since the frequency and intensity of the resonance are easily affected by the surrounding environment, and the displacement of the wavelength or the change of the signal intensity is generated, the detection of the analyte can be performed by using the change of the local dielectric constant. Therefore, as long as the analyte is bound to the particle, we can measure the optical change by optical instrument. It is conceivable that the surface of the nanoparticle is like a tiny detector that can measure very high optical changes in the nanometer range.
先前的研究已發現,當成對的奈米粒子間距小於約2.5粒子半徑時,會發生電漿子偶合作用(plasmonic coupling)而產生明顯的光譜位移(spectral shifts),請參見Anker,J.N.等人,Nature Materials 7:442,2008。本身具有明確偶合特質的Au-LSPR晶片,已被應用於LSPR生化感測方法,其訊號產生係基於吸光值與電漿子條帶波長的結合。先前使用金奈米結構的LSPR技術,在進行感測時光譜位移量僅有3nm以下,以致在提升偵測靈敏度方面無法有效突破。先前雖曾有提出一種Optical Enhancement System(OES),於先前的量測抗原步驟,額外再進行抗原-抗體(此抗體表面有進行標定)的動作,藉由標定物與金奈米結構進行較巨大的電漿偶合效應,而使得位移量大大提升(Kim,H.M.等人,Sensors 9:2334,2009)。然而,OES 技術本身必須利用到加上標定之次級抗體,故已經失去原先LSPR所具有之不須標定(label-free)的優勢。 Previous studies have found that when paired nanoparticle spacing is less than about 2.5 particle radii, plasmonic coupling occurs to produce significant spectral shifts, see Anker, JN et al. Nature Materials 7: 442, 2008. The Au-LSPR wafer, which has its own unique coupling characteristics, has been applied to the LSPR biosensing method, and its signal generation is based on the combination of the absorbance value and the plasma sub-band wavelength. Previously using the LSPR technology of the Golden Nanostructure, the spectral displacement was only 3 nm or less during sensing, so that there was no effective breakthrough in improving the detection sensitivity. Although an Optical Enhancement System (OES) has been proposed in the past, in the previous measurement of the antigen step, the action of the antigen-antibody (the surface of the antibody is calibrated) is additionally performed, and the calibration is complicated with the structure of the gold nanostructure. The plasma coupling effect greatly increases the amount of displacement (Kim, HM et al., Sensors 9 : 2334, 2009). However, the OES technology itself must utilize the calibrated secondary antibody and has lost the advantage of the original LSPR without label-free.
本發明為解決上述LSPR生化感測方法的限制問題,遂提出一種於偵測方法進行時藉由添加裸金粒子,將其修飾於待測物上,以增強LSPR訊號的方法。本發明所研發之方法能以低成本、短時間之分析過程及簡易製備的方式,來偵測低濃度的待測物,例如以偵測帕金森氏症之標記物(anti-α-synuclein antibody)為例,其靈敏度可達到3.8ng/mL,且整體偵測過程僅需耗時約3小時。 The invention solves the limitation problem of the above-mentioned LSPR biosensing method, and proposes a method for enhancing the LSPR signal by adding bare gold particles to the object to be tested when the detecting method is performed. The method developed by the invention can detect low concentration of the test object by low-cost, short-time analysis process and simple preparation, for example, to detect the anti-α-synuclein antibody (anti-α-synuclein antibody) For example, the sensitivity can reach 3.8 ng/mL, and the overall detection process takes only about 3 hours.
於是,本發明之一方面係基於以上之目的,提供一種用於偵測低濃度待測物之高靈敏度侷域表面電漿子共振(LSPR)生化感測套組,其包含一電漿子金屬奈米結構基板,包含一基材、包埋於該基材上之單層奈米金屬粒子,及一修飾於該基材表面或該奈米金屬粒子上之接收器(receptor);及一裸金粒子懸浮溶液,包含懸浮於一緩衝液中之裸金粒子,其中該裸金粒子之粒徑係介於5~100nm。於本發明之一些具體實施態樣,所述之緩衝液可包括PBS緩衝液及MES緩衝液等。於本發明之一具體實施態樣,所述之緩衝液為0.1mM PBS緩衝液。 Therefore, in one aspect of the present invention, based on the above object, a high sensitivity localized surface plasmon resonance (LSPR) biochemical sensing set for detecting a low concentration analyte is provided, which comprises a plasmonic metal a nanostructure substrate comprising a substrate, a single layer of nano metal particles embedded on the substrate, and a receptor modified on the surface of the substrate or the nano metal particles; and a bare The gold particle suspension solution comprises bare gold particles suspended in a buffer, wherein the naked gold particles have a particle diameter of 5 to 100 nm. In some embodiments of the invention, the buffer may include PBS buffer, MES buffer, and the like. In one embodiment of the invention, the buffer is 0.1 mM PBS buffer.
於本發明之一些具體實施態樣,所述之基材為一光學玻璃(optical glass)或高光穿透性塑膠(high transparency plastic)。 In some embodiments of the invention, the substrate is an optical glass or a high transparency plastic.
於本發明之一些具體實施態樣,所述之奈米金屬粒子係選自金、銀、銅、鉑及其合金奈米粒子。於本發明之一具體實施態,所述之奈米金屬粒子為金奈米粒子。 In some embodiments of the invention, the nano metal particles are selected from the group consisting of gold, silver, copper, platinum, and alloyed nanoparticles thereof. In one embodiment of the invention, the nano metal particles are gold nanoparticles.
於本發明之具體實施態樣,所述之裸金粒子係指其表面上未經任何化學分子修飾或官能化之金粒子。所述之裸金粒子粒徑較佳為5~50nm,且最佳為10nm。 In a specific embodiment of the invention, the bare gold particles refer to gold particles whose surface is not modified or functionalized by any chemical molecules. The bare gold particles preferably have a particle diameter of 5 to 50 nm, and most preferably 10 nm.
於本發明之一些具體實施態樣,所述之接收器(receptor)為一與該待測物相對應之抗體或抗原。於本發明之一項具體實施態樣,所述之待測物為帕金森氏症之生物標記物,可為α-突觸核蛋白(α-synuclein)或抗-α-突觸核蛋白抗體(anti-α-synuclein antibody)。 In some embodiments of the present invention, the receptor is an antibody or an antigen corresponding to the analyte. In a specific embodiment of the present invention, the test substance is a biomarker of Parkinson's disease, which may be α-synuclein or anti-α-synuclein antibody. (anti-α-synuclein antibody).
本發明之另一方面,係關於一種用於偵測低濃度待測物之侷域表面電漿子共振(LSPR)生化感測方法,包含:提供一電漿子晶片,其於基材上包埋單層奈米金屬粒子;於該電漿子晶片表面上修飾一接收器(receptor),該接收器係與待測物相對應之抗體或抗原;接著修飾待測物,並同時滴加裸金粒子,使裸金粒子修飾於待測物上;及偵測該待測物之LSPR訊號。 Another aspect of the invention relates to a localized surface plasmon resonance (LSPR) biosensing method for detecting a low concentration analyte, comprising: providing a plasmonic wafer packaged on a substrate Buried a single layer of nano metal particles; modifying a receptor on the surface of the plasmonic wafer, the receiver is an antibody or an antigen corresponding to the analyte; and then modifying the analyte and simultaneously dropping the naked Gold particles, which modify the bare gold particles on the object to be tested; and detect the LSPR signal of the object to be tested.
於本發明之一項具體實施態樣,所述之待測物為帕金森氏症之生物標記物。於本發明之一項具體實施態樣,所述之待測物為α-突觸核蛋白(α-synuclein)。於本發明之一項具體實施態樣,所述之待測物為抗-α-突觸核蛋白抗體(anti-α-synuclein antibody)。 In a specific embodiment of the present invention, the test object is a biomarker of Parkinson's disease. In a specific embodiment of the present invention, the analyte is α-synuclein. In a specific embodiment of the present invention, the test substance is an anti-α-synuclein antibody.
圖1為奈米金簇在電漿子金奈米粒子晶片上形成之示意圖。(A)金奈米粒子晶片上所包埋之固態金奈米粒子(Au NP)直接和待測物相對應之抗原or抗原(A)產生鍵結,並於修飾分析物(D)時,同時滴加裸金粒子(Au-NPs)溶液,使其和待測物產生鍵結;(B)修飾於待測物上的裸金粒子藉由聚集作用(aggregation)而於電漿子晶片上形成奈米金簇(gold-nanoparticle-based clusters),藉以增強LSPR訊號。 Figure 1 is a schematic diagram showing the formation of nanogold clusters on a plasmonic gold nanoparticle wafer. (A) The solid gold nanoparticles (Au NP) embedded on the gold nanoparticle wafer directly bond with the antigen or antigen (A) corresponding to the analyte, and when the analyte (D) is modified, At the same time, a solution of bare gold particles (Au-NPs) is added to bond with the analyte; (B) the bare gold particles modified on the analyte are aggregated on the plasmonic wafer by aggregation. Gold-nanoparticle-based clusters are formed to enhance the LSPR signal.
圖2係顯示以FE-SEM觀察形成在電漿子金奈米粒子晶片上之奈米金簇(紅圈處)SEM圖。 Fig. 2 is a SEM image showing the nano-gold clusters (red circles) formed on the plasmonic gold nanoparticles wafer by FE-SEM.
圖3為偵測1μg/mL IgG抗原的UV-Vis光譜圖。 Figure 3 is a UV-Vis spectrum of 1 μg/mL IgG antigen detected.
圖4係偵測抗-α-突觸核蛋白抗體之UV-Vis消光光譜圖,顯示使用本發明之LSPR生化感測方法偵測不同濃度抗-α-突觸核蛋白抗體(1ppm,0.1ppm及0.0038ppm)的消光強度改變量。 Figure 4 is a UV-Vis extinction spectrum of anti-α-synuclein antibodies, showing that different concentrations of anti-α-synuclein antibodies (1 ppm, 0.1 ppm) were detected using the LSPR biosensing method of the present invention. And the amount of extinction intensity change of 0.0038 ppm).
圖5係以本發明之LSPR生化感測方法偵測PBS緩衝液、人類抗-IgG(1ug/ml)及抗-α-突觸核蛋白抗體(3.8ng/mL)之吸光值強度變化量。誤差值(Error bars)表示進行三重複實驗產生的標準偏差。 Fig. 5 is a graph showing changes in the intensity of absorbance of PBS buffer, human anti-IgG (1 ug/ml) and anti-α-synuclein antibody (3.8 ng/mL) by the LSPR biosensing method of the present invention. Error bars indicate the standard deviation produced by performing the three replicate experiments.
本發明之其他特色及優點將於下列實施範例中被進一步舉例與說明,而該實施範例僅作為輔助說明,並非用於限制本發明之範圍。 The other features and advantages of the present invention are further exemplified and illustrated in the following examples, which are intended to be illustrative only and not to limit the scope of the invention.
奈米電漿子晶片基板之製備Preparation of nano plasma wafer substrate
奈米電漿子晶片基板可利用習知的方法製備得,包括(例如)雷射激光、微波、微波電漿等加熱法。可用於製備本發明奈米電漿子晶片基板之金屬膜包括金、銀、銅、鉑及其合金等。於本發明之一實施例,是利用微波電漿當作加熱源,進行材料表面的處理,而得到具有特殊金屬奈米結構之電漿子晶片。其原理為金屬膜因受熱形成奈米結構,且由於受到微波與微波電漿兩種作用下,使得進一步金屬奈米結構與玻璃基板介面間產生瞬間的高溫,因此在所製得之金屬奈米結構基板中,形成之金屬奈米顆粒的底部包覆一層玻璃結構。 Nano plasmonic wafer substrates can be prepared by conventional methods, including, for example, laser, microwave, microwave plasma, and the like. The metal film which can be used to prepare the nanoplasm plasma chip substrate of the present invention includes gold, silver, copper, platinum, alloys thereof and the like. In one embodiment of the present invention, the microwave plasma is used as a heating source to perform surface treatment of the material to obtain a plasmonic wafer having a special metal nanostructure. The principle is that the metal film forms a nanostructure due to heat, and due to the action of microwave and microwave plasma, an external high temperature is generated between the metal nanostructure and the glass substrate interface, so that the prepared metal nanometer is produced. In the structural substrate, the bottom of the formed metal nanoparticle is coated with a glass structure.
做為本發明一具體實例之金奈米電漿子晶片基板的製備方法簡述如下。首先,在玻璃基板上濺鍍一層金薄膜,之後再放入微波電漿內處理,處理時間僅僅只需30秒,之後便可以在該基板上形成金奈米顆粒。本發明之金奈米電漿子晶片基板上所形成之金奈米粒子大小約為9±3nm。 A method for preparing a gold nano plasma substrate as an embodiment of the present invention is briefly described below. First, a gold film is sputtered on the glass substrate and then placed in a microwave plasma for a treatment time of only 30 seconds, after which the gold nanoparticles can be formed on the substrate. The size of the gold nanoparticles formed on the gold nano plasma substrate of the present invention is about 9 ± 3 nm.
於奈米電漿子晶片基板表面修飾接收器(receptor)Refining the receiver on the surface of the nano plasma substrate
本發明所述之“接收器”意指與待測物相對應之抗原或抗體。於上述製得之金奈米電漿子晶片基板上,滴加40μl與待測物相對應之抗原或抗體溶液,並於室溫下靜置1小時後,以1X PBS緩衝液、超純水沖洗數次,再用氮氣吹乾。封阻(blocking)步驟:將晶片滴加40μl之5%的BSA溶液,並於室溫下靜置30分鐘後,以1X PBS緩衝液、超純水沖洗數次,再用氮氣吹乾。 The "receiver" as used in the present invention means an antigen or an antibody corresponding to an analyte. On the gold nano plasma substrate prepared above, 40 μl of an antigen or antibody solution corresponding to the test substance was added dropwise, and allowed to stand at room temperature for 1 hour, followed by IX PBS buffer and ultrapure water. Rinse several times and dry with nitrogen. Blocking step: 40 μl of 5% BSA solution was added dropwise to the wafer, and allowed to stand at room temperature for 30 minutes, and then washed several times with IX PBS buffer, ultrapure water, and then dried with nitrogen.
修飾待測物Modification of the test object
本發明方法之特徵在於,於修飾待測物之同時滴加裸金粒子緩衝溶液,使其和待測物產生鍵結,而使奈米金簇修飾於待測物上,以增強LSPR訊號。將晶片滴加40μl的待測物溶液,並於37℃下靜置1小時後,繼續滴加40μl的10nm裸金粒子緩衝溶液(懸浮於0.1mM PBS緩衝液),在靜置於室溫下20分鐘後,以1X PBS緩衝液、超純水沖洗數次,再用氮氣吹乾。圖2顯示奈米金簇在金奈米粒子晶片上形成的SEM圖。 The method of the present invention is characterized in that the bare gold particle buffer solution is added dropwise while modifying the test object to bond with the test object, and the nano gold cluster is modified on the test object to enhance the LSPR signal. 40 μl of the test solution was added dropwise to the wafer, and after standing at 37 ° C for 1 hour, 40 μl of a 10 nm naked gold particle buffer solution (suspended in 0.1 mM PBS buffer) was added dropwise, and the mixture was allowed to stand at room temperature. After 20 minutes, it was washed several times with 1X PBS buffer, ultrapure water, and then dried with nitrogen. Figure 2 shows an SEM image of a nanogold cluster formed on a gold nanoparticle wafer.
以在感測晶片表面修飾一人類IgG抗體做為接收器(receptor)為例,我們先於電漿子晶片上修飾抗-IgG抗體(anti-IgG antibody)後,再對不同濃度的IgG抗原(IgG)進行偵測。圖3為偵測1μg/mL IgG的UV吸收度強度變化量圖。以人類IgG抗體做為接收器(receptor),所得到之感測晶片其吸收高峰將落在540±2nm。使用此感測晶片來偵測人類IgG時,由於抗原接上去後會使所引起的光學變化量落在540nm左右。 Taking a human IgG antibody as a receptor on the surface of the sensing wafer as an example, we modified the anti-IgG antibody on the plasmonic wafer and then applied different concentrations of IgG antigen. IgG) for detection. Figure 3 is a graph showing the change in UV absorbance intensity of 1 μg/mL IgG. Using a human IgG antibody as a receptor, the resulting sensing wafer will have an absorption peak at 540 ± 2 nm. When the sensing wafer is used to detect human IgG, the amount of optical change caused by the antigen is dropped to about 540 nm.
以本發明之高靈敏度LSPR生化感測方法偵測帕金森氏症之標記物(anti-α-Syn抗體)Detection of Parkinson's disease marker (anti-α-Syn antibody) by the high sensitivity LSPR biosensing method of the present invention
帕金森氏症的標記物α-突觸核蛋白(α-synuclein,α-Syn)本來就存在於我們的腦中,但是當出現過量的α-突觸核蛋白時,便會使α-突觸核蛋白開始產生聚集,最後變成Lewy body(路易士體),且對神經細胞有害。此時,腦神經細胞便開始產生對抗α-突觸核蛋白的抗-α-突觸核蛋白抗體(anti-α-Syn antibody)並擴散至血液中。在實務上,欲偵測帕金森氏症的標記物,不僅可以偵測腦脊髓液中的α-突觸核蛋白(α-Syn),也可以偵測血液(血漿LSPR生化感測血清)中的抗-α-突觸核蛋白抗體,或是血液(血漿或血清)中呈寡聚體(oligomer)或纖維(fibril)形態的α-突觸核蛋白。然而,綜觀現有技術,皆未能以低成本、短時間之分析過程及簡易製備的方式,來偵測帕金森氏症之標記物(α-突觸核蛋白或其抗體)。於是,本發明進一步提供利用本發明方法及套組偵測低濃度帕金森氏症之標記物(α-synuclein)的抗體之實例,以證明本發明方法相較於習知偵測方法的進步性。 Parkinson's disease marker α-synuclein (α-Syn) is present in our brain, but when there is an excess of α-synuclein, it will cause α-burst The nucleoprotein begins to accumulate and eventually becomes Lewy body and is harmful to nerve cells. At this point, the brain nerve cells begin to produce an anti-α-Syn antibody against α-synuclein and diffuse into the blood. In practice, to detect Parkinson's disease markers, not only can detect α-synuclein (α-Syn) in cerebrospinal fluid, but also detect blood (plasma LSPR biosensing serum). An anti-α-synuclein antibody, or an alpha-synuclein in the form of an oligomer (oligomer) or fibril in blood (plasma or serum). However, in view of the prior art, it has not been possible to detect a marker of Parkinson's disease (α-synuclein or an antibody thereof) by a low-cost, short-time analysis process and simple preparation. Thus, the present invention further provides an example of an antibody that detects a low concentration of Parkinson's disease marker (α-synuclein) using the method and kit of the present invention to demonstrate the advancement of the method of the present invention over conventional detection methods. .
依前述之方法,先於電漿子金奈米粒子晶片上修飾α-突觸核蛋白(α-Syn,購自ENZO LIFE SCIENCES),再針對抗-α-Syn抗體(anti-α-Syn,購自SANTA CRUZ BIOTECHNOLOGY,INC)進行偵測。由圖4之結果顯示,吸光值變化量隨著待測物抗-α-突觸核蛋白抗體之濃度增加而增大。 According to the method described above, α-synuclein (α-Syn, purchased from ENZO LIFE SCIENCES) was modified on the plasmonic gold nanoparticle wafer, and then anti-α-Syn antibody (anti-α-Syn, Purchased from SANTA CRUZ BIOTECHNOLOGY, INC). From the results of Fig. 4, the amount of change in absorbance increases as the concentration of the anti-α-synuclein antibody of the test substance increases.
參見圖5之結果,經由比較空白組(PBS緩衝液)、控制組(抗-IgG)和實驗組(抗-α-Syn)的數據可以發現,待測物3.8ng/mL抗-α-Syn抗體的吸收強度變化量大於PBS緩衝液和1μg/mL抗-IgG的吸收度強度變化量,且3.8ng/mL抗-α-Syn抗體的吸收強度變化量也大於PBS緩衝液的三倍標凖偏差(參照圖5之右表),因此以本發明之偵測方法已成功定性偵測3.8ng/mL的抗-α-Syn抗體,且有機會偵測到更低濃度 的抗-α-Syn抗體。 Referring to the results of Fig. 5, it was found by comparison of blank group (PBS buffer), control group (anti-IgG) and experimental group (anti-α-Syn) that the test substance was 3.8 ng/mL anti-α-Syn The amount of change in the absorption intensity of the antibody was greater than the change in the absorbance intensity of the PBS buffer and 1 μg/mL anti-IgG, and the change in the absorption intensity of the 3.8 ng/mL anti-α-Syn antibody was also greater than the triple mark of the PBS buffer. Deviation (refer to the right table of Figure 5), thus successfully detecting 3.8 ng/mL of anti-α-Syn antibody by the detection method of the present invention, and having the opportunity to detect a lower concentration Anti-α-Syn antibody.
茲將本發明方法與習知相關技術比較之偵測極限及偵測過程總耗時統整於下表1。 The detection limits and the total time-consuming process of the detection process compared to the prior art are summarized in Table 1 below.
經由以上之比較結果顯示,本發明之高靈敏度LSPR生化感測方法,不需另外添加標記藥劑或是二次抗體,就能成功偵測低濃度或小分子待測物,可有效降低高成本的花費;且偵測時間僅需3小時左右,相較於其他偵測方式可大幅地縮短偵測時間。 The above comparison results show that the high-sensitivity LSPR biosensing method of the present invention can successfully detect low-concentration or small-molecule analytes without additional labeling agents or secondary antibodies, and can effectively reduce high cost. Cost; and the detection time is only about 3 hours, which can greatly shorten the detection time compared to other detection methods.
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