TWI459965B - Biocompartiple confeito-like gold nanoparticles, method for making the same, and their biomedical applications - Google Patents
Biocompartiple confeito-like gold nanoparticles, method for making the same, and their biomedical applications Download PDFInfo
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本發明是有關於糖花狀金奈米粒子(C-AuNPs)、糖花狀金奈米粒子的製造方法及糖花狀金奈米粒子的生物醫學應用。The present invention relates to a method for producing a sugar-like gold nanoparticle (C-AuNPs), a sugar-like gold nanoparticle, and a biomedical application of a sugar-like gold nanoparticle.
生物可相容的金奈米粒子較佳地被使用為活體組織中的標記。同時，非等向性的金奈米粒子已引起了廣大的注意，因為金奈米粒子在近紅外線(near-infrared，NIR)範圍中具有一強吸收帶，而近紅外線範圍中的光線則能深入地穿透人體。此外，當非等向性的金奈米粒子吸收近紅外線，它們能產生足夠的熱能來殺死癌細胞。而金奈米柱為典型的非等向性奈米粒子中之一類，且被研究作為影像系統及用在治療癌症，但在奈米柱的實際利用上有一些主要的問題，即，麻煩的合成製程及奈米柱的毒性。為了合成奈米柱，需要晶種(seed particle)及濃縮的界面活性劑溶液，且反應時間長(至少幾個小時)。所使用的界面活性劑具毒性且難以從所獲得的金奈米柱移除。這些問題限制了金奈米柱的實際利用。基於多道製程及/或保護劑(protecting agent)的毒性，其他的非等向性奈米粒子也有類似的問題。Biocompatible gold nanoparticles are preferably used as labels in living tissue. At the same time, the anisotropic Jinnai particles have attracted a lot of attention, because the Jinnai particles have a strong absorption band in the near-infrared (NIR) range, while the light in the near-infrared range can Penetrate deeply into the human body. In addition, when non-isotropic gold nanoparticles absorb near infrared rays, they generate enough heat to kill cancer cells. The Jinnai column is one of the typical anisotropic nanoparticles and has been studied as an imaging system and used to treat cancer. However, there are some major problems in the practical use of the nano column, namely, troublesome. Synthetic process and toxicity of the nano column. In order to synthesize a nano column, a seed particle and a concentrated surfactant solution are required, and the reaction time is long (at least several hours). The surfactant used is toxic and difficult to remove from the obtained gold nano column. These problems limit the practical use of the Jinnai column. Other anisotropy nanoparticles have similar problems based on the toxicity of the multi-pass process and/or the protecting agent.
因此，需要具有近紅外線吸收能力的生物可相容之金奈米粒子，亦需要合成金奈米粒子的簡潔製程。Therefore, there is a need for a biocompatible gold nanoparticle having near infrared absorbing ability, and a simple process for synthesizing gold nanoparticles is also required.
本發明是基於意外發現在存有生物可相容的保護劑之水溶鹼性條件下使用過氧化氫(hydroxyl peroxide)作為還原劑，可自金前驅物(gold precursor)獲得糖花狀金奈米粒子且無有毒副產物。在本發明中，該還原劑，即，過氧化氫可分解為水，且可選擇生物可相容的保護劑來完成金奈米粒子之合成。因此，本發明之金奈米粒子不含毒性化合物，且能不經純化製程而直接用於醫藥應用。除此之外，本發明的合成反應可在短時間內完成且適合量產。The present invention is based on the unexpected discovery that hydroxyl peroxide is used as a reducing agent under water-soluble alkaline conditions in which a biocompatible protective agent is present, and sugar-like gold nanoparticles can be obtained from gold precursors. The particles are free of toxic by-products. In the present invention, the reducing agent, that is, hydrogen peroxide, can be decomposed into water, and a biocompatible protective agent can be selected to complete the synthesis of the gold nanoparticles. Therefore, the gold nanoparticle of the present invention does not contain a toxic compound and can be directly used for medical applications without a purification process. In addition to this, the synthesis reaction of the present invention can be completed in a short time and is suitable for mass production.
在一方面，本發明提供一種製造金奈米粒子的方法，其包括在存有生物可相容的保護劑之水溶鹼性條件下以過氧化氫還原金前驅物。在本發明的部份具體實施例中，生物可相容的保護劑係選自於由檸檬酸鹽、聚環氧乙烷-聚環氧丙烷嵌段共聚物(poly(ethylene oxide)-poly(propylene oxide) block copolymer，PEO-PPO block copolymer)(例如，PF-127，一種商業可獲得的生物可相容三嵌段共聚物(triblock copolymer))及聚乙烯四氫咯酮(poly(vinyl pyrrolidone))所組成的群組。In one aspect, the invention provides a method of making a gold nanoparticle comprising reducing a gold precursor with hydrogen peroxide under water-soluble basic conditions in which a biocompatible protective agent is present. In some embodiments of the invention, the biocompatible protective agent is selected from the group consisting of citrate, polyethylene oxide-polypropylene oxide block copolymer (poly(ethylene oxide)-poly(poly(ethylene oxide)-poly( Propylene oxide) block copolymer, PEO-PPO block copolymer) (for example, PF-127, a commercially available biocompatible triblock copolymer) and poly(vinyl pyrrolidone) )) The group consisting of.
另一方面，本發明提供藉由本文描述的方法製造出的金奈米粒子，其為生物可相容的、無毒的。In another aspect, the invention provides a gold nanoparticle produced by the methods described herein that is biocompatible, non-toxic.
本發明另外也提供一種癌症治療的方法，此方法包括將本文描述之金奈米粒子引入至癌細胞以及用放射線照射癌細胞來殺死癌細胞。具體而言，放射線為波長785 nm的近紅外線輻射。The invention additionally provides a method of cancer treatment comprising introducing the gold nanoparticles described herein into cancer cells and irradiating the cancer cells with radiation to kill the cancer cells. Specifically, the radiation is near-infrared radiation having a wavelength of 785 nm.
本發明進一步提供一種藥物傳遞(drug delivery)的方法，此方法包括將吸附在本文描述之金奈米粒子上的藥物引入至細胞，以及用放射線照射細胞來使奈米粒子變形為球狀奈米粒子，進而在不損傷細胞的情況下達到控制性的藥物釋放。具體而言，放射線為波長633 nm的輻射。The present invention further provides a method of drug delivery, which comprises introducing a drug adsorbed on the gold nanoparticles described herein into a cell, and irradiating the cell with radiation to deform the nanoparticle into a spherical nanoparticle. The particles, in turn, achieve controlled drug release without damaging the cells. Specifically, the radiation is radiation having a wavelength of 633 nm.
本發明也提供了如本文所描述之金奈米粒子於製備作為癌症治療藥劑之組合物或藥物傳遞的載體之用途。The invention also provides the use of a gold nanoparticle as described herein for the preparation of a composition or drug delivery vehicle as a therapeutic agent for cancer.
一般相信，基於本文的描述，該技術領域中具有通常知識者能夠將本發明做用最大範圍的使用，而不需要更進一步的舉例說明。因此，以下的描述應該被理解是為了論述本發明之目的，而非以任何方式限制本發明的範圍。It is generally believed that those skilled in the art, based on the description herein, will be able to use the invention in the broadest scope, without further exemplification. Therefore, the following description is to be construed as illustrative and not restrictive
除非另外定義，在本文使用的所有科技術語具有之意義相同於該技術領域中具有通常知識者的一般理解。本文提及的所有公開資料皆納入參考，以便揭露並描述與引證公開資料有關之方法與/或材料。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as the ordinary of ordinary skill in the art. All published materials referred to herein are incorporated by reference to disclose and describe the methods and/or materials relating to the disclosure of the disclosure.
除非文意另有規定清楚，如本文中所使用的，單數形式「一」及「該」包括了複數個參照物。因此，例如，「一樣本」之理解包括了多個如此的樣本和該技術領域中所熟知的此樣本之相等物。As used herein, the singular forms """ Thus, for example, the understanding of "the same" includes a plurality of such samples and equivalents of such samples as are well known in the art.
在一方面，本發明提供了一種製造金奈米粒子的方法，其包括在存有生物可相容的保護劑之水溶鹼性條件下使用過氧化氫來還原金前驅物。In one aspect, the invention provides a method of making a gold nanoparticle comprising reducing hydrogen precursor using hydrogen peroxide under water-soluble basic conditions in which a biocompatible protective agent is present.
如本文中所使用的，金前驅物是指一種前驅物質，此種前驅物質包括氧化狀態大於零(例如，正一價金、正三價金)且能夠被還原成金原子的金材料。具體而言，金鹽，包括但不限於四氯金酸鈉、三氯化金、四溴金酸鈉和四氯金酸鉀以及前述物質之氫氧化物和溶劑化物，而此金鹽可以用來作為本發明的金前驅物。在某些實例中，金前驅物是溶解於水中，形成金前驅物水溶液，以提供後續製程使用。As used herein, a gold precursor refers to a precursor material that includes a gold material having an oxidized state greater than zero (eg, positive monovalent gold, positive trivalent gold) and capable of being reduced to a gold atom. Specifically, the gold salt includes, but is not limited to, sodium tetrachloroaurate, gold trichloride, sodium tetrabromogold and potassium tetrachloroaurate, and hydroxides and solvates of the foregoing, and the gold salt can be used. It is used as the gold precursor of the present invention. In some instances, the gold precursor is dissolved in water to form a gold precursor aqueous solution to provide subsequent processing.
如本文中所使用的，保護劑是一種物質或一種化合物，其可以控制和穩定金屬奈米粒子的粒子大小分佈。具體而言，保護劑可以通過化學或物理鍵結之方式結合至金屬奈米粒子，從而防止金屬奈米粒子聚集，並控制和穩定金屬奈米粒子的粒子大小分佈，使粒子大小分佈位於一個適當的範圍中。通過添加保護劑，可維持具有微小粒徑的金屬奈米粒子懸浮於溶液中之條件。各種用以合成金奈米粒子的保護劑在其技術領域中是為人熟知且可獲得的。跟據本發明，該保護劑是生物可相容的。As used herein, a protective agent is a substance or a compound that controls and stabilizes the particle size distribution of the metal nanoparticles. Specifically, the protective agent can be bonded to the metal nanoparticles by chemical or physical bonding, thereby preventing the aggregation of the metal nanoparticles, and controlling and stabilizing the particle size distribution of the metal nanoparticles, so that the particle size distribution is at an appropriate level. In the scope of. By adding a protective agent, conditions in which metal nanoparticles having a fine particle diameter are suspended in a solution can be maintained. Various protecting agents for synthesizing the gold nanoparticles are well known and available in the art. According to the invention, the protectant is biocompatible.
「生物可相容的」乙詞意指保護劑在一合理的給予劑量下不會引起動物嚴重毒性的或有害的生物反應。典型地，生物可相容的保護劑是生物惰性的(biological inert)，且對於活體細胞或組織是無毒的；例如，當保護劑添加至細胞會導致少於30%的細胞死亡，較佳地少於20%的細胞死亡，更佳地低於10%細胞死亡。在本發明中所使用之生物可相容的保護劑之適當實例包括但不限於檸檬酸鹽、聚環氧乙烷-聚環氧丙烷嵌段共聚物以及聚乙烯四氫咯酮。在某些實例中，在金前驅物溶解於水中後，形成金前驅物水溶液，生物可相容的保護劑被添加到金前驅物水溶液，形成反應混合物，以提供後續製程使用。特定而言，加入一定份量的該金前驅物使其在反應混合物中的濃度為從0.01至5 mM，較佳地是從0.01至1 mM，更佳地從0.05至0.5 mM，並加入一定份量的生物可相容的保護劑，使其在反應混合物中之濃度為從0.005到1 wt%，較佳地從0.01到0.5 wt%，及更佳地從0.01到0.2 wt%。By "biocompatible" is meant a protective agent that does not cause a serious toxic or harmful biological reaction in an animal at a reasonable dosage. Typically, biocompatible protective agents are biological inerts and are non-toxic to living cells or tissues; for example, when a protective agent is added to the cells, resulting in less than 30% cell death, preferably Less than 20% of cells die, more preferably less than 10% of cells die. Suitable examples of biocompatible protective agents for use in the present invention include, but are not limited to, citrate, polyethylene oxide-polypropylene oxide block copolymers, and polyethylene tetrahydroketone. In some instances, after the gold precursor is dissolved in water, an aqueous gold precursor solution is formed and a biocompatible protective agent is added to the aqueous gold precursor solution to form a reaction mixture to provide subsequent processing. Specifically, a certain amount of the gold precursor is added to have a concentration in the reaction mixture of from 0.01 to 5 mM, preferably from 0.01 to 1 mM, more preferably from 0.05 to 0.5 mM, and a certain amount is added. The biocompatible protective agent has a concentration in the reaction mixture of from 0.005 to 1 wt%, preferably from 0.01 to 0.5 wt%, and more preferably from 0.01 to 0.2 wt%.
根據本發明，過氧化氫被使用作為還原劑來還原金前驅物，以便製造本發明的金奈米粒子。在某些實例中，生物可相容的保護劑添加到金前驅物水溶液形成反應混合物之後，，接著加入過氧化氫到該反應混合物中。在某些實例中，加入過氧化氫使其在反應混合物中的濃度為從1到200 mM，較佳地從10到100 mM，更佳地從10至50 mM。According to the present invention, hydrogen peroxide is used as a reducing agent to reduce the gold precursor to produce the gold nanoparticles of the present invention. In some instances, a biocompatible protective agent is added to the gold precursor aqueous solution to form a reaction mixture, followed by the addition of hydrogen peroxide to the reaction mixture. In certain instances, hydrogen peroxide is added to a concentration in the reaction mixture of from 1 to 200 mM, preferably from 10 to 100 mM, more preferably from 10 to 50 mM.
根據本發明，使用過氧化氫還原金前驅物以製造本發明的金奈米粒子，而前述之還原是在水溶鹼性條件中進行的。具體而言，水溶鹼性條件的pH約為10或更大，較特定地是介於10至13之間，更特定地是介於10至12之間。在某些實例中，當過氧化氫添加到該反應混合物之後，接著藉由把鹼(base)加入到反應混合物中來調整反應混合物的pH。上述鹼可以是任何合適的鹼，例如氫氧化鈉，並且可加入一適當份量，以將pH調整為前述數值。在一實例中，該鹼可伴隨強烈的攪拌而一次性的添加到該反應混合物中。According to the present invention, the gold precursor is reduced using hydrogen peroxide to produce the gold nanoparticles of the present invention, and the aforementioned reduction is carried out in water-soluble alkaline conditions. In particular, the pH of the water-soluble alkaline conditions is about 10 or greater, more specifically between 10 and 13, more specifically between 10 and 12. In certain instances, after hydrogen peroxide is added to the reaction mixture, the pH of the reaction mixture is then adjusted by adding a base to the reaction mixture. The above base may be any suitable base such as sodium hydroxide, and a suitable amount may be added to adjust the pH to the aforementioned value. In one example, the base can be added to the reaction mixture in one portion with vigorous agitation.
在調整反應混合物的pH後，反應混合物可維持於一合適的溫度一段時間，而這段時間足夠使本發明的金奈米粒子分散液形成。在一些具體實施例中，反應混合物可保持在環境溫度、高於環境溫度或低於環境溫度，例如介於約0℃至60℃之間，介於約10至40℃之間，或介於約15至約35℃之間。在一些具體實施例中，反應混合物可維持在一個合適的溫度一段時間，這段時間介於約0.5小時、約1小時、約2小時、約4小時之間，或甚至更多。After adjusting the pH of the reaction mixture, the reaction mixture can be maintained at a suitable temperature for a period of time sufficient to form the gold nanoparticle dispersion of the present invention. In some embodiments, the reaction mixture can be maintained at ambient temperature, above ambient temperature, or below ambient temperature, such as between about 0 ° C and 60 ° C, between about 10 and 40 ° C, or between Between about 15 and about 35 ° C. In some embodiments, the reaction mixture can be maintained at a suitable temperature for a period of time between about 0.5 hours, about 1 hour, about 2 hours, about 4 hours, or even more.
在一特定具體實施例中，本發明的方法進行如下：(i)將金鹽溶解於水中，以製備金前驅物水溶液，(ii)將生物可相容的保護劑(例如檸檬酸鹽、聚環氧乙烷-聚環氧丙烷嵌段共聚物或聚乙烯四氫咯酮)溶解於金前驅物水溶液，以製造反應混合物，(iii)將過氧化氫添加至該反應混合物，(iv)隨後加入鹼水溶液，以調整最終的反應混合物之pH至10或更高，以及(iv)將最終的反應混合物放置在約25度℃的環境約1小時。本發明的方法之運作實例提供於以下的說明中。In a specific embodiment, the method of the invention is carried out as follows: (i) dissolving a gold salt in water to prepare an aqueous solution of a gold precursor, (ii) a biocompatible protective agent (eg, citrate, poly Ethylene oxide-polypropylene oxide block copolymer or polyethylene tetrahydrofuranone is dissolved in an aqueous solution of gold precursor to produce a reaction mixture, (iii) hydrogen peroxide is added to the reaction mixture, (iv) subsequently An aqueous base solution is added to adjust the pH of the final reaction mixture to 10 or higher, and (iv) the final reaction mixture is placed in an environment of about 25 degrees C for about 1 hour. An example of the operation of the method of the present invention is provided in the following description.
在另一方面，本發明提供了利用本文中描述方的法製造出之金奈米粒子。In another aspect, the invention provides a gold nanoparticle produced by the method described herein.
根據本發明，依上述方法製造出的金奈米粒子是無毒的、生物可相容的，這些金奈米粒子不需經過純化的步驟便可直接利用於醫療應用。According to the present invention, the gold nanoparticles produced by the above method are non-toxic and biocompatible, and these gold nanoparticles can be directly utilized in medical applications without a purification step.
特定而言，藉由穿透式電子顯微鏡(TEM)、掃描式電子顯微鏡(SEM)的分析，本發明的金奈米粒子被發現具有糖花狀之形狀。較特定而言，本發明的金奈米粒子之平均粒子大小是從20至500 nm，更特定而言從50到300 nm，而平均粒子大小是以直徑作為衡量基準。這些奈米粒子的形狀和大小都是均勻的，且每一奈米粒子具有多個微小突起(直徑約30 nm，長度約40 nm)，這些突起是從奈米粒子的本體往外突出。此外，相對於尺寸較大的本體，這些突起具有較小的尺寸。更特定而言，本發明的金奈米粒子具有一寬廣的吸收帶，此吸收帶延伸到近紅外線區域。具體而言，吸收帶是從300延伸到1200 nm。更具體而言，在450至800 nm之間具相對較強的吸收帶。Specifically, the gold nanoparticles of the present invention were found to have a sugar-like shape by analysis by a transmission electron microscope (TEM) or a scanning electron microscope (SEM). More specifically, the average particle size of the gold nanoparticles of the present invention is from 20 to 500 nm, more specifically from 50 to 300 nm, and the average particle size is measured by diameter. These nanoparticles are uniform in shape and size, and each nanoparticle has a plurality of minute protrusions (about 30 nm in diameter and about 40 nm in length) which protrude outward from the body of the nanoparticle. Moreover, these protrusions have a smaller size than the larger size body. More specifically, the gold nanoparticles of the present invention have a broad absorption band that extends into the near infrared region. Specifically, the absorption band extends from 300 to 1200 nm. More specifically, there is a relatively strong absorption band between 450 and 800 nm.
本發明的金奈米粒子的特點之一是具有在近紅外範圍內的強吸收帶。因此，它們可在生物醫學應用上用於作為造影試劑及癌細胞殺手。此外，糖花狀結構是熱不穩定的，並且可藉由強烈的近紅外線光波照射而變成球狀結構。，此糖花狀結構之變形可達成吸附在本發明的金奈米粒子上之藥物之控制釋放。這些特徵指出，本發明的金奈米粒子在造影和治療上的成果與奈米柱一樣優越，而奈米柱粒子在生物醫學應用上還存有一些問題。One of the characteristics of the gold nanoparticles of the present invention is that it has a strong absorption band in the near infrared range. Therefore, they can be used as contrast agents and cancer cell killers in biomedical applications. Further, the sugar-like structure is thermally unstable, and can be changed into a spherical structure by intense near-infrared light irradiation. The deformation of the sugar-like structure can achieve controlled release of the drug adsorbed on the gold nanoparticles of the present invention. These features indicate that the nano-particles of the present invention are as superior to the nano-pillars in contrast and treatment, and that nano-pillar particles have some problems in biomedical applications.
更特定而言，當本發明的金奈米粒子存在於癌細胞中，可以透過一短時間的近紅外線雷射(例如，波長在785 nm)照射這些癌細胞(例如，海拉細胞(HeLa cell))，以將癌細胞殺死。此癌溶解(carcinolysis)現象可能歸因於金奈米粒子在近紅外線區域的強烈離子吸收效應。另一方面，包括金奈米粒子的癌細胞在633 nm波長的近紅外線照射下仍可存活，633 nm接近金奈米粒子的離子吸收帶。在此條件下，金奈米粒子迅速轉變成微小的球狀奈米粒子，而所生成的微小奈米粒子之光敏感性比金奈米粒子來的低。由該轉變可知本發明的金奈米粒子可用於控制藥物釋放的設計。More specifically, when the gold nanoparticles of the present invention are present in cancer cells, these cancer cells can be irradiated through a short-time near-infrared laser (for example, at a wavelength of 785 nm) (for example, HeLa cells) )) to kill cancer cells. This cancer carcinogenesis phenomenon may be attributed to the strong ion absorption effect of the gold nanoparticles in the near-infrared region. On the other hand, cancer cells including gold nanoparticles can survive at near-infrared irradiation at a wavelength of 633 nm, and 633 nm is close to the ion absorption band of the gold nanoparticles. Under these conditions, the gold nanoparticles are rapidly converted into tiny spherical nanoparticles, and the generated light nanoparticles are less sensitive to light than the gold nanoparticles. From this transition, it is known that the gold nanoparticles of the present invention can be used to control the design of drug release.
因此，在一具體實施例中，本發明提供了一種治療癌症的方法，其包括將本文描述的金奈米粒子引入癌細胞以及利用放射線照射癌細胞來將其殺死。特定而言，放射線是波長785 nm的近紅外線輻射。Accordingly, in one embodiment, the invention provides a method of treating cancer comprising introducing a gold nanoparticle as described herein into a cancer cell and illuminating the cancer cell with radiation to kill it. In particular, the radiation is near-infrared radiation having a wavelength of 785 nm.
在另一具體實施例中，本發明提供了一種藥物傳遞的方法，其包括將吸附於本文描述之金奈米粒上的藥物引入細胞，並且利用放射線照射細胞，使奈米粒子變形為球狀奈米粒子，進而在不損傷細胞的情況下讓藥物的釋放獲得控制。特定而言，放射線是波長為633 nm的輻射。In another specific embodiment, the present invention provides a method of drug delivery comprising introducing a drug adsorbed on the gold nanoparticles described herein into a cell, and irradiating the cell with radiation to deform the nanoparticle into a spherical nai. The rice particles, in turn, allow the release of the drug to be controlled without damaging the cells. In particular, the radiation is radiation having a wavelength of 633 nm.
下面的實例進一步舉例說明本發明，然而以下的舉例說明是為了論述本發明之目的，而並非用以限制本發明。The following examples are intended to illustrate the invention, but are not intended to limit the invention.
二水四氯金酸鈉(NaAuCl4 ‧2H2 O)和三團聯聚合物(聚環氧乙烷-聚環氧丙烷嵌段共聚物是購自美國的西格瑪奧瑞奇公司(Sigma Aldrich Co.)。無水檸檬酸(Cit)、聚乙烯四氫咯酮(PVP，平均分子量：58000)、氫氧化鈉、以及35 wt%的過氧化氫水溶液是購自美國的Acros Organics公司。所有的化學藥品均為試劑等級並且未經過進一步純化。電阻率為18 MΩ‧cm的超純水(利用密理博國際公司(Millipore)的Milli-Q超純水純化系統備製)則使用於所有的合成步驟與研究測量中。Sodium tetrachloroaurate dihydrate (NaAuCl 4 ‧2H 2 O) and a triplet polymer (polyethylene oxide-polypropylene oxide block copolymer is purchased from Sigma Aldrich Co.) .) Anhydrous citrate (Cit), polyethylene tetrahydrofuranone (PVP, average molecular weight: 58,000), sodium hydroxide, and 35 wt% aqueous hydrogen peroxide solution are purchased from Acros Organics, USA. All chemistry The drugs are of reagent grade and have not been further purified. Ultrapure water with a resistivity of 18 MΩ ‧ cm (prepared by Millipore's Milli-Q ultrapure water purification system) is used in all synthesis steps With research measurements.
金奈米粒子的合成是在一個50 cm3 、溫度為環境溫度的玻璃瓶中進行。特定而言，用28 cm3 的水稀釋4 cm3 、1 mM的四氯金酸鈉水溶液，以及將一指定份量的保護劑溶解於此溶液中。過氧化氫水溶液(80 mm3 )加入到上述的溶液，以及100 mM的氫氧化鈉水溶液(8 cm3 )接著加入到前述的溶液中，並劇烈攪拌前述的溶液。5分鐘後，降低攪拌速度並且繼續攪拌1小時。反應溶液然後靜置一夜以使反應完成，如此即可獲得金奈米粒子分散液。The synthesis of the gold nanoparticles is carried out in a 50 cm 3 glass bottle at ambient temperature. Specifically, a 4 cm 3 , 1 mM aqueous solution of sodium tetrachloroaurate was diluted with 28 cm 3 of water, and a specified amount of a protective agent was dissolved in the solution. An aqueous hydrogen peroxide solution (80 mm 3 ) was added to the above solution, and a 100 mM aqueous sodium hydroxide solution (8 cm 3 ) was added to the aforementioned solution, and the aforementioned solution was vigorously stirred. After 5 minutes, the stirring speed was lowered and stirring was continued for 1 hour. The reaction solution was then allowed to stand overnight to complete the reaction, and thus a gold nanoparticle dispersion was obtained.
本發明的金奈米粒子係利用一鍋法(one-pot process)的方式合成。首先，用28 cm3 的水稀釋四氯金酸鈉水溶液(1 mM，4 cm3 )，並且將一指定份量(16.0毫克)的檸檬酸(一種保護劑)溶解於此溶液。在此溶液中，金鹽的濃度和保護劑的濃度分別約為0.125 mM和0.05 wt%。過氧化氫水溶液(35 wt%，80 cm3 )加入到上述溶液(過氧化氫在此溶液中的濃度約為29 mM)，以及將氫氧化鈉水溶液(100 mM，8 cm3 )一次性地倒入前述溶液並劇烈攪拌前述溶液，以調整溶液的pH至大約10.6。5分鐘後，降低攪拌速度，並且在溫度為25℃之條件保持攪拌1小時。最後，因此獲得金奈米粒子分散液。圖1舉例說明了本發明之金奈米粒子的合成方法圖解。The gold nanoparticles of the present invention are synthesized by a one-pot process. First, an aqueous solution of sodium tetrachloroaurate (1 mM, 4 cm 3 ) was diluted with 28 cm 3 of water, and a specified portion (16.0 mg) of citric acid (a protective agent) was dissolved in the solution. In this solution, the concentration of the gold salt and the concentration of the protective agent were about 0.125 mM and 0.05 wt%, respectively. An aqueous hydrogen peroxide solution (35 wt%, 80 cm 3 ) was added to the above solution (hydrogen peroxide in the solution at a concentration of about 29 mM), and an aqueous sodium hydroxide solution (100 mM, 8 cm 3 ) was used once. The solution was poured and the solution was vigorously stirred to adjust the pH of the solution to about 10.6. After 5 minutes, the stirring speed was lowered, and stirring was maintained for 1 hour at a temperature of 25 °C. Finally, a gold nanoparticle dispersion is thus obtained. Figure 1 illustrates an illustration of a method of synthesizing the gold nanoparticles of the present invention.
本發明的金奈米粒子係利用一鍋法的方式合成。首先，用28 cm3 的水稀釋四氯金酸鈉水溶液(1 mM，4 cm3 )，並且將一指定份量(40.0毫克)的聚環氧乙烷-聚環氧丙烷嵌段共聚物(一種保護劑)溶解於此溶液。在此溶液中，金鹽的濃度和保護劑的濃度分別約為0.125 mM和0.125 wt%。過氧化氫水溶液(35 wt%，80 cm3 )加入到上述溶液(過氧化氫在此溶液中的濃度約為29 mM)，以及將氫氧化鈉水溶液(100 mM，8 cm3 )一次性地倒入前述溶液並劇烈攪拌前述溶液，以調整溶液的pH至大約11.4。5分鐘後，降低攪拌速度，並且在溫度為25℃之條件保持攪拌1小時。最後，因此獲得金奈米粒子分散液。圖1舉例說明了本發明之金奈米粒子的合成方法圖解。The gold nanoparticles of the present invention are synthesized by a one-pot method. First, dilute the aqueous solution of sodium tetrachloroaurate (1 mM, 4 cm 3 ) with 28 cm 3 of water, and a specified amount (40.0 mg) of polyethylene oxide-polypropylene oxide block copolymer (a kind) The protective agent) is dissolved in this solution. In this solution, the concentration of the gold salt and the concentration of the protective agent were about 0.125 mM and 0.125 wt%, respectively. An aqueous hydrogen peroxide solution (35 wt%, 80 cm 3 ) was added to the above solution (hydrogen peroxide in the solution at a concentration of about 29 mM), and an aqueous sodium hydroxide solution (100 mM, 8 cm 3 ) was used once. The solution was poured and the solution was vigorously stirred to adjust the pH of the solution to about 11.4. After 5 minutes, the stirring speed was lowered, and stirring was maintained for 1 hour at a temperature of 25 °C. Finally, a gold nanoparticle dispersion is thus obtained. Figure 1 illustrates an illustration of a method of synthesizing the gold nanoparticles of the present invention.
本發明的金奈米粒子係利用一鍋法的方式合成。首先，用28 cm3 的水稀釋四氯金酸鈉水溶液(1 mM，4 cm3 )，並且將特定份量(40.0毫克)的聚乙烯四氫咯酮(一種保護劑)溶解於此溶液。在此溶液中，金鹽的濃度和保護劑的濃度分別約為0.125 mM和0.125 wt%。過氧化氫水溶液(35 wt%，80 cm3 )加入到上述溶液(過氧化氫在此溶液中的濃度約為29 mM)，以及將氫氧化鈉水溶液(100 mM，8 cm3 )一次性地倒入前述溶液並劇烈攪拌前述溶液，以調整溶液的pH至大約11.6。5分鐘後，降低攪拌速度，並且在溫度為25℃之條件保持攪拌1小時。最後，因此獲得金奈米粒子分散液。圖1舉例說明了本發明之金奈米粒子的合成方法圖解。The gold nanoparticles of the present invention are synthesized by a one-pot method. First, an aqueous solution of sodium tetrachloroaurate (1 mM, 4 cm 3 ) was diluted with 28 cm 3 of water, and a specific portion (40.0 mg) of polyethylene tetrahydrofurone (a protective agent) was dissolved in the solution. In this solution, the concentration of the gold salt and the concentration of the protective agent were about 0.125 mM and 0.125 wt%, respectively. An aqueous hydrogen peroxide solution (35 wt%, 80 cm 3 ) was added to the above solution (hydrogen peroxide in the solution at a concentration of about 29 mM), and an aqueous sodium hydroxide solution (100 mM, 8 cm 3 ) was used once. The solution was poured and the solution was vigorously stirred to adjust the pH of the solution to about 11.6. After 5 minutes, the stirring speed was lowered, and stirring was maintained for 1 hour at a temperature of 25 °C. Finally, a gold nanoparticle dispersion is thus obtained. Figure 1 illustrates an illustration of a method of synthesizing the gold nanoparticles of the present invention.
穿透式電子顯微鏡影像是利用日立的H-7000儀器拍攝出的，拍攝時加速電壓為100 kV。金奈米粒子分散液被倒在經鍍碳處理之銅網(carbon-coated copper grid)上，經空氣乾燥後，然後作為觀察樣本。掃描式電子顯微鏡影像是利用日本電子(JEOL)的JSM-6500F電子顯微鏡拍攝出的。紫外線-可見光-近紅外線(UV-VIS-NIR)吸收光譜是利用JASCO的V-670分光光度計記錄下，而V-670分光光度計中採用光路徑為1 cm的石英皿(quartz cell)。The transmission electron microscope image was taken using a Hitachi H-7000 instrument with an acceleration voltage of 100 kV. The gold nanoparticle dispersion was poured on a carbon-coated copper grid, air dried, and then used as an observation sample. The scanning electron microscope image was taken using a JSM-6500F electron microscope of JEOL. The UV-Vis-NIR absorption spectrum was recorded using a JASCO V-670 spectrophotometer, while the V-670 spectrophotometer used a quartz cell with a light path of 1 cm.
在實例1中獲得的金奈米粒子可通過視覺觀察和適當的儀器來分析，適當的儀器包括穿透式電子顯微鏡、掃描式電子顯微鏡以及紫外線-可見光-近紅外線吸收光譜儀。The gold nanoparticles obtained in Example 1 can be analyzed by visual observation and appropriate instruments, and suitable instruments include a transmission electron microscope, a scanning electron microscope, and an ultraviolet-visible-near infrared absorption spectrometer.
一般瞭解，金奈米粒子溶液的顏色取決於奈米粒子的大小及形狀。個別的微小金奈米粒子呈現紅色，而當粒子聚集時，顏色會從紅色變為到藍色。在肉眼觀察(未顯示數據)的過程中，其顯示出，利用檸檬酸、聚環氧乙烷-聚環氧丙烷嵌段共聚物或聚乙烯四氫咯酮作為保護劑(如同在實例1中)所合成之本發明的金奈米粒子，顏色範圍是從藍紫到深藍色。在穿透式電子顯微鏡和掃式電子顯微鏡分析(圖2)的過程中，其顯示出，本發明的金奈米粒子具從20至500 nm之平均粒子大小，更特定而言具從50到300 nm之平均粒子大小，而且本發明的金奈米粒子具有糖花狀的形狀，每一金奈米粒子具有多個微小突起(直徑約30 nm，長度約40 nm)，這些突起是從奈米粒子的本體往外突出。此外，相對於尺寸較大的本體，這些突起具有較小的尺寸。在光譜分析(圖3)的過程中，其顯示出，本發明的金奈米粒子不僅在可見光範圍內表現出吸收能力，並且在近紅外線範圍也具有吸收能力，特定地是在300到1200 nm的範圍中具有吸收能力，更特定地是在450到800 nm的範圍內具有相對較強的吸收能力，而球狀金奈米粒子(控制組)僅在可見光範圍表現出吸收能力(近紅外線範圍內無吸收能力)。It is generally understood that the color of the gold nanoparticle solution depends on the size and shape of the nanoparticle. Individual tiny gold nanoparticles appear red, and as the particles gather, the color changes from red to blue. In the course of visual observation (data not shown), it was shown that citric acid, polyethylene oxide-polypropylene oxide block copolymer or polyethylene tetrahydrofuranone was used as a protective agent (as in Example 1). The gold nanoparticles of the present invention synthesized have a color ranging from blue purple to dark blue. In the course of transmission electron microscopy and scanning electron microscopy analysis (Fig. 2), it is shown that the gold nanoparticles of the invention have an average particle size from 20 to 500 nm, more specifically from 50 to The average particle size of 300 nm, and the gold nanoparticles of the present invention have a sugar-like shape, and each of the gold nanoparticles has a plurality of minute protrusions (about 30 nm in diameter and about 40 nm in length), and these protrusions are from Nye. The body of the rice particles protrudes outward. Moreover, these protrusions have a smaller size than the larger size body. In the course of spectral analysis (Fig. 3), it is shown that the gold nanoparticles of the present invention exhibit absorption not only in the visible range but also in the near infrared range, specifically at 300 to 1200 nm. The range has absorption capacity, more specifically, it has a relatively strong absorption capacity in the range of 450 to 800 nm, while the spherical gold nanoparticles (control group) exhibits absorption only in the visible range (near infrared range) No absorption capacity inside).
光學顯微鏡觀察是使用共軛焦掃描雷射顯微鏡(Leica TCS SP5)完成的。使用顯微鏡進行雷射照射時，波長為785 nm(功率為1.07瓦(W))、633 nm(功率為10毫瓦(mW))以及561 nm(功率為10毫瓦(mW))。Optical microscopy was performed using a conjugate focal scanning laser microscope (Leica TCS SP5). When irradiated with a microscope, the wavelength is 785 nm (1.07 watts (W)), 633 nm (10 mW), and 561 nm (10 mW).
本發明的糖花狀金奈米粒子係如同在實例1中之方式合成。加入葉酸水溶液(2 mM，0.4 cm3 )至糖花狀金奈米粒子分散液(40 cm3 )中。糖花狀金奈米粒子與葉酸水溶液的混合物以3000 rpm離心分離10分鐘，然後，將包括奈米粒子的1 cm3 之部分再次重新分散到8 cm3 ，以調整濃度至0.5 mM(以Au計)。為了與本發明做比較，合成球狀金奈米粒子和板狀金奈米粒子如下：The sugar-like gold nanoparticles of the present invention were synthesized in the same manner as in Example 1. A folic acid aqueous solution (2 mM, 0.4 cm 3 ) was added to the sugar-like gold nanoparticle dispersion (40 cm 3 ). The mixture of the sugar-like gold nanoparticles and the aqueous folic acid solution was centrifuged at 3000 rpm for 10 minutes, and then the 1 cm 3 portion including the nanoparticles was redispersed again to 8 cm 3 to adjust the concentration to 0.5 mM (with Au). meter). For comparison with the present invention, synthetic spherical gold nanoparticles and platy gold nanoparticles are as follows:
四氯金酸鈉水溶液(1 mM，10 cm3 )放在小玻璃瓶中攪拌煮沸。檸檬酸鈉(trisodium citrate)水溶液(1 wt%，1 cm3 )加入到上述溶液中。然後，反應溶液在劇烈攪拌下於100℃回流10分鐘。在上述溶液的顏色改變為紅色後，將上述溶液靜置冷卻。將葉酸水溶液(2 mM，0.025 cm3 )加入到所獲得的金奈米粒子分散液中。然後，用水將金奈米粒子分散液稀釋到20 cm3 ，以調整濃度至0.5 mM(以Au計)。An aqueous solution of sodium tetrachloroaurate (1 mM, 10 cm 3 ) was placed in a small glass jar and stirred to boil. An aqueous solution of trisodium citrate (1 wt%, 1 cm 3 ) was added to the above solution. Then, the reaction solution was refluxed at 100 ° C for 10 minutes with vigorous stirring. After the color of the above solution was changed to red, the solution was allowed to stand to cool. An aqueous solution of folic acid (2 mM, 0.025 cm 3 ) was added to the obtained gold nanoparticle dispersion. Then, the gold nanoparticle dispersion was diluted to 20 cm 3 with water to adjust the concentration to 0.5 mM (in terms of Au).
四氯金酸鈉水溶液(1 mM，10 cm3 )和檸檬酸水溶液(1 wt%，1 cm3 )與35 cm3 的水混合，並將反應溶液放在環境溫度下靜置過夜。加入葉酸水溶液(2 mM，0.4 cm3 )到所獲得的金奈米粒子分散液中。然後，將所獲得的金奈米粒子分散液以3000 rpm離心10分鐘。然後，將包括奈米粒子的1 cm3 之部分再次重新分散到8 cm3 ，以調整濃度至0.5 mM(以Au計)。An aqueous solution of sodium tetrachloroaurate (1 mM, 10 cm 3 ) and an aqueous solution of citric acid (1 wt%, 1 cm 3 ) were mixed with 35 cm 3 of water, and the reaction solution was allowed to stand at ambient temperature overnight. An aqueous solution of folic acid (2 mM, 0.4 cm 3 ) was added to the obtained gold nanoparticle dispersion. Then, the obtained gold nanoparticle dispersion was centrifuged at 3000 rpm for 10 minutes. Then, the 1 cm 3 portion including the nanoparticles was redispersed again to 8 cm 3 to adjust the concentration to 0.5 mM (in Au).
將金奈米粒子分散液(0.1 cm3 )加入海拉細胞培養液中(5x105 個細胞)，並在37℃下培養細胞2小時。然後，在顯微鏡下用雷射光照射細胞20-40秒。The gold nanoparticle dispersion (0.1 cm 3 ) was added to HeLa cell culture medium (5× 10 5 cells), and the cells were cultured at 37 ° C for 2 hours. The cells are then irradiated with laser light for 20-40 seconds under a microscope.
加入金奈米粒子分散液之葉酸是被假設吸附到奈米粒子的表面，以促進海拉細胞(子宮頸癌細胞系)攝取金奈米粒子。在以金奈米粒子培養2小時的時間後，透過共軛焦掃描雷射顯微鏡來觀察細胞，以確認細胞是否存活。金奈米粒子並未破壞這些細胞，且奈米粒子經確認位於細胞內(未顯示數據)。可以觀察到，本發明之個別金奈米粒子是暗場圖像中的亮點，即使經過長時間(幾天)後也可以被觀察到此現象，因此證實了癌細胞將本發明之金奈米粒子攝取到它們的體內，但卻沒有發生癌溶解現象。因此，觀察證實了本發明的金奈米粒子是生物可相容的，就如同從合成的過程可預計。然而，攝入有金奈米粒子的細胞在波長785 nm的雷射照射下，幾分鐘內就會被殺死(圖4(a)，右邊)。這表明本發明的金奈米粒子吸收光線並產生熱能來殺死癌細胞。The folic acid added to the gold nanoparticle dispersion is assumed to be adsorbed onto the surface of the nanoparticle to promote the uptake of the gold nanoparticles by the HeLa cells (cervical cancer cell line). After incubation with the gold nanoparticles for 2 hours, the cells were observed by a conjugated focus scanning laser microscope to confirm whether the cells survived. The gold nanoparticles did not destroy these cells, and the nanoparticles were confirmed to be located inside the cells (data not shown). It can be observed that the individual gold nanoparticles of the present invention are bright spots in the dark field image, and this phenomenon can be observed even after a long period of time (a few days), thus confirming that the cancer cells will be the gold nanoparticles of the present invention. The particles ingested into their bodies, but no cancer dissolved. Thus, observations confirm that the gold nanoparticles of the present invention are biocompatible, as can be expected from the course of the synthesis. However, cells ingested with gold nanoparticles are killed within a few minutes at a wavelength of 785 nm (Fig. 4(a), right). This indicates that the gold nanoparticles of the present invention absorb light and generate thermal energy to kill cancer cells.
另一方面，儘管此波長與其表面電漿能帶一致，攝入有金奈米粒子的細胞在波長633 nm的照射下不會受損，但在此同時本發明的金奈米粒子之亮點變暗(圖4(a)，左邊)。這種現象意味著，本發明的金奈米粒子有效地吸收了雷射光，並迅速改變它們的形狀而成為球形奈米粒子。這表明，糖花狀金奈米粒子也可以作為藥物釋放系統，並透過此波長的雷射照射加以控制。On the other hand, although this wavelength is consistent with its surface plasma energy band, cells ingesting the gold nanoparticles are not damaged by irradiation at a wavelength of 633 nm, but at the same time, the bright spots of the gold nanoparticles of the present invention become Dark (Figure 4 (a), left). This phenomenon means that the gold nanoparticles of the present invention effectively absorb the laser light and rapidly change their shape to become spherical nano particles. This suggests that the sugar-like gold nanoparticles can also be used as a drug delivery system and controlled by laser irradiation at this wavelength.
因此，在不同波長的雷射照射下，本發明的金奈米粒子會顯示不同的行為，從而提供不同的用途，如癌症治療和藥物傳遞。Thus, the gold nanoparticles of the present invention exhibit different behaviors under different wavelengths of laser illumination, thereby providing different uses, such as cancer treatment and drug delivery.
為了進行比較，小的球狀金奈米粒子(直徑：10至20 nm；圖4(b)，左邊與右邊)和大的板狀金奈米粒子(直徑：100 nm～；圖4(c)，左邊與右邊)都以類似的步驟做檢驗，結果觀察到了顯著的差異。雖然板狀和球狀金奈米粒子會吸收波長561 nm的雷射光，但只有板狀金奈米粒子會殺死在此波長照射下的細胞。以球狀金奈米粒子處理過的細胞在波長為561 nm(圖4(b)，左邊)和785 nm(圖4(b)，右邊)之雷射照射下都存活著，以板狀金奈米粒子處理過的細胞在波長為561 nm(圖4(c)，左邊)和785 nm(圖4(c)，右邊)之雷射照射下都死亡。For comparison, small spherical gold nanoparticles (diameter: 10 to 20 nm; Figure 4 (b), left and right) and large platy gold nanoparticles (diameter: 100 nm ~; Figure 4 (c ), both left and right) were tested in a similar manner and the results were observed to be significant. Although plate and spherical gold nanoparticles absorb laser light with a wavelength of 561 nm, only plate-shaped gold nanoparticles kill cells that are irradiated at this wavelength. Cells treated with globular gold nanoparticles survived under laser irradiation at 561 nm (Fig. 4(b), left) and 785 nm (Fig. 4(b), right), with plate gold Nanoparticle-treated cells died under laser irradiation at 561 nm (Fig. 4(c), left) and 785 nm (Fig. 4(c), right).
現在將參照以下實施例更特定地詳細描述本發明，而提出這些詳細描述是為了論述本發明之目的，並非是本發明範圍之限制。The present invention will now be described in detail with reference to the accompanying exemplary embodiments,
為了舉例說明本發明之目的，以下圖式中顯示了目前被認為是較佳的實施例。然而，應被瞭解的是，本發明並不限制於以下顯示的較佳實施例。To exemplify the purpose of the present invention, the embodiments which are presently considered to be preferred are shown in the following drawings. However, it should be understood that the invention is not limited to the preferred embodiments shown below.
在下列圖式中：In the following figures:
圖1顯示了本發明之金奈米粒子的合成方法圖解。Figure 1 shows an illustration of the synthesis of the gold nanoparticles of the present invention.
圖2顯示了本發明之金奈米粒子的影像，其中本發明之金奈米粒子是藉由不同保護劑來合成的，(a)與(d)是藉由檸檬酸，(b)與(e)是藉由三團聯聚合物(PF-127)，(c)與(f)是藉由聚乙烯四氫咯酮，而這些影像是利用穿透式電子顯微鏡拍攝(上方欄位；(a)、(b)及(c))以及利用掃瞄式電子顯微鏡拍攝(下方欄位；(d)、(e)及(f))。Figure 2 shows an image of the gold nanoparticles of the present invention, wherein the gold nanoparticles of the present invention are synthesized by different protective agents, (a) and (d) are by citric acid, (b) and e) is by triplet polymer (PF-127), (c) and (f) are by polyethylene tetrahydrofuranone, and these images are taken by a penetrating electron microscope (upper field; a), (b), and (c)) and photographing with a scanning electron microscope (lower fields; (d), (e), and (f)).
圖3顯示了本發明之金奈米粒子的紫外線-可見光-近紅外線吸收光譜(不同形式的虛線)以及傳統球狀金奈米粒子的紫外線-可見光-近紅外線吸收光譜(實線)，其中本發明之金奈米粒子是藉由不同保護劑來合成的，保護劑包括聚乙烯四氫咯酮、聚環氧乙烷-聚環氧丙烷嵌段共聚物以及檸檬酸。Figure 3 shows the ultraviolet-visible-near-infrared absorption spectrum (dashed line of different forms) of the gold nanoparticles of the present invention and the ultraviolet-visible-near infrared absorption spectrum (solid line) of the conventional spherical gold nanoparticles, wherein The inventive gold nanoparticles are synthesized by different protective agents including polyethylene tetrahydrofuranone, polyethylene oxide-polypropylene oxide block copolymer, and citric acid.
圖4顯示了以不同金奈米粒子處理過的海拉細胞在不同波長的雷射照射下之結果，其中(a)小圖提及以本發明之糖花狀金奈米粒子處理過後的細胞在波長633 nm(左邊)以及波長785 nm(右邊)的雷射照射下之結果，(b)小圖提及以球狀金奈米粒子處理過後的細胞在波長561 nm(左邊)以及波長785 nm(右邊)的雷射照射下之結果，(c)小圖提及以板狀金奈米粒子處理過後的細胞在波長561 nm(左邊)以及波長785 nm(右邊)的雷射照射下之結果。Figure 4 shows the results of different wavelengths of laser irradiation of HeLa cells treated with different gold nanoparticles, wherein (a) the small figure refers to the cells treated with the sugar-like gold nanoparticles of the present invention. The results of laser irradiation at a wavelength of 633 nm (left) and a wavelength of 785 nm (right), (b) small figures refer to cells treated with spherical gold nanoparticles at a wavelength of 561 nm (left) and a wavelength of 785 The result of the laser irradiation of nm (right), (c) The small figure mentions that the cells treated with the plate-shaped gold nanoparticles are irradiated by laser at a wavelength of 561 nm (left) and a wavelength of 785 nm (right). result.
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