近紅外光激發(fā)的功能納米材料用于腫瘤的靶向治療
發(fā)布時(shí)間：2018-08-04 14:14
【摘要】：癌癥,即惡性腫瘤,是嚴(yán)重威脅人類(lèi)健康和社會(huì)發(fā)展的重大疾病。癌癥的形成是由身體內(nèi)細(xì)胞發(fā)生突變,產(chǎn)生不受身體機(jī)能控制的分裂所致。惡性腫瘤的細(xì)胞能侵占、破壞相近的組織和器官。并且,癌細(xì)胞可以從腫瘤組織中脫落,然后跟著血液或淋巴系統(tǒng)發(fā)生轉(zhuǎn)移。它的難以治愈性、致死性已經(jīng)嚴(yán)重威脅到了人類(lèi)的健康,人們對(duì)于癌癥治療的研究也從未間斷過(guò)。在過(guò)去相當(dāng)長(zhǎng)的一段時(shí)間里,人們致力于解決傳統(tǒng)的手術(shù)、放療、化療等治療方法引起的易復(fù)發(fā)、毒副作用大等問(wèn)題,提出了靶向治療策略。但是,靶向治療雖然理論上能夠只對(duì)腫瘤發(fā)揮作用,但是在真正的治療過(guò)程中卻只有很少量的藥物能夠在腫瘤部位起作用,治療效果不理想。因此,尋找到一種能夠?qū)崿F(xiàn)更好靶向效果的治療策略是目前研究的熱點(diǎn),具有重大意義。近年來(lái),納米材料因具有小尺寸效應(yīng)表面效應(yīng)量子尺寸效應(yīng)等優(yōu)勢(shì)而得到了普遍的發(fā)展應(yīng)用。隨著研究的不斷深入,各種納米材料也被廣泛的應(yīng)用到了癌癥治療的研究中,進(jìn)而產(chǎn)生了一些新的治療方法。其中,能夠運(yùn)用近紅外光只照射腫瘤部位的光熱療法和光動(dòng)力療法由于對(duì)正常組織損傷較少得到了廣泛關(guān)注。光熱治療法是利用具有高光熱轉(zhuǎn)換效率的納米材料,在外部光源(一般是近紅外光)的照射下將光能轉(zhuǎn)化為熱能來(lái)殺死癌細(xì)胞的一種治療方法。半導(dǎo)體硫化銅納米材料是近幾年新發(fā)展起來(lái)的一種光熱材料,目前也得到了廣泛的發(fā)展。光動(dòng)力學(xué)療法是用特定波長(zhǎng)的激光照射腫瘤處,使腫瘤組織吸收的光敏劑受到激發(fā)得到能量,把能量傳遞給周?chē)难?生成活性很強(qiáng)的單線(xiàn)態(tài)氧,單線(xiàn)態(tài)氧和相鄰的生物大分子發(fā)生氧化反應(yīng),產(chǎn)生細(xì)胞毒性作用,進(jìn)而導(dǎo)致細(xì)胞受損乃至死亡,達(dá)到治療腫瘤的目的。但是,雖然新治療模式的發(fā)展提高了一定的靶向性但是由于仍然存在靶向腫瘤部位納米顆粒量很少的問(wèn)題,腫瘤最終的治療效果仍然差強(qiáng)人意。因此,在現(xiàn)有能夠靶向腫瘤部位納米粒子量的基礎(chǔ)上提高治療效果,還是增多能夠真正靶向到腫瘤部位納米材料的量都是解決治療問(wèn)題的重點(diǎn)。本文基于功能化的納米材料,設(shè)計(jì)合成了在近紅外光激發(fā)下可實(shí)現(xiàn)靶向精確治療癌癥并且防止其復(fù)發(fā)的功能納米材料。本論文主要開(kāi)展了以下兩方面的工作:1、設(shè)計(jì)合成了一種能夠靶向進(jìn)入細(xì)胞核的光熱納米材料用于腫瘤的有效光熱治療。納米材料包括具有光熱效應(yīng)的硫化銅納米材料,在其表面包裹了一層介孔二氧化硅,然后通過(guò)酰胺鍵作用將靶向細(xì)胞核的多肽TAT和靶向腫瘤細(xì)胞的環(huán)肽RGD成功的連接到硫化銅的表面。當(dāng)980 nm激光照射后,硫化銅中被激發(fā)的電子從高能級(jí)向低能級(jí)躍遷時(shí),會(huì)以光或熱量的形式釋放能量,釋放的熱量會(huì)導(dǎo)致吸收體局部溫度升高。980 nm作為近紅外光具有較深的組織穿透性,并且對(duì)正常組織損傷較少。TAT多肽的存在使硫化銅納米顆�？梢猿晒M(jìn)入到細(xì)胞核內(nèi),從而將硫化銅在光照下產(chǎn)生的熱量集中的在細(xì)胞核內(nèi)發(fā)揮作用,使內(nèi)部DNA損傷蛋白質(zhì)變性,達(dá)到更快、更好的治療效果。c(RGDyC)多肽可以與癌細(xì)胞表面過(guò)表達(dá)的αvβ3受體結(jié)合,當(dāng)將RGD通過(guò)共價(jià)鍵連接到硫化銅表面時(shí),通過(guò)靜脈注射進(jìn)體內(nèi)靶向到腫瘤細(xì)胞,再進(jìn)入到腫瘤細(xì)胞細(xì)胞核內(nèi)進(jìn)而光熱殺死細(xì)胞。癌細(xì)胞在治療的過(guò)程中能夠快速有效全面的被殺死,進(jìn)一步也就可以達(dá)到防止腫瘤復(fù)發(fā)的目的。2、設(shè)計(jì)了一種能夠靶向腫瘤微環(huán)境而不進(jìn)入正常組織的功能納米材料實(shí)現(xiàn)特異性光動(dòng)力學(xué)治療。該研究選擇在上轉(zhuǎn)換納米顆粒的表面修飾了兩段不同長(zhǎng)短的DNA鏈,其中長(zhǎng)的DNA鏈?zhǔn)歉缓珻堿基的并且在其末端修飾了光敏劑Ce6,另一條短的DNA鏈末端修飾了葉酸。當(dāng)整個(gè)納米顆粒在血液中循環(huán)到達(dá)腫瘤部位后,由于腫瘤部位酸性的微環(huán)境使富含C堿基的長(zhǎng)鏈DNA發(fā)生折疊,從而使短鏈DNA上的葉酸得以暴露,實(shí)現(xiàn)特異性靶向癌細(xì)胞的目的。同時(shí),DNA鏈發(fā)生折疊后使末端Ce6靠近了上轉(zhuǎn)換納米粒子,在近紅外光激發(fā)下可產(chǎn)生單線(xiàn)態(tài)氧實(shí)現(xiàn)特異性光動(dòng)力學(xué)治療,而不對(duì)正常細(xì)胞產(chǎn)生損傷。
[Abstract]:Cancer, a malignant tumor, is a major disease that seriously threatens human health and social development. The formation of cancer is caused by the mutation of the cells in the body, resulting from the division of the body, which is not controlled by the body. The cells of the malignant tumor can invade and destroy the similar tissues and organs. And the cancer cells can fall off from the tumor tissue and follow them. The metastasis of blood or lymphatic system. It is difficult to cure. Lethality has been a serious threat to human health. Research on cancer treatment has never been interrupted. In the past a long period of time, people are committed to solving the recurrence of traditional surgery, radiotherapy, chemotherapy and other treatments. However, although targeted therapy can only play a role in tumors in theory, only a small amount of drugs can play a role in the tumor site in the real treatment process, and the treatment effect is not ideal. Therefore, it is a hot study to find a therapeutic strategy that can achieve better target effect. In recent years, nanomaterials have been widely used for their advantages such as small size effect, surface effect, quantum size effect and so on. With the development of research, various nanomaterials have been widely used in the research of cancer treatment, and some new therapies have been produced. Photothermal therapy and photodynamic therapy, which only irradiates the tumor site with near infrared light, is widely concerned because of less damage to normal tissues. Photothermal therapy is a treatment for the use of nanomaterials with high photothermal conversion efficiency to transform light energy into heat to kill cancer cells under external light (generally near infrared light) irradiation. Method. Semiconducting copper sulfide nanomaterial is a new kind of photothermal material developed in recent years, and it has been widely developed in recent years. Photodynamic therapy is to irradiate the tumor with a specific wavelength of laser, so that the photosensitizer absorbed by the tumor tissue is excited to get energy and transfer the energy to the surrounding oxygen to produce a very active single line. The oxidative reaction of state oxygen, single state oxygen and adjacent biological macromolecules produces cytotoxic effects, resulting in cell damage and death to achieve the purpose of cancer treatment. However, although the development of the new treatment model improves a certain target, but there is still a small amount of nanoparticles in the target tumor site, the tumor is still present. The effect of the final treatment is still poor. Therefore, it is important to improve the therapeutic effect on the basis of the amount of nanoparticles that can target the tumor site, or to increase the amount of nanomaterials that can actually target the tumor site. Based on the functionalized nanomaterials, this paper has been designed and synthesized in the near infrared light excitation. The functional nanomaterials can be implemented to target cancer and prevent their recurrence. The main work of this paper is two aspects: 1, an effective photothermal treatment for tumors that can be targeted to the nucleus is designed and synthesized. The nanomaterials, including the photothermal effect of Copper Sulfide Nanomaterials, have been designed. The surface is coated with a layer of mesoporous silica, and then the polypeptide TAT of the target nucleus and the cyclic peptide RGD that target the tumor cells are successfully connected to the surface of the copper sulfide through the amide bond action. When the 980 nm laser is irradiated, the electrons in the copper sulfide are released from the high energy level to the low energy level, and release the energy in the form of light or heat. The heat can lead to the increase of the local temperature of the absorber,.980 nm has a deeper tissue penetration as the near infrared light, and the presence of less.TAT peptide in the normal tissue causes the copper nanoparticles to be successfully entered into the nucleus, thus making the heat of copper sulfide in the light exerting a role in the nucleus. Internal DNA damage protein denaturation faster, better therapeutic effect, better therapeutic effect,.C (RGDyC) polypeptide can be combined with the overexpressed alpha v beta 3 receptor on the surface of cancer cells. When RGD is connected to the surface of copper sulfide through a covalent bond, it is targeted to the tumor cell by intravenous injection into the body and then into the cell nucleus of the tumor and then kills the cell in the cell nucleus of the tumor. Cancer cells can be killed quickly, effectively and comprehensively in the process of treatment, and further to achieve the purpose of preventing the recurrence of cancer,.2 has been designed to achieve specific photodynamic therapy that can target the tumor microenvironment instead of the normal tissue. The study chooses surface modification of the up conversion nanoparticles. A DNA chain of two different length and short length, of which the long DNA chain is rich in C base and modifies the photosensitizer Ce6 at its end, and the other short DNA chain ends with folic acid. As the whole nanoparticles circulate in the blood, the long chain DNA rich in the C base is folded because of the acidic microenvironment of the tumor. The folic acid on the short chain DNA can be exposed to target cancer cells specifically. At the same time, after the DNA chain is folded, the terminal Ce6 is close to the up conversion nanoparticles, and the single state oxygen can be produced by the near infrared light to achieve the specific photodynamic therapy and not damage the normal cells.
【學(xué)位授予單位】：山東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：TB383.1;TQ460.1
本文編號(hào)：2164140
[Abstract]:Cancer, a malignant tumor, is a major disease that seriously threatens human health and social development. The formation of cancer is caused by the mutation of the cells in the body, resulting from the division of the body, which is not controlled by the body. The cells of the malignant tumor can invade and destroy the similar tissues and organs. And the cancer cells can fall off from the tumor tissue and follow them. The metastasis of blood or lymphatic system. It is difficult to cure. Lethality has been a serious threat to human health. Research on cancer treatment has never been interrupted. In the past a long period of time, people are committed to solving the recurrence of traditional surgery, radiotherapy, chemotherapy and other treatments. However, although targeted therapy can only play a role in tumors in theory, only a small amount of drugs can play a role in the tumor site in the real treatment process, and the treatment effect is not ideal. Therefore, it is a hot study to find a therapeutic strategy that can achieve better target effect. In recent years, nanomaterials have been widely used for their advantages such as small size effect, surface effect, quantum size effect and so on. With the development of research, various nanomaterials have been widely used in the research of cancer treatment, and some new therapies have been produced. Photothermal therapy and photodynamic therapy, which only irradiates the tumor site with near infrared light, is widely concerned because of less damage to normal tissues. Photothermal therapy is a treatment for the use of nanomaterials with high photothermal conversion efficiency to transform light energy into heat to kill cancer cells under external light (generally near infrared light) irradiation. Method. Semiconducting copper sulfide nanomaterial is a new kind of photothermal material developed in recent years, and it has been widely developed in recent years. Photodynamic therapy is to irradiate the tumor with a specific wavelength of laser, so that the photosensitizer absorbed by the tumor tissue is excited to get energy and transfer the energy to the surrounding oxygen to produce a very active single line. The oxidative reaction of state oxygen, single state oxygen and adjacent biological macromolecules produces cytotoxic effects, resulting in cell damage and death to achieve the purpose of cancer treatment. However, although the development of the new treatment model improves a certain target, but there is still a small amount of nanoparticles in the target tumor site, the tumor is still present. The effect of the final treatment is still poor. Therefore, it is important to improve the therapeutic effect on the basis of the amount of nanoparticles that can target the tumor site, or to increase the amount of nanomaterials that can actually target the tumor site. Based on the functionalized nanomaterials, this paper has been designed and synthesized in the near infrared light excitation. The functional nanomaterials can be implemented to target cancer and prevent their recurrence. The main work of this paper is two aspects: 1, an effective photothermal treatment for tumors that can be targeted to the nucleus is designed and synthesized. The nanomaterials, including the photothermal effect of Copper Sulfide Nanomaterials, have been designed. The surface is coated with a layer of mesoporous silica, and then the polypeptide TAT of the target nucleus and the cyclic peptide RGD that target the tumor cells are successfully connected to the surface of the copper sulfide through the amide bond action. When the 980 nm laser is irradiated, the electrons in the copper sulfide are released from the high energy level to the low energy level, and release the energy in the form of light or heat. The heat can lead to the increase of the local temperature of the absorber,.980 nm has a deeper tissue penetration as the near infrared light, and the presence of less.TAT peptide in the normal tissue causes the copper nanoparticles to be successfully entered into the nucleus, thus making the heat of copper sulfide in the light exerting a role in the nucleus. Internal DNA damage protein denaturation faster, better therapeutic effect, better therapeutic effect,.C (RGDyC) polypeptide can be combined with the overexpressed alpha v beta 3 receptor on the surface of cancer cells. When RGD is connected to the surface of copper sulfide through a covalent bond, it is targeted to the tumor cell by intravenous injection into the body and then into the cell nucleus of the tumor and then kills the cell in the cell nucleus of the tumor. Cancer cells can be killed quickly, effectively and comprehensively in the process of treatment, and further to achieve the purpose of preventing the recurrence of cancer,.2 has been designed to achieve specific photodynamic therapy that can target the tumor microenvironment instead of the normal tissue. The study chooses surface modification of the up conversion nanoparticles. A DNA chain of two different length and short length, of which the long DNA chain is rich in C base and modifies the photosensitizer Ce6 at its end, and the other short DNA chain ends with folic acid. As the whole nanoparticles circulate in the blood, the long chain DNA rich in the C base is folded because of the acidic microenvironment of the tumor. The folic acid on the short chain DNA can be exposed to target cancer cells specifically. At the same time, after the DNA chain is folded, the terminal Ce6 is close to the up conversion nanoparticles, and the single state oxygen can be produced by the near infrared light to achieve the specific photodynamic therapy and not damage the normal cells.
【學(xué)位授予單位】：山東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：TB383.1;TQ460.1
【參考文獻(xiàn)】
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相關(guān)會(huì)議論文 前1條
1 周傳農(nóng);;腫瘤光動(dòng)力治療研究新進(jìn)展[A];第六屆全國(guó)光生物學(xué)學(xué)術(shù)研討會(huì)論文集[C];2004年
，本文編號(hào)：2164140
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