近红外光激发的功能纳米材料用于肿瘤的靶向治疗
发布时间:2018-08-04 14:14
【摘要】:癌症,即恶性肿瘤,是严重威胁人类健康和社会发展的重大疾病。癌症的形成是由身体内细胞发生突变,产生不受身体机能控制的分裂所致。恶性肿瘤的细胞能侵占、破坏相近的组织和器官。并且,癌细胞可以从肿瘤组织中脱落,然后跟着血液或淋巴系统发生转移。它的难以治愈性、致死性已经严重威胁到了人类的健康,人们对于癌症治疗的研究也从未间断过。在过去相当长的一段时间里,人们致力于解决传统的手术、放疗、化疗等治疗方法引起的易复发、毒副作用大等问题,提出了靶向治疗策略。但是,靶向治疗虽然理论上能够只对肿瘤发挥作用,但是在真正的治疗过程中却只有很少量的药物能够在肿瘤部位起作用,治疗效果不理想。因此,寻找到一种能够实现更好靶向效果的治疗策略是目前研究的热点,具有重大意义。近年来,纳米材料因具有小尺寸效应表面效应量子尺寸效应等优势而得到了普遍的发展应用。随着研究的不断深入,各种纳米材料也被广泛的应用到了癌症治疗的研究中,进而产生了一些新的治疗方法。其中,能够运用近红外光只照射肿瘤部位的光热疗法和光动力疗法由于对正常组织损伤较少得到了广泛关注。光热治疗法是利用具有高光热转换效率的纳米材料,在外部光源(一般是近红外光)的照射下将光能转化为热能来杀死癌细胞的一种治疗方法。半导体硫化铜纳米材料是近几年新发展起来的一种光热材料,目前也得到了广泛的发展。光动力学疗法是用特定波长的激光照射肿瘤处,使肿瘤组织吸收的光敏剂受到激发得到能量,把能量传递给周围的氧,生成活性很强的单线态氧,单线态氧和相邻的生物大分子发生氧化反应,产生细胞毒性作用,进而导致细胞受损乃至死亡,达到治疗肿瘤的目的。但是,虽然新治疗模式的发展提高了一定的靶向性但是由于仍然存在靶向肿瘤部位纳米颗粒量很少的问题,肿瘤最终的治疗效果仍然差强人意。因此,在现有能够靶向肿瘤部位纳米粒子量的基础上提高治疗效果,还是增多能够真正靶向到肿瘤部位纳米材料的量都是解决治疗问题的重点。本文基于功能化的纳米材料,设计合成了在近红外光激发下可实现靶向精确治疗癌症并且防止其复发的功能纳米材料。本论文主要开展了以下两方面的工作:1、设计合成了一种能够靶向进入细胞核的光热纳米材料用于肿瘤的有效光热治疗。纳米材料包括具有光热效应的硫化铜纳米材料,在其表面包裹了一层介孔二氧化硅,然后通过酰胺键作用将靶向细胞核的多肽TAT和靶向肿瘤细胞的环肽RGD成功的连接到硫化铜的表面。当980 nm激光照射后,硫化铜中被激发的电子从高能级向低能级跃迁时,会以光或热量的形式释放能量,释放的热量会导致吸收体局部温度升高。980 nm作为近红外光具有较深的组织穿透性,并且对正常组织损伤较少。TAT多肽的存在使硫化铜纳米颗粒可以成功进入到细胞核内,从而将硫化铜在光照下产生的热量集中的在细胞核内发挥作用,使内部DNA损伤蛋白质变性,达到更快、更好的治疗效果。c(RGDyC)多肽可以与癌细胞表面过表达的αvβ3受体结合,当将RGD通过共价键连接到硫化铜表面时,通过静脉注射进体内靶向到肿瘤细胞,再进入到肿瘤细胞细胞核内进而光热杀死细胞。癌细胞在治疗的过程中能够快速有效全面的被杀死,进一步也就可以达到防止肿瘤复发的目的。2、设计了一种能够靶向肿瘤微环境而不进入正常组织的功能纳米材料实现特异性光动力学治疗。该研究选择在上转换纳米颗粒的表面修饰了两段不同长短的DNA链,其中长的DNA链是富含C碱基的并且在其末端修饰了光敏剂Ce6,另一条短的DNA链末端修饰了叶酸。当整个纳米颗粒在血液中循环到达肿瘤部位后,由于肿瘤部位酸性的微环境使富含C碱基的长链DNA发生折叠,从而使短链DNA上的叶酸得以暴露,实现特异性靶向癌细胞的目的。同时,DNA链发生折叠后使末端Ce6靠近了上转换纳米粒子,在近红外光激发下可产生单线态氧实现特异性光动力学治疗,而不对正常细胞产生损伤。
[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.
【学位授予单位】:山东师范大学
【学位级别】:硕士
【学位授予年份】:2017
【分类号】:TB383.1;TQ460.1
本文编号: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.
【学位授予单位】:山东师范大学
【学位级别】:硕士
【学位授予年份】:2017
【分类号】:TB383.1;TQ460.1
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