本文選題：納米材料　切入點(diǎn)：植物多酚　出處：《暨南大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：腫瘤的轉(zhuǎn)移是癌癥發(fā)病率和死亡率的主要原因。雖然早期診斷和抗腫瘤藥物的研發(fā)工作取得了很大進(jìn)展,使癌癥患者的生存率明顯提高。然而仍然有許多因素限制了抗腫瘤藥物的治療療效,復(fù)發(fā)和轉(zhuǎn)移仍是未解決的難題。腫瘤的浸潤(rùn)和遷移是由多基因參與,多條信號(hào)轉(zhuǎn)導(dǎo)途徑共同交叉調(diào)控的一個(gè)復(fù)雜過(guò)程。因此針對(duì)腫瘤侵襲轉(zhuǎn)移中的一些關(guān)鍵環(huán)節(jié)專門設(shè)計(jì)有效作用靶點(diǎn),成為開發(fā)抗腫瘤侵襲和轉(zhuǎn)移藥物研究的一大熱點(diǎn)。為了適合在生物醫(yī)學(xué)領(lǐng)域中應(yīng)用,理想納米材料的合成方法是避免使用有毒的化學(xué)試劑,并能更好地控制納米粒子的形狀和大小。因此,基于對(duì)腫瘤轉(zhuǎn)移分子水平上的認(rèn)識(shí),本論文從天然產(chǎn)物植物多酚中尋找具有良好活性的植物成分,從形貌、大小和靶向配體的角度設(shè)計(jì)合成了三種納米材料,系統(tǒng)地研究了其抗腫瘤侵潤(rùn)和轉(zhuǎn)移的作用,并對(duì)其抑制機(jī)制進(jìn)行了深入探討。本研究論文分為四章:第一章:緒論部分,介紹了腫瘤浸潤(rùn)轉(zhuǎn)移的分子生物學(xué)機(jī)制。闡明了納米粒子的綠色合成方法及其物理化學(xué)性質(zhì)對(duì)生物系統(tǒng)的影響。最后綜述了抗侵襲和轉(zhuǎn)移納米藥物的研究進(jìn)展。第二章:為了篩選合適形貌的硒納米粒子進(jìn)行細(xì)胞生物學(xué)行為的研究,我們利用鞣酸(TA)作為還原劑和表面修飾劑,制備出了梭型、球型和花型三種不同形貌的TA-Se NPs。相對(duì)于梭型和花型,球型TA-Se NPs表現(xiàn)出更好的細(xì)胞吸收和抑制癌細(xì)胞生長(zhǎng)的效果。因此我們選擇球型TA-Se NPs(B)做為進(jìn)一步實(shí)驗(yàn)的研究對(duì)象。研究發(fā)現(xiàn)TA-Se NPs能夠抑制體內(nèi)和體外由b FGF誘導(dǎo)的血管生成。在對(duì)納米粒子抑制血管生成機(jī)理研究中發(fā)現(xiàn),TA-Se NP能與b FGF結(jié)合,導(dǎo)致b FGF與高親和力受體(FGFR)的結(jié)合力受到影響,從而減少了MAPK/Erk和P13K/AKT通路信號(hào)分子的激活,進(jìn)而抑制了血管生成。同時(shí)TA-Se NP也能通過(guò)下調(diào)細(xì)胞內(nèi)b FGF的表達(dá)來(lái)參與對(duì)內(nèi)皮細(xì)胞的遷移、管形成等的調(diào)節(jié)。第三章:納米硒的綠色化學(xué)合成往往會(huì)導(dǎo)致納米的尺寸較大,從而限制了其作為抗腫瘤藥物的應(yīng)用。因此我們利用沒食子酸(GA)作為還原劑和封端劑,通過(guò)簡(jiǎn)單的綠色合成方法制備出粒徑為60 nm的硒/釕復(fù)合納米粒子(GA-Se/Ru NPs)。Se/Ru復(fù)合納米粒子的粒徑和形態(tài)能通過(guò)改變GA的濃度加以調(diào)控,并且Ru也是調(diào)節(jié)和控制尺寸的關(guān)鍵性因素。此外GA-Se/Ru NPs能夠通過(guò)誘導(dǎo)細(xì)胞凋亡來(lái)抑制He La細(xì)胞的生長(zhǎng),而對(duì)正常的HK-2細(xì)胞無(wú)明顯毒性。另外GA-Se/Ru NPs通過(guò)下調(diào)MMP-2和MMP-9的蛋白表達(dá)有效地抑制了宮頸癌He La細(xì)胞的浸潤(rùn)和遷移。研究結(jié)果表明由GA介導(dǎo)合成的Se/Ru復(fù)合納米粒子展現(xiàn)了更強(qiáng)的抗癌效果。第四章:功能化的納米粒子可以通過(guò)受體介導(dǎo)的內(nèi)吞作用促進(jìn)腫瘤細(xì)胞對(duì)納米粒子的攝入,從而能更有效地發(fā)揮其抗腫瘤的治療作用。在這一章中,由于表沒食子兒茶素沒食子酸酯(EGCG)與在肝癌細(xì)胞中過(guò)表達(dá)的67-k Da層粘連蛋白受體(67LR)具有高親和力。因此我們?cè)O(shè)計(jì)用EGCG功能化負(fù)載有發(fā)光釕配合物的納米釕粒子(Ru NPs),以實(shí)現(xiàn)更高效的抗腫瘤功效。合成出的納米粒子(Ru BB-loaded EGCG-Ru NPs)對(duì)肝癌細(xì)胞具有較高的選擇性。細(xì)胞對(duì)Ru BB-loaded EGCG-Ru NPs的內(nèi)化作用可以被67LR抗體和層粘連蛋白抑制,表明67LR介導(dǎo)的內(nèi)吞作用在肝癌細(xì)胞對(duì)Ru BB-loaded EGCG-Ru NPs的攝入中起到了關(guān)鍵作用。TEM和共聚焦顯微圖像顯示納米粒子主要聚集在SMMC-7721細(xì)胞的細(xì)胞質(zhì)中。進(jìn)一步的結(jié)果表明EGCG功能化的納米粒子以其特異性分子靶點(diǎn)方式顯示出增強(qiáng)的抗腫瘤活性。Ru BB-loaded EGCG-Ru NPs表現(xiàn)出對(duì)人肝癌細(xì)胞SMMC-7721具有ROS介導(dǎo)的直接細(xì)胞毒性,且具有促腫瘤細(xì)胞凋亡及抗腫瘤細(xì)胞侵襲作用,而對(duì)正常細(xì)胞L-02無(wú)細(xì)胞毒性。此外,裸鼠移植瘤體內(nèi)模型實(shí)驗(yàn)表明Ru BB-loaded EGCG-Ru NPs具有較高的抗腫瘤功效。
[Abstract]:Tumor metastasis is a major cause of cancer morbidity and mortality. Although early diagnosis and antitumor drug research and development work has made great progress, the survival rate of cancer patients improved significantly. However, there are still many factors that restrict the therapeutic effect of anticancer drugs, the problem of recurrence and metastasis is still unresolved. Tumor invasion and migration is a multi gene, a complex process of multiple signal transduction regulation. Therefore the common cross tumor invasion of some key links in the transfer of specially designed effective targets, has become a hot topic in the development of tumor invasion and metastasis. In order to study drugs suitable for application in the biomedical field, the ideal synthesis method nano material is to avoid the use of toxic chemical reagents, and can better control the shape and size of nanoparticles. Therefore, based on the molecular level of tumor metastasis Understanding the search of plant ingredients, with good activity from natural products of plant polyphenols from morphology, size and targeting ligand design from the perspective of three kinds of nano materials were synthesized and studied systematically the tumor invasion and metastasis, and the inhibition mechanism were discussed in this paper. Divided into four chapters: the first chapter: the introduction part, introduces the molecular mechanism of tumor invasion and metastasis. Illustrates the influence of green synthesis of nanoparticles and their physical and chemical properties of biological systems. Finally summarizes the research progress of nano drug and anti invasion transfer. The second chapter: in order to study the selenium nanoparticles screening suitable for biological morphology the behavior of cells, we use tannic acid (TA) as the reducing agent and surface modifying agent, was prepared by spindle type, ball type and pattern of three different morphologies of TA-Se NPs. relative to the spindle and flowers Type, ball type TA-Se NPs showed better absorption of cells and inhibiting the growth of cancer cells. So we choose the ball type TA-Se NPs (B) as the research object for further study. The study found that TA-Se NPs can inhibit the angiogenesis induced by B FGF in vivo and in vitro. In the study found to inhibit the generation mechanism of vascular nanoparticles in TA-Se, the combination of NP and B FGF, B FGF and lead to high affinity receptor (FGFR) binding force is affected, thereby reducing the activation of MAPK/Erk and P13K/AKT signaling pathway, thereby inhibiting angiogenesis. TA-Se and NP can down regulate expression of intracellular B FGF to participate in the migration of endothelial cells the tube formation regulation. The third chapter: green chemical synthesis of nano selenium nanoparticles often leads to a larger size, which limits its application as anticancer drugs. So we use gallic acid (GA) as Reductant and capping agent, through the green synthesis method has the advantages of simple preparation of a particle size of 60 nm selenium / ruthenium composite nanoparticles (GA-Se/Ru NPs).Se/Ru composite nanoparticles with particle size and morphology can be regulated by changing the concentration of GA, and Ru is the key factor to regulate and control the size. In addition to GA-Se/Ru NPs to inhibit He La by inducing the apoptosis of cell growth, and has no obvious toxicity to normal HK-2 cells. In addition GA-Se/Ru NPs through down-regulation of MMP-2 and MMP-9 protein expression was effectively inhibited La cell He cancer invasion and migration. The results show that GA mediated by Se/Ru composite nanoparticles synthesized show anticancer effect stronger. The fourth chapter: the endocytosis of nanoparticles functionalized by receptor mediated tumor cells to promote the intake of nanoparticles, which can exert its anti-tumor therapy more effectively . in this chapter, the epigallocatechin gallate (EGCG) and the expression of 67-k in HCC cells Da laminin receptor (67LR) with high affinity. So we design using EGCG functionalized nano luminescent ruthenium ruthenium complexes (Ru NPs), in order to achieve more efficient anti-tumor efficacy. Nanoparticles synthesized (Ru BB-loaded EGCG-Ru NPs) has a high selectivity to hepatocellular carcinoma cells. Ru BB-loaded EGCG-Ru cells on the internalization of NPs can be 67LR antibody and laminin inhibition showed that 67LR mediated endocytosis plays a key role in.TEM and confocal micrograph of nanoparticles mainly accumulated in the cytoplasm of SMMC-7721 cells in human hepatocellular carcinoma cells Ru BB-loaded EGCG-Ru intake on NPs. Further results show that EGCG nanoparticles functionalized with specific molecular targets of Shi Xian Is shown to enhance the antitumor activity of.Ru BB-loaded EGCG-Ru NPs has shown direct cytotoxicity mediated by ROS on human hepatocellular carcinoma cell line SMMC-7721, and has the effect of promoting tumor cell apoptosis and invasion of tumor cells, but no cytotoxicity to normal cells L-02. In addition, nude mice model in vivo experiments show that Ru BB-loaded EGCG-Ru NPs has high the anti tumor effect.

【學(xué)位授予單位】：暨南大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R73-37
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本文編號(hào)：1623990