本文關鍵詞：靶向碳納米管載藥體系的功能化設計及抗腫瘤活性、光熱治療的研究　出處：《暨南大學》2016年碩士論文　論文類型：學位論文

  更多相關文章： 碳納米管 藥物傳遞系統(tǒng) 抗腫瘤 靶向 化學治療 光熱治療

【摘要】：碳納米管具有特殊的結構特征,被廣泛用于電化學,機械性能,生物醫(yī)藥領域的研究。由于具有大的比表面積,可以較高程度的吸附或共價鍵合大部分分子,同時物理特性如在近紅外的強吸收,可用于光熱治療,基于此,我們利用碳納米管的特性,選用不同修飾劑對其進行表面功能化,并負載不同的抗腫瘤藥物,同時研究了光熱治療與化學治療結合的抗腫瘤活性及作用機制。本文的主要研究內容如下:1.生物素靶向多壁碳納米管體系抑制膠質瘤C6細胞增殖的機制研究。本章用生物素(Biotin)表面功能化修飾多壁碳納米管,制備具有特異性識別腫瘤細胞的Biotin@MWCNTs/Oxa體系。通過MTT法篩選表明其能夠有效抑制膠質瘤C6細胞的增殖。此外,Biotin能夠特異性識別腫瘤細胞膜上的生物素受體,能顯著提高藥物在腫瘤細胞內的累積量。同時,Biotin@MWCNTs/Oxa能夠通過受體介導和肌動蛋白、網(wǎng)格蛋白、脂質筏蛋白介導的內吞作用進入細胞,并在溶酶體釋放,引起ROS的過量產(chǎn)生,造成DNA損傷,進而抑制C6細胞的增殖。2.靶向單壁碳納米管和靶向多壁碳納米管載藥體系的抗腫瘤活性和機制對比。本章通過RGD-c表面功能化修飾SWCNTs體系和MWCNTs體系,并從多個方面來對比了兩者的區(qū)別,比如載藥率,安全性,選擇性,藥物釋放速率及分子機制等。SWCNTs體系在載藥率,藥物釋放速率和細胞選擇性吸收上具有相對的優(yōu)勢,其原因是SWCNTs體系的比表面積更大。而在抗腫瘤活性方面,對比其不同正常細胞下的安全系數(shù),SWCNTs體系與MWCNTs體系各有各自的優(yōu)勢。流式分析結果顯示DOX@SWCNTs-F127-RGD和DOX@MWCNTs-F127-RGD均是引起細胞凋亡和G0/G1期阻滯來誘導MCF-7細胞死亡的。3.功能化多壁碳納米管載藥體系在熱化療方面的抗腫瘤活性及作用機制研究。本章內容設計并制備了具有pH響應的三嵌段聚合物和靶向多肽AE105雙重修飾的碳納米管體系,同時負載水溶性差的有機硒化合物PSeD作為抗腫瘤藥物。利用碳納米管體系在近紅外的吸收并將之轉化為熱能的特性,結合PSeD的細胞毒性,探索了其抑制三陰乳腺癌MDA-MB-231細胞的增殖、侵襲、轉移及相關分子機制。功能化修飾的碳納米管體系能夠在腫瘤微環(huán)境中更多的聚集,從而增加進入腫瘤細胞的量,而AE105能夠選擇性與腫瘤細胞膜上的uPAR結合,從而識別腫瘤細胞。當PSeD@MPPTA-AE105進入腫瘤細胞后,在808 nm激光的照射下,碳納米管迅速升溫,而負載的PSeD由于升溫后分子間劇烈的運動,從材料上脫落,當溫度升到42℃及以上時,導致癌細胞死亡,而對于已侵襲、轉移的細胞,由PSeD發(fā)揮后續(xù)的殺滅作用。相關的分子機制研究顯示:PSeD@MPPTA-AE105在808 nm激光照射下,引起胞內ROS累積,從而引起與DNA損傷相關蛋白ATM,P-His,P-Chk1,P-Chk2和BRCA1的過度表達,繼而激活p53通路和MAPKs信號通路,進一步激活Caspase級聯(lián)反應,最后促使細胞凋亡;同時,PSeD@MPPTA-AE105抑制FAK及不同位點磷酸化FAK蛋白的表達,激活了MMPs和uPA蛋白,并下調了uPA,uPAR和MMP-2/-9的表達水平,同時上調了TIMP-1(金屬蛋白酶抑制劑)的表達水平,最終抑制MDA-MB-231細胞的侵襲和轉移。PSeD@MPPTA-AE105在光熱治療和化學治療結合上取得了有效的結果,將進一步探索其在動物水平的抗腫瘤作用。
[Abstract]:Carbon nanotubes have special structure characteristics, is widely used in electrochemistry, mechanical properties, biological medicine research field. Because of its large specific surface area, adsorption or covalent bond with a higher degree of most molecules, and physical properties such as strong absorption in the near infrared, can be used in photothermal therapy, based on this, we use the characteristics carbon nanotubes with different modifiers, the functional surface of the load, and the different anti-tumor drugs, and studied the antitumor activity and mechanism of combination of photothermal therapy and chemotherapy. The main contents are as follows: Study on the mechanism of proliferation of C6 glioma cells to inhibit 1. biotin targeting system carbon nanotubes. This chapter with biotin (Biotin) functionalized multiwalled carbon nanotubes, prepared with specific recognition of tumor cells by Biotin@MWCNTs/Oxa MTT method showed that the screening system. It can effectively inhibit the proliferation of C6 cells. Furthermore, Biotin can specifically recognize tumor cells on the membrane of biotin receptor, can significantly increase the drug accumulation in tumor cells. At the same time, Biotin@MWCNTs/Oxa can be mediated by the receptor and actin, clathrin, endocytosis of lipid raft mediated by protein into cells and, in the lysosomal release, caused by excessive ROS, causing DNA damage, compared the antitumor activity and mechanism of the proliferation of.2. target and inhibit C6 cells to single walled carbon nanotubes and multi walled carbon nanotubes targeting drug delivery system. This chapter through the function of RGD-c surface modification of SWCNTs system and MWCNTs system, and from the A comparison of the differences between the two aspects, such as drug loading rate, safety, selectivity, drug release rate and molecular mechanism of.SWCNTs system in the drug loading rate, the drug release rate and cell with selective absorption Have a comparative advantage, the reason is the SWCNTs system of greater surface area. But in anti-tumor activity, comparing the different normal cells under the safety factor, SWCNTs system and MWCNTs system have their own advantages. Flow cytometry analysis showed that DOX@SWCNTs-F127-RGD and DOX@ MWCNTs-F127-RGD are active and the mechanism of antitumor research drug delivery system in thermal chemotherapy induced apoptosis and G0/G1 phase arrest of MCF-7 cell death induced by.3. functionalized multi walled carbon nanotubes. The contents of this chapter is to design and pH response of three block polymer and AE105 dual targeting peptide modified carbon nanotube system prepared organic selenium compounds PSeD and loaded with water soluble poor as anticancer drugs. The use of carbon nanotube system in near infrared absorption and converted into heat energy characteristics, combined with the cytotoxicity of PSeD, explore its inhibition of three negative breast MDA-MB-231 cancer cell proliferation, invasion, metastasis and related molecular mechanism. The functionalized carbon nanotube system can gather more in the tumor microenvironment, thereby increasing the amount of tumor cells into AE105, and can selectively and tumor cell membrane uPAR binding, thereby identifying tumor cells. When PSeD@MPPTA-AE105 into tumor cells. In the 808 nm laser irradiation, carbon nanotubes and rapid warming, the load of the PSeD due to heating after intermolecular strenuous exercise, detached from the material, when the temperature rose to 42 degrees or more, resulting in cancer cell death, for invasion, metastasis of cells by PSeD. Study on the killing effect of subsequent play the molecular mechanism showed that PSeD@MPPTA-AE105 in the 808 nm laser irradiation caused by intracellular ROS accumulation, causing the associated protein ATM, P-Chk1, P-His and DNA damage, over expression of P-Chk2 and BRCA1, then activate The p53 pathway and MAPKs pathway, and further activate the Caspase cascade, finally induce apoptosis; at the same time, the expression of PSeD@MPPTA-AE105 and inhibition of FAK in different sites of phosphorylation of FAK protein, activation of MMPs and uPA protein, and down-regulation of uPA expression levels of uPAR and MMP-2/-9, and upregulation of TIMP-1 (inhibitor of metalloproteinase expression) finally, the inhibition of MDA-MB-231 cell invasion and metastasis of.PSeD@MPPTA-AE105 effectively results in the combination of heat treatment and chemical treatment, will further explore its antitumor effect in animal level.

【學位授予單位】：暨南大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R91;R96

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