本文選題：介孔二氧化硅納米粒子 + 利妥昔單抗��； 參考：《東南大學》2017年博士論文

【摘要】：目的迄今為止化療仍然是惡性淋巴瘤全身治療的主要手段之一,但是化療過程中不可避免地伴隨著嚴重毒副作用的發(fā)生,從而限制了其在臨床工作中的有效應用。因此,為了降低抗腫瘤藥物的毒副作用,提高藥物的主動靶向性,增強藥物的抗腫瘤療效,我們構建了一種以介孔二氧化硅納米粒子(MSNs)為載體的控釋靶向性藥物投遞系統(tǒng),即Rituximab修飾的荷載細胞毒性藥物鹽酸多柔比星(DOX)的MSNs納米粒子(RDMSNs)。該靶向性藥物投遞系統(tǒng)既能特異性靶向B細胞淋巴瘤細胞膜受體又能在細胞內(nèi)的弱酸性環(huán)境中釋放藥物發(fā)揮抗腫瘤作用。我們運用RDMSNs靶向性藥物投遞系統(tǒng)治療B細胞淋巴瘤,評價其抗腫瘤療效,探討其抗腫瘤的作用機制。方法1.RDMSNs靶向性藥物投遞系統(tǒng)的構建和表征:首先通過共聚法合成了羧基修飾的MSNs納米粒子,并以其作為藥物載體負載抗腫瘤藥物DOX,構建細胞內(nèi)pH值響應性的藥物投遞系統(tǒng)。在此基礎上,為了進一步優(yōu)化納米粒子,我們將Amine-PEG2000-Biotin修飾到MSNs納米粒子母核表面,最后通過生物素-親和素橋接方法連接B細胞淋巴瘤細胞膜表面高表達的CD20受體靶向的配體Rituximab,構成靶向腫瘤細胞的RDMSNs靶向性納米粒子。分別通過掃描電子顯微鏡(SEM)、透射電子顯微鏡(TEM)、傅里葉變換紅外光譜儀、激光粒度分析儀、紫外分光光度計等儀器對所制備的納米粒子進行物理表征,計算納米粒子的包封率和載藥率,抗體的鏈接效率;通過體外透析實驗了解載藥納米粒在不同pH值的條件下釋藥特性。2. RDMSNs的細胞靶向性評價及體外細胞毒性研究:分別采用CD20+的Raji細胞和CD20-的Jurkat細胞驗證RDMSNs納米粒子的靶向性性能;并使用流式細胞儀(FCM)、共聚焦激光掃描顯微鏡(CLSM)和TEM檢測和觀察細胞內(nèi)的DOX熒光強度和納米粒子分布和數(shù)量。為了驗證RDMSNs納米粒子的細胞靶向性性能及體外細胞毒性效應,分別以CD20+的Raji和Daudi細胞株及CD20-的Jurkat細胞株為體外研究模型,采用CCK-8法評估載藥納米粒子的細胞毒效應。并且通過CLSM觀察不同納米粒子作用于細胞后細胞凋亡時核的形態(tài)學變化,FCM評價不同納米粒子作用于細胞后的細胞凋亡率。3. RDMSNs對Raji細胞淋巴瘤的治療療效及體內(nèi)熒光成像研究:構建Raji細胞株裸鼠皮下移植瘤模型,當腫瘤體積達到100mm3左右時,將荷瘤裸鼠隨機分為4組:Saline組,Free DOX組,DMSNs組和RDMSNs組,每組5只,按照2.0mg/kg尾靜脈注射給藥,4天給一次藥,連續(xù)4次,探討載藥納米粒子的抗腫瘤療效,并測定腫瘤生長體積及體重,計算抑瘤率,取各組裸鼠心臟、肝臟、脾臟、肺臟、腎臟行HE染色檢查觀察藥物的安全性。采用TUNEL法檢測各組腫瘤組織細胞的凋亡情況,免疫組織化學染色后,觀察腫瘤細胞凋亡相關蛋白Bax、caspase-3、Bcl-2及增殖細胞相關的核抗原Ki67的表達。此外,還采用近紅外活體成像方法評價Cy5.5-DMSNs和Cy5.5-RDMSNs納米粒子對B細胞淋巴瘤的靶向性性能。結果1.成功構建了結構明確的MSN-COOH納米粒子,以其作為載體制備RDMSNs靶向性納米粒子。SEM和TEM顯示納米粒子大小一致和形態(tài)規(guī)則,傅里葉變換紅外光譜儀證實羧基基團被成功連接;RDMSNs靶向性載藥納米粒子的粒徑和zeta電位分別是56.3±11.2 nm和-31.5±5.2 mv; RDMSNs靶向性納米粒子DOX的載藥率和包封率分別是(23.5±4.7)%和(45.2±6.2)%;抗體Rituximab的連接率為(66.2±4.1)%;體外藥物釋放實驗顯示在pH 5.0的條件下藥物釋放率明顯高于pH 7.4的條件(P0.05),提示RDMSNs靶向性納米粒子具有pH值響應性的釋藥特性。2. Raji和Jurkat細胞株分別與RDMSNs靶向性納米粒子孵育2h后,FCM檢測細胞內(nèi)DOX熒光強度發(fā)現(xiàn)Raji細胞株中的熒光強度大約是Jurkat細胞株的三倍(P0.01),同樣在CLSM下觀察到Raji細胞株中的熒光強度明顯高于Jurkat細胞株,通過TEM也觀察到類似的結果。在Raji、Daudi和Jurkat細胞株中,RDMSNs靶向性納米粒子對Raji和Daudi細胞株的細胞毒性效應高于DMSNs組和FreeDOX組(P0.05),且其細胞毒性效應呈現(xiàn)濃度依賴性。而DMSNs和RDMSNs對Jurkat細胞株的細胞毒性效應無差異。在細胞凋亡實驗中,CLSM觀察到RDMSNs組具有凋亡細胞核形態(tài)學變化的細胞株明顯多于其他治療組。FCM檢測顯示24h對照組,MSNs組,FreeDOX組,DMSNs 組和 RDMSNs 組 Raji 細胞凋亡率分別是(3.0± 0.4) %,(3.9 ±0.6) %,(18.2 ± 1.2) %, (10.1 ± 1.2) % 和(23.3 ± 1.4) %, RDMSNs 組凋亡率明顯高于其他組(P0.05)。且RDMSNs組凋亡率呈現(xiàn)濃度依賴性(P0.01)。3.在RDMSNs納米粒子抗腫瘤療效評估實驗中,Saline組、Free DOX組和DMSNs組的平均腫瘤體積分別是 623.5±156.9mm3, 481.2±55.2mm3 和 335.6±57.3mm3,而RDMSNs處理組的平均腫瘤體積是98.0±51.8 mm3,與其他三組相比差異具有統(tǒng)計學意義(P0.05)。Saline組、RDMSNs組和DMSNs組裸鼠平均體重分別是25.2±0.9g、22.4±0.5g和21.6±0.5g,而Free DOX處理組的平均腫瘤體積是18.1±0.6g,與其他三組相比差異具有統(tǒng)計學意義(P0.01)。Free DOX組,DMSNs組和RDMSNs組的腫瘤抑制率分別為(22.79±4.37)%, (46.22±6.03)%和(84.28±5.92)%,RDMSNs 組的腫瘤抑制率最高,RDMSNs組分別與Free DOX組和DMSNs組相比差異具有統(tǒng)計學意義(P0.01)。這些結果表明RDMSNs組抗腫瘤作用最強且毒副作用較小。Free DOX組裸鼠的心臟HE染色顯示心肌纖維排列紊亂,而Saline組,RDMSNs組和DMSNs組裸鼠心臟、肝臟、脾臟、肺臟、腎臟HE染色顯示未見明顯病理學改變,表明載藥納米粒子在體內(nèi)具有良好的生物安全性。在TUNEL染色實驗中,RDMSNs組腫瘤組織中綠色熒光最多,凋亡細胞數(shù)量最多。腫瘤組織免疫組化染色結果顯示,與Saline組和Free DOX組相比,Bax和caspase-3蛋白在DMSNs組和RDMSNs組中表達量明顯增加,而Bcl-2蛋白和Ki67抗原表達量明顯減少,并且在RDMSNs組中Bax和caspase-3蛋白表達最強,Bcl-2蛋白和Ki67抗原表達最弱,表明RDMSNs靶向性納米粒子具有較強的誘導細胞凋亡能力和抗細胞增殖能力。在近紅外活體成像實驗中,24h時間點Cy5.5-RDMSNs靶向組熒光信號最強,主要聚集于腫瘤區(qū)域,此后,隨著時間延長熒光信號逐漸減弱。Cy5.5-DMSNs非靶向組具有類似的活體成像結果,但熒光信號半定量分析發(fā)現(xiàn)6h后腫瘤區(qū)域的熒光信號強度較Cy5.5-RDMSNs靶向組弱(P0.05)。結論1. RDMSNs靶向性納米粒子結構完整、形態(tài)均一、載藥量高,其結構中的PEG成分及表面修飾的Rituximab使載藥納米粒子具備了靶向性給藥的性能,并且具有pH值響應性的控釋藥物性能。2. RDMSNs靶向性納米粒子能夠被淋巴瘤B細胞特異性的內(nèi)吞,是通過受體介導的內(nèi)吞作用進入淋巴瘤B細胞內(nèi)。RDMSNs靶向性納米粒子在細胞內(nèi)所形成的溶酶體或核內(nèi)體的酸性環(huán)境中能夠促進藥物釋放,增加了細跑內(nèi)化療藥物的累積,從而發(fā)揮了增強的細胞毒性效應和較高的誘導細胞凋亡能力。3. RDMSNs靶向性納米粒子具有特異性的靶向性功能和增強的抗腫瘤活性,較低的毒副作用,較強的凋亡誘導能力。控釋靶向性藥物投遞系統(tǒng)RDMSNs有可能成為化療藥物的載體,將藥物靶向于淋巴瘤B細胞,提高化療藥物的療效,減輕化療藥物的毒副反應,為B細胞淋巴瘤的靶向治療提供了一個嶄新平臺。
[Abstract]:Objective chemotherapy is still one of the main methods for the systemic treatment of malignant lymphoma, but it is inevitably accompanied by severe toxic and side effects in the course of chemotherapy, which restricts its effective application in clinical work. Therefore, in order to reduce the side effects of antitumor drugs, improve the active targeting of the drug and enhance the drug We have constructed a controlled release targeting drug delivery system based on mesoporous silica nanoparticles (MSNs), the Rituximab modified load cytotoxic drug DOX MSNs nanoparticles (RDMSNs). The targeting drug delivery system can not only specifically target B cell lymphoma cells. Membrane receptors can also release drugs in the weak acid environment of cells. We use RDMSNs targeting drug delivery system to treat B cell lymphoma, evaluate its antitumor effect, and explore the mechanism of its anti-tumor action. Methods the construction and characterization of 1.RDMSNs targeting drug delivery system were synthesized by copolymerization method first. The carboxyl modified MSNs nanoparticles, which are used as drug carriers to load the antitumor drug DOX, construct the intracellular pH responsive drug delivery system. On this basis, in order to further optimize the nanoparticles, we modify the Amine-PEG2000-Biotin to the surface of the MSNs nanoparticle nucleus and finally connect with the biotin avidin bridging method. The CD20 receptor targeting ligand Rituximab, which is highly expressed on the membrane surface of B cell lymphoma cells, constitutes RDMSNs targeted nanoparticles for target tumor cells. By scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectrometer, laser particle size analyzer, ultraviolet spectrophotometer and other instruments The nanoparticles were characterized by physical characterization, and the encapsulation efficiency and drug delivery rate of the nanoparticles were calculated and the efficiency of the antibody was linked. The cell targeting evaluation and in vitro cytotoxicity of the drug loaded nanoparticles under the conditions of different pH values of.2. RDMSNs were investigated by the dialysis experiment in vitro: the Raji cells of CD20+ and the Jurkat cells of CD20- were used separately. To verify the targeting properties of RDMSNs nanoparticles, and use flow cytometry (FCM), confocal laser scanning microscopy (CLSM) and TEM to detect and observe the DOX fluorescence intensity and the distribution and quantity of nanoparticles in the cells. In order to verify the cell targeting and cytotoxic effects of RDMSNs nanoparticles, the Raji and Daudi of CD20+ are used respectively. The cell strain and the Jurkat cell line of CD20- were used as the model in vitro, and the cytotoxic effect of drug loaded nanoparticles was evaluated by CCK-8 method. And the morphological changes of nucleus were observed by different nanoparticles on the apoptosis of cells after cell apoptosis by CLSM. FCM was used to evaluate the apoptosis rate of different nanoparticles after cell apoptosis.3. RDMSNs to Raji cells. The therapeutic effect and fluorescence imaging in vivo: a model of subcutaneous transplantation of Raji cells in nude mice was constructed. When the tumor volume reached about 100mm3, the tumor bearing nude mice were randomly divided into 4 groups: Saline group, Free DOX group, DMSNs group and RDMSNs group, each group was injected in accordance with 2.0mg/kg tail vein, for 4 days for 4 consecutive times. The tumor growth volume and body weight were measured and the tumor suppressor rate was calculated. The safety of the drugs was observed by HE staining in the heart, liver, spleen, lungs and kidney of nude mice. The apoptosis of the tumor tissue cells was detected by TUNEL method. The apoptosis related protein Bax of tumor cells was observed after immunohistochemical staining. Caspase-3, Bcl-2 and the expression of nuclear antigen Ki67 related to proliferating cells. In addition, the targeting properties of Cy5.5-DMSNs and Cy5.5-RDMSNs nanoparticles for B cell lymphoma were evaluated by near infrared imaging methods. Results 1. successfully constructed a clearly structured MSN-COOH nanoparticle, which was used as a carrier to prepare RDMSNs targeted nanoparticles. SEM and TEM showed the uniform size and shape rule of nanoparticles. The Fourier transform infrared spectrometer confirmed that the carboxyl group was successfully connected; the particle size and zeta potential of the RDMSNs targeted drug loaded nanoparticles were 56.3 + 11.2 nm and -31.5 + 5.2 MV, respectively, and the drug loading rate and encapsulation efficiency of RDMSNs targeted nanoparticles were (23.5 + 4.7)% and 45.2 + respectively. 6.2)%, the connection rate of antibody Rituximab was (66.2 + 4.1)%, and the release rate of drug release in vitro showed that the drug release rate was significantly higher than that of pH 7.4 (P0.05) under the condition of pH 5, suggesting that RDMSNs targeted nanoparticles had pH responsive release properties,.2. Raji and Jurkat fine cell lines incubated with RDMSNs targeted nanoparticles respectively. The fluorescence intensity of DOX in the cell was measured to be about three times as high as that of the Jurkat cell line (P0.01). The fluorescence intensity of the Raji cell line was also observed under CLSM. The similar results were observed in the Raji cell lines by TEM. The cytotoxic effect of Audi cell line was higher than that of group DMSNs and FreeDOX group (P0.05), and its cytotoxic effect showed concentration dependence. There was no difference between DMSNs and RDMSNs on the cytotoxicity of Jurkat cell lines. In the apoptosis experiment, CLSM observed that the cell lines with the morphological changes of apoptotic cells in the RDMSNs group were obviously more than other treatments. .FCM test showed that the apoptosis rate of Raji cells in group MSNs, FreeDOX, DMSNs and RDMSNs was (3 + 0.4)%, (3.9 + 0.6)%, (18.2 + 1.2)%, (10.1 + 1.2)% and (23.3 + 1.4)% (23.3 + 1.4)%) in group DMSNs and RDMSNs group, and the apoptotic rate in RDMSNs group was significantly higher than that in other groups (P0.05). The apoptotic rate in RDMSNs group was concentration dependent (P0.01).3. in the The average tumor volume of Saline group, Free DOX group and DMSNs group was 623.5 + 156.9mm3, 481.2 + 55.2mm3 and 335.6 + 57.3mm3 respectively, and the average tumor volume of RDMSNs treatment group was 98 + 51.8 mm3, and the difference between the other three groups was statistically significant (P0.05).Saline group, RDMSNs group and The average weight of the group nude mice was 25.2 0.9g, 22.4 + 0.5g and 21.6 + 0.5g, while the average tumor volume of the Free DOX treatment group was 18.1 + 0.6g, and the difference was statistically significant (P0.01).Free DOX group compared with the other three groups. The tumor inhibition rate of the DMSNs and RDMSNs groups was (22.79 + 4.37)%, (46.22 + 6.03)% and (84.28 + 5.92)%, and the swelling of the RDMSNs group The tumor inhibition rate was the highest in group RDMSNs and group Free DOX and DMSNs group respectively (P0.01). These results showed that group RDMSNs had the strongest anti tumor effect and the heart HE staining of.Free DOX group of.Free DOX group showed the disorder of myocardial fiber arrangement, while the Saline, RDMSNs, and DMSNs group nude mice heart, liver, spleen, lung The HE staining of the kidney showed no obvious pathological changes, which showed that the drug loaded nanoparticles had good biological safety in the body. In the TUNEL staining experiment, the green fluorescence of the tumor tissue of the group RDMSNs was the most and the number of apoptotic cells was the most. The immunohistochemical staining results of the tumor tissue showed, compared with the group Saline and the Free DOX group, Bax and caspase-3. The expression of protein in group DMSNs and RDMSNs group increased obviously, while the expression of Bcl-2 protein and Ki67 antigen decreased obviously, and the expression of Bax and caspase-3 protein was the strongest in RDMSNs group, and the expression of Bcl-2 protein and Ki67 antigen was the weakest. It showed that RDMSNs targeted nanoparticles have strong ability to induce apoptosis and anti cell proliferation. In the infrared imaging experiment, the 24h time point Cy5.5-RDMSNs target group fluorescence signal is the strongest, mainly concentrated in the tumor area. After that, the fluorescence signal gradually weakened and the.Cy5.5-DMSNs non target group has similar living body imaging results, but the fluorescence signal semi quantitative analysis found that the fluorescence signal intensity of the tumor region after 6h is Cy5.5-R. DMSNs target group is weak (P0.05). Conclusion 1. RDMSNs targeted nanoparticles have complete structure, uniform morphology and high drug loading. The PEG components in the structure and the surface modified Rituximab make the drug nanoparticles have the performance of the targeted drug delivery, and the pH value responsiveness of the controlled-release drug.2. RDMSNs target nanoparticles can be lymphatic. The specific endocytosis of tumor B cells is through the receptor mediated endocytosis into the B cells of lymphoma, which can promote the release of drugs in the acid environment of the lysosomes or nuclear bodies formed by the.RDMSNs targeting nanoparticles in the cells, increasing the accumulation of chemotherapeutic drugs in the fine run, and exerts an enhanced cytotoxic effect and higher level of cytotoxicity. .3. RDMSNs targeted nanoparticles have specific targeting function and enhanced anti-tumor activity, lower toxic and side effects and strong apoptosis induction ability. The controlled release targeting drug delivery system RDMSNs may be a carrier of chemotherapeutic drugs, targeting the drug to lymphoma B cells and improving chemotherapeutic drugs. The therapeutic effect can reduce the side effects of chemotherapeutic drugs and provide a new platform for targeted therapy of B cell lymphoma.

【學位授予單位】：東南大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R733.1

【相似文獻】

相關期刊論文 前10條

1 張學勇,劉濤,李世雪;急性淋巴細胞白血病存活6年繼發(fā)淋巴瘤1例[J];新醫(yī)學;2000年03期

2 雷鳴,張英豪,藺濤;原發(fā)性脾型淋巴瘤的診斷和治療(附3例報告)[J];肝膽外科雜志;2001年02期

3 ;血管內(nèi)大B細胞淋巴瘤[J];臨床與實驗病理學雜志;2002年01期

4 陸志成,周道銀;小兒胸水查見惡性淋巴瘤細胞二例[J];江西醫(yī)學檢驗;2004年02期

5 林競韌;肖揚;;以三系減少表現(xiàn)為主的淋巴瘤1例[J];廣東醫(yī)學;2006年08期

6 李亞琴;張俊;司曉楓;龐潔;;血管內(nèi)皮生長因子與淋巴瘤的相關性研究[J];甘肅醫(yī)藥;2008年04期

7 郭智;譚曉華;陳豐;石宇杰;張明;張育葵;胡碧川;紀妍;瞿嶸;;細胞因子誘導的殺傷細胞治療難治性淋巴瘤的臨床研究[J];中華實用診斷與治療雜志;2009年10期

8 Kawamoto K;Nakamura S;Iwashita A;劉勇;;原發(fā)性胃T細胞淋巴瘤的臨床病理特征[J];臨床與實驗病理學雜志;2011年01期

9 孫靜;姚燁;陳琳軍;鄧曉輝;郝思國;;淋巴瘤細胞胞外體生物學特性及其抗淋巴瘤效應的研究[J];實用醫(yī)學雜志;2012年14期

10 夏樂敏;陳秋生;張莉;;小腸黏膜相關淋巴組織結外邊緣區(qū)B細胞淋巴瘤1例報告[J];現(xiàn)代腫瘤醫(yī)學;2012年12期

相關會議論文 前10條

1 鄒萍;;疑難危重淋巴瘤診治的思考[A];2009年浙江省血液病學學術年會論文集[C];2009年

2 沈志祥;周勵;;復發(fā)難治性淋巴瘤的治療進展[A];第10屆全國實驗血液學會議論文摘要匯編[C];2005年

3 朱平;;淋巴瘤的分子診斷學方法評價[A];第七屆全國血液免疫學學術大會暨2008年浙江省血液病學術年會論文匯編[C];2008年

4 周曉曦;;跨膜型TNF-α在淋巴瘤中的表達及其抗體的靶向治療[A];第13屆全國實驗血液學會議論文摘要[C];2011年

5 王華慶;錢正子;張會來;;外周T細胞淋巴瘤的診治新策略[A];第十一屆中國抗癌協(xié)會全國淋巴瘤學術大會教育論文集[C];2009年

6 陳兵;歐陽建;邵曉雁;周敏;;肝脾T細胞淋巴瘤中樞神經(jīng)系統(tǒng)浸潤1例[A];中華醫(yī)學會第八次全國血液學學術會議論文匯編[C];2004年

7 顏次慧;楊銘;李雙靜;熊冬生;;抗CD20 ScFv-TRAIL融合蛋白的構建表達及其對BJAB淋巴瘤細胞生長的抑制作用[A];第13屆全國實驗血液學會議論文摘要[C];2011年

8 唐建發(fā);;外周T細胞淋巴瘤合并黑熱病形態(tài)學特點觀察[A];第五屆全國中醫(yī)藥免疫學術研討會——暨環(huán)境·免疫與腫瘤防治綜合交叉會議論文匯編[C];2009年

9 周郁鴻;;惰性淋巴瘤的治療進展[A];2006年浙江省血液病學學術年會論文匯編[C];2006年

10 張巧花;侯淑玲;;難治性彌漫大B細胞淋巴瘤研究進展[A];第一屆全國難治性淋巴瘤學術研討會暨第二屆全國多發(fā)性骨髓瘤學術研討會（國家級血液系統(tǒng)惡性腫瘤繼續(xù)醫(yī)學教育學習班）繼續(xù)教育集[C];2007年

相關重要報紙文章 前10條

1 安陽地區(qū)醫(yī)院副院長、主任醫(yī)師 李新剛;從羅京去世談淋巴瘤的防治[N];安陽日報;2009年

2 王彥艷 上海交通大學醫(yī)學院附屬瑞金醫(yī)院血液科 上海血液學研究所醫(yī)生;以科學態(tài)度面對淋巴瘤[N];文匯報;2013年

3 楊霞 寧習源;我國利用分子靶向技術治療難治性淋巴瘤獲突破[N];中國中醫(yī)藥報;2003年

4 錢巖;35年來首個治療兩種類型淋巴瘤的藥物問世[N];中國醫(yī)藥報;2011年

5 顧蓓紅;淋巴瘤遇到勁敵[N];光明日報;2000年

6 ;淋巴瘤該不該放、化療？[N];健康時報;2006年

7 時仲省;高思敏;運用PCR技術“搜索”惡性淋巴瘤細胞[N];中國醫(yī)藥報;2002年

8 楊淑娟;美研究出對腫瘤細胞具高親和性肽[N];中國醫(yī)藥報;2006年

9 劉向;德國先靈公司研制出治療B細胞淋巴瘤新藥[N];經(jīng)濟參考報;2004年

10 張?zhí)锟?細胞調(diào)亡的意義[N];中國人口報;2002年

相關博士學位論文 前10條

1 周守兵;基于介孔二氧化硅的控釋靶向性藥物投遞系統(tǒng)的構建及對B細胞淋巴瘤的治療研究[D];東南大學;2017年

2 李華飛;抗CD20納米抗體梳的構建及其抗淋巴瘤作用研究[D];第二軍醫(yī)大學;2015年

3 宋國齊;microRNA-224在彌漫大B細胞淋巴瘤中的表達及其功能研究[D];東南大學;2015年

4 張楊;EB病毒誘發(fā)淋巴瘤基因表達譜及miRNA表達譜的分析研究[D];南華大學;2016年

5 周香香;Klotho調(diào)控IGF-1R信號通路在非霍奇金淋巴瘤中的作用及機制研究[D];山東大學;2017年

6 裴強;腦脊液IL10在原發(fā)中樞彌漫大B細胞淋巴瘤中的臨床價值及調(diào)控機制初步探索[D];北京協(xié)和醫(yī)學院;2017年

7 戴五敏;結外NK/T細胞淋巴瘤及Burkitt淋巴瘤的治療及預后相關研究[D];北京協(xié)和醫(yī)學院;2017年

8 李小龍;高光敏性Y型酞菁氧鈦納米粒子的制備及其光電性能研究[D];天津大學;2016年

9 王孜;外周T細胞淋巴瘤中轉(zhuǎn)錄因子GATA3的預后分析和體外研究[D];北京協(xié)和醫(yī)學院;2015年

10 王昊天;雷利度胺對腫瘤相關巨噬細胞的作用及其對淋巴瘤生長的影響[D];北京協(xié)和醫(yī)學院;2012年

相關碩士學位論文 前10條

1 趙志偉;鼻腔NK/T細胞淋巴瘤的臨床分析[D];福建醫(yī)科大學;2015年

2 殷少寧;MicroRNA-21與NK/T細胞淋巴瘤生長調(diào)控及臨床特征的關系[D];河北醫(yī)科大學;2015年

3 王太昊;HBV感染與淋巴瘤p53、Bcl-2表達、病理類型及臨床特征的相關性研究[D];河北醫(yī)科大學;2015年

4 喬立嬌;179例彌漫大B細胞淋巴瘤臨床病理特征及預后分析[D];寧夏醫(yī)科大學;2015年

5 宋秋娟;彌漫大B細胞淋巴瘤中miR-29b的表達及功能研究[D];鄭州大學;2015年

6 蘇紅;MicroRNA-320d通過調(diào)控靶基因CDK6抑制彌漫大B細胞淋巴瘤細胞增殖[D];山西醫(yī)科大學;2015年

7 李娟;胞膜表面CD20蛋白表達下降的彌漫大B細胞淋巴瘤的臨床病理特征分析[D];復旦大學;2014年

8 張以若;胃腸道彌漫大B細胞淋巴瘤臨床特征、CD10，Bcl-6和VEGF表達與預后的相關性研究[D];安徽醫(yī)科大學;2015年

9 徐玉蓮;IRF8對彌漫性大B細胞淋巴瘤的生長調(diào)控研究[D];寧波大學;2015年

10 唐文靜;~(18)F-FDG PET/CT在鼻型NK/T細胞淋巴瘤分期及治療后隨訪中的應用[D];安徽醫(yī)科大學;2015年

，

本文編號：1782827