本文選題：肝癌 + 診治一體化　； 參考：《吉林大學(xué)》2015年博士論文

【摘要】：肝癌是嚴(yán)重危害我國人民健康的惡性腫瘤之一，盡管以手術(shù)切除為基礎(chǔ)、并輔助化療、熱療等綜合治療部分改善了肝癌的治療效果，但是肝癌患者的長期存活率仍然較低。由于大多數(shù)原發(fā)性肝癌患者的病情隱匿、潛伏期長、腫瘤生長迅速導(dǎo)致早期診斷困難，而且治療后的耐藥、復(fù)發(fā)和轉(zhuǎn)移成為了肝癌患者死亡的主要原因。因此，早期精確診斷、提高藥物的靶向性、降低治療的毒副作用成為目前肝癌診治的挑戰(zhàn)。近年來，納米技術(shù)的興起為攻克臨床上肝癌診治的難題帶來了新的機(jī)遇，而作為納米技術(shù)和生物醫(yī)學(xué)的結(jié)晶，納米醫(yī)學(xué)已成為當(dāng)前最具有轉(zhuǎn)化潛力的交叉學(xué)科之一。納米藥物載體是為納米醫(yī)學(xué)領(lǐng)域研究的熱點(diǎn)，其中無機(jī)納米粒子作為納米材料領(lǐng)域的后起之秀，以其獨(dú)特的納米結(jié)構(gòu)和性能以及良好的穩(wěn)定性、高產(chǎn)量、低成本等優(yōu)勢備受納米醫(yī)學(xué)工作者的關(guān)注。目前整合了診斷和治療特點(diǎn)的多功能納米平臺引起了研究者們的廣泛關(guān)注，此類多功能無機(jī)納米材料須具備以下三個(gè)特點(diǎn)：（1）通過多種分子影像學(xué)手段實(shí)現(xiàn)對腫瘤的早期精確診斷。（2）聯(lián)合多種治療手段協(xié)同治療腫瘤，在提高治療效果的同時(shí)降低副作用。（3）對藥物的腫瘤靶向運(yùn)輸、釋放和治療效果進(jìn)行實(shí)時(shí)示蹤，指導(dǎo)并調(diào)整給藥劑量，實(shí)現(xiàn)腫瘤的個(gè)體化治療。基于無機(jī)納米材料的上述優(yōu)點(diǎn)，本博士論文緊繞改善肝癌診治效果這一中心目標(biāo)，，針對臨床肝癌診治中早期診斷難、傳統(tǒng)化療毒性大、效果差以及基因治療靶向性差三大挑戰(zhàn)，分別以量子點(diǎn)和磁性介孔二氧化硅兩種無機(jī)納米粒子為基礎(chǔ)，發(fā)展智能分子設(shè)計(jì)、納米特性控制、靶向分子修飾等納米藥物技術(shù)，構(gòu)筑高效、安全的多功能納米平臺，開發(fā)具有靶向肝癌的基因治療和降低肝癌化療毒副作用的新型納米藥物，揭示其選擇性殺傷肝癌細(xì)胞的分子機(jī)制；利用分子影像學(xué)技術(shù)對藥物在體內(nèi)的運(yùn)輸和釋放過程進(jìn)行實(shí)時(shí)示蹤，并對肝癌治療效果與生物安全性進(jìn)行系統(tǒng)性評價(jià)；終而實(shí)現(xiàn)肝癌的診治一體化。本論文主要?jiǎng)?chuàng)新性研究成果概括如下： （1）為了實(shí)時(shí)示蹤HSV-TK/GCV自殺基因系統(tǒng)，我們成功的將量子點(diǎn)偶聯(lián)TK基因，證實(shí)生物偶聯(lián)既不影響量子點(diǎn)的發(fā)光特性，也不影響TK基因的生物學(xué)活性，實(shí)時(shí)示蹤發(fā)現(xiàn)TK基因于轉(zhuǎn)染24h進(jìn)入胞核并表達(dá)TK蛋白，確定24h為GCV的最佳給予時(shí)間，并在體內(nèi)外成功對HSV-TK/GCV自殺基因系統(tǒng)的抗肝癌效果進(jìn)行監(jiān)測，提示量子點(diǎn)可以作為示蹤HSV-TK/GCV自殺基因系統(tǒng)的理想載體。 （2）為了實(shí)現(xiàn)自殺基因的靶向肝癌治療，我們成功構(gòu)筑葉酸脂質(zhì)體擔(dān)載量子點(diǎn)自殺基因復(fù)合體（FL/QD-TK），證實(shí)其可在體外靶向和選擇性殺傷葉酸受體高表達(dá)肝癌細(xì)胞，并可在體內(nèi)外可視化示蹤TK基因運(yùn)輸和治療效果，同時(shí)具備了較好的生物安全性，提示FL/QD-TK作為一種潛在的高效低毒的納米基因藥物有望應(yīng)用于肝癌的診治一體化。 （3）為了駕馭鎘系量子點(diǎn)的生物毒性用于肝癌治療，我們成功的制備出量子點(diǎn)脂質(zhì)復(fù)合體（QD-LC），證實(shí)其可通過巨胞飲途徑大量內(nèi)吞進(jìn)入肝癌細(xì)胞產(chǎn)生大量的ROS，通過線粒體依賴的Caspase凋亡途徑選擇性殺傷肝癌細(xì)胞。QD-LC還可抑制肝癌微小瘤灶的形成，并在實(shí)現(xiàn)肝癌荷瘤有效治療的同時(shí)具備了較好的生物安全性，提示可利用鎘系量子點(diǎn)內(nèi)源性毒性實(shí)現(xiàn)肝癌的選擇性治療。 （4）為了提高化療藥物治療肝癌的有效性并降低毒副作用，我們通過優(yōu)化反應(yīng)條件制備出粒徑合適、形貌均一的Janus型磁性介孔二氧化硅納米粒子（M-MSNs），擔(dān)載化療藥物DOX得到的Janus型M-MSNs-DOX具備了外加磁場介導(dǎo)的作用，證實(shí)Janus型M-MSNs-DOX可在體內(nèi)外實(shí)現(xiàn)選擇性肝癌治療的效果，并具備了較好生物安全性。我們還證實(shí)外加磁場可增強(qiáng)Janus型M-MSNs-DOX的肝癌細(xì)胞內(nèi)吞作用和在腫瘤部位的富集，且不影響其生物安全性。最后我們在體內(nèi)外成功實(shí)現(xiàn)了肝癌診治一體化的目標(biāo)，提示Janus型M-MSNs有望解決肝癌化療靶向性差、毒副作用大的弊端，實(shí)現(xiàn)肝癌的診治一體化。 綜上所述，本論文通過構(gòu)筑多功能納米診治平臺，對肝癌靶向自殺基因治療的監(jiān)測、利用納米毒性選擇性治療肝癌以及實(shí)現(xiàn)高效低毒的肝癌化療策略進(jìn)行了系統(tǒng)而又深入的研究，不僅成功實(shí)現(xiàn)了肝癌的診治一體化，也為早日實(shí)現(xiàn)肝癌的早期診斷和個(gè)體化治療提供新方法和新思路。
[Abstract]:Liver cancer is one of the malignant tumors that seriously harm the health of the people of our country. The long-term survival rate of the patients with liver cancer is still low, although the combined treatment of surgical resection and adjuvant chemotherapy and thermotherapy has improved the therapeutic effect of liver cancer. Early diagnosis is difficult, and drug resistance, recurrence and metastasis after treatment are the main causes of death in the patients with liver cancer. Therefore, early accurate diagnosis, improving the targeting of drugs and reducing the toxic and side effects of the treatment have become the challenge for the diagnosis and treatment of liver cancer. As a new opportunity, nanomedicine, as the crystallization of nanotechnology and biomedicine, has become one of the most promising interdisciplinary subjects. Nano drug carriers are the hot spots in the field of nanomedicine. Inorganic nanoparticles are the following show in the field of nanomaterials, with their unique nanostructures and properties as well as good properties. The advantages of stability, high output, low cost and other advantages have attracted the attention of nanomedicine workers. At present, the multi-functional nano platform which integrates the characteristics of diagnosis and treatment has attracted the attention of researchers. This kind of multifunctional inorganic nanomaterial must have the following three characteristics: (1) through a variety of molecular imaging methods to realize the early stage of the tumor Accurate diagnosis. (2) combined with multiple treatments to treat tumors together to improve the effect of the treatment and reduce the side effects. (3) real-time tracing of the target transport, release and treatment effect of the drug, guiding and adjusting the dosage and realizing the individualized treatment of the tumor. Based on the above advantages of inorganic nanomaterials, this doctoral thesis is tightly wound around In order to improve the central target of the diagnosis and treatment of liver cancer, it is difficult to diagnose the early diagnosis in the diagnosis and treatment of the clinical liver cancer, the traditional chemotherapy is big, the effect is poor and the target of the gene therapy is poor three major challenges. Based on the quantum dots and the magnetic mesoporous silica two inorganic nanoparticles, the intelligent molecular design, the nano characteristic control and the target molecular repair are developed respectively. To build an efficient and safe multi-functional nanoplatform, to develop a novel and multi-functional nanoplatform for targeting liver cancer and to reduce the side effects of hepatoma chemotherapy, and to reveal the molecular mechanism of the selective killing of liver cancer cells, and the use of molecular imaging techniques to carry out real-time transport and release of drugs in the body. A systematic evaluation of the therapeutic effect and biological safety of liver cancer, and the integration of the diagnosis and treatment of liver cancer. The main innovative research results in this paper are summarized as follows:
(1) in order to trace the HSV-TK/GCV suicide gene system in real time, we successfully coupled the quantum dots with the TK gene to verify that the biological coupling does not affect the luminescence characteristics of the quantum dots and does not affect the biological activity of the TK gene. The real-time tracer found that the TK gene was transfected into the nucleus and reached the TK protein by transfecting 24h to determine the optimum giving time of the 24h as GCV, and The anti hepatoma effect of the HSV-TK/GCV suicide gene system was monitored in vitro and in vivo, suggesting that the quantum dots could be used as an ideal carrier for tracing the HSV-TK/GCV suicide gene system.
(2) in order to achieve the target liver cancer therapy of suicide gene, we successfully constructed the folic acid liposome loaded quantum dot suicide gene complex (FL/QD-TK), and confirmed that it can target and selectively kill the liver cancer cells in vitro and selectively kill the folic acid receptor, and can visualize the transport and treatment effect of TK gene in vivo and in vivo. Physical safety suggests that FL/QD-TK as a potential high effective and low toxic nanomaterials is expected to be applied in the diagnosis and treatment of liver cancer.
(3) in order to control the biotoxicity of the cadmium system quantum dots for the treatment of liver cancer, we have successfully prepared the quantum dot lipid complex (QD-LC), and confirmed that it can produce a large number of ROS by massive endocytosis into the hepatoma cells through the mega drink pathway, and selectively kill the liver cancer cell.QD-LC through the mitochondrial dependent Caspase apoptosis pathway to inhibit the liver cancer micro The formation of small tumors and the effective treatment of hepatoma bearing tumor have good biological safety. It is suggested that the endogenous toxicity of cadmium system quantum dots can be used to achieve selective treatment of liver cancer.
(4) in order to improve the efficacy and lower toxic side effects of chemotherapeutic drugs in the treatment of liver cancer, we have prepared Janus type magnetic mesoporous silica nanoparticles (M-MSNs) with suitable particle size and homogeneous morphology by optimizing the reaction conditions. The Janus M-MSNs-DOX obtained by carrying chemotherapeutic drug DOX has the effect of applied magnetic field mediated, and the Janus type M-MSNs- is confirmed. DOX can be used in the treatment of selective liver cancer in vivo and in vivo, and has good biological safety. We also confirm that the applied magnetic field can enhance the endocytosis and enrichment of Janus type M-MSNs-DOX in the tumor site, and do not affect its biological safety. Finally, we have successfully realized the goal of the integration of liver cancer in the body and the body, It is suggested that Janus M-MSNs is expected to solve the problems of poor targeting and side effects of chemotherapy for hepatocellular carcinoma and achieve the integration of diagnosis and treatment of HCC.
To sum up, this paper makes a systematic and in-depth study on the monitoring of targeted suicide gene therapy for liver cancer by constructing a multi-functional nano diagnosis and treatment platform, using nano toxic selective treatment of liver cancer and realizing high efficiency and low toxicity of liver cancer. It not only successfully realized the integration of the diagnosis and treatment of liver cancer, but also realized the liver cancer at an early date. Early diagnosis and individualized treatment provide new methods and new ideas.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R735.7

【參考文獻(xiàn)】

相關(guān)期刊論文 前5條

1 陳立,李凡,易世紅,黃紅蘭,趙春燕,魏強(qiáng);腺病毒介導(dǎo)的HSV-tk體外抗喉癌作用[J];白求恩醫(yī)科大學(xué)學(xué)報(bào);2001年06期

2 J.Perez-Rodriguez;B.D.Ehst;D.M.Fine;D.A.Bluemke;陳聰;;腎性系統(tǒng)性纖維化的發(fā)病率、相關(guān)因素及危險(xiǎn)因子評估對其的影響——33例病例報(bào)道[J];國際醫(yī)學(xué)放射學(xué)雜志;2009年02期

3 王楠;鄒明強(qiáng);薛強(qiáng);李錦豐;張帆;汪明;;量子點(diǎn)標(biāo)記DNA的應(yīng)用與進(jìn)展[J];化學(xué)試劑;2009年05期

4 Wanqing Chen;Rongshou Zheng;Siwei Zhang;Ping Zhao;Hongmei Zeng;Xiaonong Zou;Jie He;;Annual report on status of cancer in China,2010[J];Chinese Journal of Cancer Research;2014年01期

5 張艷杰;胡立華;陳鵬;馮春;劉鑫;;葉酸受體α在原發(fā)性肝癌組織及細(xì)胞中的表達(dá)[J];中國實(shí)用醫(yī)藥;2013年10期

本文編號：2056231