【摘要】：現(xiàn)代臨床醫(yī)療手段逐漸從傳統(tǒng)的"one-size-fits-all"向新型個體化治療給藥策略轉變。這樣的治療方法使醫(yī)生可以最大限度縮短診斷和治療之間的時間。診療一體化治療,就是把診斷試劑、治療試劑整合在一個單獨系統(tǒng)內,此種治療策略在個體化給藥領域起到重要的作用。最近診斷試劑普遍使用類型為:超聲(US)、核磁共振(MR)、斷層掃描(CT)、單光子發(fā)射計算機化斷層顯像(SPECT)等。通過發(fā)揮各自的優(yōu)勢,把診斷與治療試劑組合在一起,起到協(xié)同作用,達到對實時監(jiān)測治療反饋的作用。同時,診療一體化納米�？梢宰鳛橐环N工具,用來篩選既安全又有效的劑量,使得醫(yī)生在發(fā)病早期階段避免藥物不合理利用而導致對人體的副作用。在眾多載體種類中,高分子是最受歡迎的納米診療一體化平臺。在癌癥治療過程中,作為載體平臺系統(tǒng),高分子聚合物可以通過化學鍵偶聯(lián)方法,增加游離藥物的溶解度和包封率,同時可以延長藥物在體內的半衰期,保證藥物在體內的釋放。另外,高分子聚合物溶液中的粒徑大小,通過增強滲透和保留(EPR)作用,實現(xiàn)被動靶向。而且除被動靶向之外,還可以在高分子鏈上連接主動靶向分子,準確靶向病灶部位,使得藥物可以準確、高效運送到疾病部位。盡管上述以高分子為載體的診療一體化納米粒發(fā)展迅猛、具有很多優(yōu)點,但是現(xiàn)在仍然遇到很多問題需要迫切解決。第一,成本高。無毒安全的造影劑和高分子材料價格都很高,一方面,這樣無形中增加了研發(fā)的成本,很多研發(fā)實驗室并沒有充足的資金去完成大批量的研究,另一方面,增加了病人的就醫(yī)成本,很多病人并不能擔負的起昂貴的高端藥物費用,最后導致疾病進展快,耽誤及時治療;第二,在造影劑領域,尤其是涉及到造影劑自身功能與高分子載體相互作用時候物理化學性質方面的更深層次的研究很少,這對于診療一體化納米粒子整體在機體的作用效果和安全性尤為重要。第三,制備方法繁瑣,容易破壞藥物本身功能基團,引入不必要的雜質,最終導致重復試驗差,同時也不能大規(guī)模的生產。為了解決上述問題,本課題設計一種制備簡單、安全性高、藥效好的診療一體化納米粒,對抗腫瘤遞藥系統(tǒng)有非常大的意義、為今后個體化用藥領域深入研究有重要的參考價值。本課題的設計思路為,化學鍵偶聯(lián)紫杉醇的聚谷氨酸高分子在水中可以自組裝形成納米粒,納米粒外部溶于水、內部疏水,形成一個高分子載藥平臺。然后將溶于有機溶劑的造影劑逐滴加入水相中,通過超聲乳化使其變成澄清的溶液,二者作用在統(tǒng)一系統(tǒng)內,再把多余溶劑去除,最終冷凍干燥形成診療一體化納米粒子pGGA-PTX/SPION。通過動態(tài)蒸發(fā)光散射儀、透射電子顯微鏡、紫外分光光度計、熱重分析儀等精密儀器,對此多功能納米粒進行物理化學表征;用CCK-8試劑盒、普魯士藍染色、HE染色等對其抑制腫瘤效果以及對正常組織安全性進行系統(tǒng)的體外評價;動物體內實驗包括兩個方面,一方面通過核磁共振儀對此納米粒的造影效果進行評價,另一方面是通過動物造模,尾靜脈注射藥物考察藥效實驗。通過上述一系列的實驗,結果證明本實驗制備的診療一體化納米粒具有很好的診斷和治療效果。在物理化學表征方面,pGGA-PTX/SPION納米粒形態(tài)飽滿均一,大小勻稱,約110nm。通過EPR效應,被動靶向腫瘤組織。納米粒載藥量約為27.66%,造影劑含量約為6.34%,載藥量高。在體外評價中,細胞存活率pGGA-PTX/SPION與PTX相似,說明有很好的抑制腫瘤細胞的作用,在HE實驗中,此納米粒對正常組織沒有損害作用,充分體現(xiàn)了其良好的安全性能。在體內造影方面,通過核磁共振,我們可以清楚看到,藥物在腫瘤體內整個代謝過程,實現(xiàn)了藥物實時監(jiān)測。體內藥效實驗中,pGGA-PTX/SPION組抑制腫瘤增長的效果最明顯。綜上所述,我們制備的診療一體化納米粒子在未來的腫瘤診斷與治療聯(lián)合應用方面起到重要的作用,提供一種安全、有效、可行的科學研究思路。
[Abstract]:Modern clinical medical methods have gradually changed from the traditional "one-size-fits-all" to the new individualized treatment strategy. This treatment enables doctors to minimize the time between diagnosis and treatment. Integrated treatment is the integration of diagnostic reagents and therapeutic agents in a single system. Individualization plays an important role in the field of medicine. Recently, the types of diagnostic reagents are commonly used: ultrasound (US), nuclear magnetic resonance (MR), fault scan (CT), single photon emission computerized tomography (SPECT) and so on. By playing their respective advantages, the diagnosis and treatment test agents are combined together to achieve the feedback of real-time monitoring and treatment. At the same time, integrated nanoparticles can be used as a tool to screen both safe and effective doses so that doctors can avoid the irrational use of drugs at the early stage of the disease and lead to adverse effects on the human body. In many kinds of carrier species, polymer is the most popular platform for the integration of nano diagnosis and treatment. As a carrier platform system, high molecular polymer can increase the solubility and encapsulation efficiency of the free drug by chemical bond coupling method, at the same time, it can prolong the half-life of the drug in the body and ensure the release of the drug in the body. In addition, the size of the particle in the polymer solution can be achieved by enhancing the effect of EPR. Besides the passive target, besides the passive targeting, the active target molecules can be connected to the polymer chain, and the target location is accurately targeted. The drug can be accurately transported to the site of the disease. Although the integrated nanoparticles with high molecular weight have developed rapidly and have many advantages, there are still many problems to be encountered. The cost is high. On the one hand, it increases the cost of research and development, and many R & D laboratories do not have sufficient funds to complete large quantities of research. On the other hand, the cost of medical treatment is increased, and many patients can not afford to be expensive. The cost of high end drugs eventually leads to the rapid progress of the disease and delays the timely treatment. Second, in the field of contrast agents, in particular the deeper studies involving the physical and chemical properties of the contrast agent's own function and the interaction of the polymer carrier, this has a good effect on the diagnosis and treatment of the whole body in the body. Third, the preparation method is very complicated, easy to destroy the functional group of the drug itself, introduce unnecessary impurities, eventually lead to the poor repetition test, and can not be produced on a large scale at the same time. In order to solve the above problems, we design a simple, safe and effective medical treatment integrated nanoparticle, against the tumor delivery system. It has great significance for further research in the field of individualized drug use in the future. The design idea of this topic is that polyglutamic acid polymers with chemical bond coupling paclitaxel can form nanoparticles in water, and the nanoparticles are dissolved in water and internal hydrophobic, forming a polymer carrier platform. The contrast agent of the solvent is added to the water phase by drop by drop into a clarified solution by phacoemulsification. The two acts in a unified system, then the superfluous solvents are removed, and the final freeze drying is used to form an integrated nanoparticle pGGA-PTX/SPION. for diagnosis and treatment through a dynamic evaporative light scattering instrument, a transdermal electron microscope, a UV spectrophotometer, and a thermogravimetric analysis. A physical and chemical characterization of the multifunction nanoparticles was carried out by a precision instrument such as a CCK-8 kit, Prussian blue staining, and HE staining. The effects of the tumor and the safety of normal tissue were evaluated in vitro. In vivo experiments in animals included two aspects, and one side through MRI was used for the effect of the nanoparticles. On the other hand, the pGGA-PTX/ SPION nanoparticles have a good diagnosis and treatment effect. In the physical and chemical characterization, the morphology of the nanoparticles is full and uniform in size, about 110nm. The EPR effect was used to target the tumor tissue passively. The drug loading amount was about 27.66%, the contrast agent content was about 6.34%, and the drug loading was high. In the in vitro evaluation, the cell survival rate was similar to that of the PTX, indicating that the tumor cells had a good inhibitory effect on the tumor cells. In the HE experiment, the nanorgrain had no damage to normal tissues and fully embodied it. Good safety performance. In vivo imaging, through nuclear magnetic resonance, we can clearly see that the drug can monitor the whole metabolic process in the body of the tumor. In vivo pharmacodynamics experiment, the effect of the pGGA-PTX/SPION group on inhibiting the growth of tumor is most obvious. In summary, we have prepared the integrated nanoparticles in the future. The combination of tumor diagnosis and treatment plays an important role in providing a safe, effective and feasible scientific research train of thought.
【學位授予單位】：華東師范大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R943

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1 鄭明彬;趙鵬飛;羅震宇;龔萍;張鵬飛;盛宗海;高冠慧;蔡林濤;;納米技術在癌癥診療一體化中的應用[J];科學通報;2014年31期

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