本文選題：水凝膠 + 局部凝膠藥物遞送　； 參考：《華東師范大學》2017年碩士論文

【摘要】：局部藥物遞送系統(tǒng)應用于腫瘤的化療是一種將藥物直接遞送并作用于腫瘤細胞的化療手段。相比較于傳統(tǒng)的化療手段,其主要特點為局部藥物濃度高,相對藥物劑量低,生物毒性低,機體適應性好。近年來,有越來越多的學者研究將水凝膠作為一種局部藥物遞送載體遞送抗腫瘤藥用于腫瘤的化療。水凝膠作為一種新型的生物友好型材料越來越被普遍研究用于組織功能領(lǐng)域和藥物遞送載體領(lǐng)域。水凝膠是一種以水為介質(zhì)的親水性聚合物,在水中能夠溶脹并保持大量水分而又不能溶解的具有三維網(wǎng)絡結(jié)構(gòu)的交聯(lián)體,并且在水中能有足夠的穩(wěn)定性,柔軟而富有彈性的功能高分子。高分子鏈上的親水基團以氫鍵與水分子相連接,使其具有強大的鎖水功能,能保住90%以上的水分,因此水凝膠兼具固體和流體的性質(zhì)。水凝膠擁有良好的生物親和性和生物粘附性,獨特的物理化學結(jié)構(gòu)使得它可以作為一種局部藥物遞送系統(tǒng)用于腫瘤的化療。本課題設(shè)計的是一種光聚合水凝膠PEGDA-HA。PEGDA-HA水凝膠由聚乙二醇二丙烯酸酯(PEGDA),低分子量的HA,和光引發(fā)劑Irgacure 2959通過紫外光激發(fā)聚合而成。在制備過程中,我們探究了聚乙二醇二丙烯酸酯和光引發(fā)劑Irgacure2959不同質(zhì)量比例聚合成凝膠的凝膠時間和化學降解速率的關(guān)系,并確定了比較合適的引發(fā)劑和單體質(zhì)量比。為了提高水凝膠的生物相容性,在凝膠體系中加入了一種聚合物填充材料低分子量的HA。實驗過程中我們探究了不同低分子量HA含量的水凝膠的溶脹速率及其降解速率與HA含量的關(guān)系。由此確定了 PEGDA、HA、和Irgacure2959三者的比例關(guān)系。從而制備了 PEGDA-HA光聚合水凝膠。我們將PEGDA-HA凝膠遞送紫杉醇納米粒PLGA-PTX,共同組成了PEGDA-HA/PLGA-PTX局部凝膠藥物遞送系統(tǒng)。實驗過程中,我們通過乳化-溶劑揮發(fā)法制備了 PLGA包裹紫杉醇的納米粒PLGA-PTXNPs。通過TEM,DLS對該NPs進行了表征。實驗結(jié)果表明PLGA-PTX NPs形態(tài)呈現(xiàn)非常明顯的核殼結(jié)構(gòu),包封率為74.04%,載藥量為7.4%,納米粒粒徑為170±10.2nm,n=3,PDI=0.309±0.089,n=3,粒徑分布比較均一。zeta 電位為-4.64±0.05mV,n=3。通過CCK8實驗,我們測得了該PLGA-PTXNPs的IC50值為10-5 527mg/mL。通過包載Dio熒光素,我們測得PLGA-PTXNPs能夠被NCI-H460細胞攝取,通過流式細胞儀的定量數(shù)據(jù)與激光共聚焦數(shù)據(jù),我們可以看到NCI-H460細胞對PLGA-PTXNPs的攝取比率達到了 96%。由PEGDA-HA/PLGA-PTX凝膠的紫杉醇藥物釋放曲線可知,藥物釋放速度呈現(xiàn)先快后慢的趨勢,在前20小時釋放了近30%的藥量,在給藥后40小時內(nèi)釋放了近50%的藥量,此后藥物釋放逐漸減緩。至給藥后100小時內(nèi)釋放了 65%藥量。雖然此后釋藥速度有所減緩,但是一直呈現(xiàn)了上升趨勢,可以預計,該局部凝膠藥物遞送系統(tǒng)可以維持腫瘤部位20天的持續(xù)藥物釋放。通過藥效學實驗數(shù)據(jù)我們可以發(fā)現(xiàn),實驗組PEGDA-HA/PLGA-PTX組在沒有對老鼠造成減重的毒性反應情況下,實現(xiàn)了抑制腫瘤細胞生長和殺滅腫瘤細胞的效果。觀察對比實驗組PEGDA-HA/PLGA-PTX組和對照組PBS組的HE染色熒光圖片我們可以發(fā)現(xiàn),實驗組除了腫瘤組織,均沒有觀察到有組織壞死現(xiàn)象。對比實驗組PEGDA-HA/PLGA-PTX組和對照組PBS組的TUNEL染色熒光圖片,我們可以發(fā)現(xiàn),只有在實驗組的腫瘤組織觀察到組織細胞凋亡現(xiàn)象。以上實驗結(jié)果說明,我們課題設(shè)計的PEGDA-HA/PLGA-PTX局部凝膠藥物遞送系統(tǒng)是一種生物相容性非常好的局部藥物遞送系統(tǒng),通過局部直接給藥的方式直接作用于腫瘤部位,在給藥后20天內(nèi)均表現(xiàn)了良好的抑制腫瘤生長和殺滅腫瘤細胞的藥效學結(jié)果。
[Abstract]:Local drug delivery system used in tumor chemotherapy is a means of direct delivery and action to tumor cells. Compared with traditional chemotherapy, the main characteristics are high local drug concentration, low drug dose, low biological toxicity and good adaptability. In recent years, more and more scholars have studied water coagulation. Gelatin is used as a local drug delivery carrier to deliver chemotherapeutic agents for cancer. Hydrogels are widely used as a new biofriendly material to be widely used in the field of tissue function and drug delivery carriers. Hydrogel is a hydrophilic polymer with water as medium, which can expand and maintain a large amount of water in water. Water can not be dissolved in a three-dimensional network structure of the cross body, and in the water can have enough stability, soft and elastic functional polymer. The hydrophilic group on the polymer chain connects with the water molecule by hydrogen bonds, making it strong water locking function and can hold more than 90% water, so the hydrogel has both solid and solid. The properties of fluid. Hydrogels have good biocompatibility and bioadhesion. The unique physical and chemical structure makes it a local drug delivery system for cancer chemotherapy. This topic is designed for a polyhydrogel PEGDA-HA.PEGDA-HA hydrogel consisting of polyglycol two acrylate (PEGDA), low molecular weight H A, and photopolymerization of photoinitiator Irgacure 2959 by UV excitation. In the process of preparation, we explored the relationship between the gel time and the chemical degradation rate of the gels with different mass ratios of polyethylene glycol two acrylate and photoinitiator Irgacure2959, and determined the suitable initiator and monomer mass ratio. The biocompatibility of hydrogels by adding a low molecular weight HA. experiment with a polymer filling material in the gel system, we explored the relationship between the swelling rate of the hydrogels with different low molecular weight HA content and the relationship between the degradation rate and the HA content. Thus, the proportion relationship between the PEGDA, HA, and Irgacure2959 three was determined. PEGDA-HA photopolymerization hydrogel. We sent the PEGDA-HA gel to paclitaxel nanoparticles PLGA-PTX, together to form a PEGDA-HA/PLGA-PTX local gel delivery system. In the experiment, we prepared the PLGA encapsulated paclitaxel nanoparticles PLGA-PTXNPs. via the emulsification solvent evaporation method, and DLS was used to characterize the NPs. The results show that the morphology of PLGA-PTX NPs has a very obvious nuclear shell structure, the encapsulation efficiency is 74.04%, the drug loading is 7.4%, the nano particle size is 170 + 10.2nm, n=3, PDI=0.309 0.089, n=3, the uniform.Zeta potential is -4.64 + 0.05mV, and n=3. through CCK8 experiment, we have measured the PLGA-PTXNPs. Fluorescein, we measured that PLGA-PTXNPs was able to be absorbed by NCI-H460 cells. Through quantitative data of flow cytometry and confocal laser confocal data, we can see that the ratio of NCI-H460 cells to PLGA-PTXNPs uptake reached 96%. by the paclitaxel release curve of PEGDA-HA/PLGA-PTX gel, and the release rate of the drug was fast and then slow. The trend, releasing nearly 30% of the dose in the first 20 hours and releasing nearly 50% of the dose within 40 hours after the administration, the release of the drug slowed down gradually. 65% doses were released within 100 hours after the administration. Although the release rate has slowed down since then, the drug delivery system has been on the rise, and it is expected that the local gel delivery system can be maintained. After 20 days of sustained drug release on the tumor site, we can find that in the experimental group PEGDA-HA/PLGA-PTX, the effect of inhibiting the growth of tumor cells and killing the tumor cells was achieved without the toxic reaction to the mice caused by weight reduction in the experimental group. The H of group PEGDA-HA/PLGA-PTX and the control group PBS group were observed and compared. We can find that there is no tissue necrosis in the experimental group except the tumor tissue. Compared with the PEGDA-HA/PLGA-PTX group in the experimental group and the PBS group in the control group, we can find that the apoptosis of the tissue cells is observed only in the tumor tissue of the experimental group, and the results of the experiment are explained by the experimental results. The PEGDA-HA/PLGA-PTX local gel delivery system, designed by us, is a highly biocompatible local drug delivery system, which directly acts on the tumor site by local direct drug delivery, and shows good pharmacodynamic results in the 20 days after administration to inhibit tumor growth and kill tumor cells.
【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;R96

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相關(guān)期刊論文 前2條

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2 Wanqing Chen;Rongshou Zheng;Hongmei Zeng;Siwei Zhang;Jie He;;Annual report on status of cancer in China, 2011[J];Chinese Journal of Cancer Research;2015年01期

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本文編號：1922204