本文選題：藥物傳送系統(tǒng) + 納米水凝膠�。� 參考：《蘭州大學》2016年碩士論文

【摘要】：長期以來,科研工作者一直致力于研究和發(fā)展生物相容且生物可降解的刺激響應性藥物傳送系統(tǒng),以期實現藥物在病變位點的主動或被動靶向傳送和釋放,從而減少藥物的毒副作用、改善藥物在人體內的生物分布以及疾病治療效果。納米水凝膠憑借自身的諸多優(yōu)點在藥物運輸系統(tǒng)應用方面表現出了巨大的潛力,受到了越來越多的關注。納米水凝膠的生物相容性十分良好,較大的比表面積可進行多元化修飾和生物接合,復雜的內部網絡有助于藥物分子的負載,親水性表面以及穩(wěn)定的交聯結構可增加納米水凝膠的體內循環(huán)時間。合成類納米水凝膠的較慢的生物可降解性和較低的生物相容性是其用作藥物載體的主要阻礙因素,生物相容的天然多糖材料則存在著載藥效率低和體內降解性能欠佳等缺陷。本論文針對上述問題分別以合成類甲基丙烯酸(MAA)和天然類海藻酸鈉(SA)為主要原料,并采用生物相容性良好的聚乙二醇(PEG)分子進行修飾,通過不同的合成方法制備了載藥性能優(yōu)良、生物相容且生物可降解的單重或雙重刺激響應性納米水凝膠。采用紅外光譜(FTIR)進行結構的表征,通過透射電鏡(TEM)和動態(tài)光散射(DLS)考察形貌和粒徑,通過四甲基偶氮唑鹽微量酶反應比色法(MTT)考察載體的細胞相容性,并進行了抗癌藥物阿霉素(DOX)的負載和控制釋放方面的研究。本學位論文的研究工作及取得的主要成果包括以下三個方面:1.采用蒸餾沉淀一步法,以MAA和聚乙二醇單甲醚甲基丙烯酸酯(PEGMA)為單體、N,N'-雙(丙稀酰)胱胺(BACy)為交聯劑,在AIBN的引發(fā)下,制備了生物相容且可體內降解的納米水凝膠(PMPB)。采用FTIR表征了不同交聯度PMPB納米水凝膠的結構,重點研究了高交聯度納米水凝膠的刺激響應性藥物釋放行為。通過TEM考察了該納米水凝膠的體外降解行為,實驗表明該PMPB納米水凝膠微球在10 mM GSH或DTT作用下基本全部發(fā)生降解,降解成了透射電鏡下基本不可見的線型聚合物鏈。PMPB納米水凝膠的阿霉素負載效率可高達95%以上。后續(xù)的釋放實驗表明,PMPB納米水凝膠具有十分明顯的pH和氧化還原響應性。最后,選擇MTT法評估了PMPB納米水凝膠的細胞相容性,實驗結果表明PMPB納米水凝膠具有良好的細胞相容性。2.采用碳二亞胺(EDCI)催化的均相胱胺交聯法制備接枝有PEG的氧化海藻酸鈉納米水凝膠(OSA-mPEG),該類天然多糖型納米水凝膠與合成類水凝膠相比顯示出了生物相容性良好等突出優(yōu)點。在TEM觀察下,較高氧化度OSA-mPEG納米水凝膠(DO%=20%)的形貌較為規(guī)整,平均粒徑約為45 nm。DLS測試結果表明該納米水凝膠的單分散性良好,負載DOX后其粒徑縮小至170nm�？疾炝瞬煌軇┡浔�、醋酸用量、DOX加入量對OSA-mPEG納米水凝膠藥物負載過程的影響,載體主要通過與藥物DOX反應生成的席夫堿鍵來進行藥物負載,較高氧化度納米水凝膠具有較好負載結果,負載量和封裝效率分別為22.7±0.4%和59.4±1.9%。在載藥納米水凝膠的控釋實驗中,較高氧化度納米水凝膠表現出了較好的pH響應釋放性能。細胞毒性和細胞攝入實驗表明,較高氧化度納米水凝膠的細胞相容性良好,負載有DOX的納米水凝膠則對細胞顯示出了一定的殺傷力且可被細胞內在化并釋放DOX。3.采用簡單易行的鈣離子交聯法分別制備了原位負載藥物DOX的SA、OSA、OSA-mPEG納米水凝膠,并將其用于DOX的負載和控釋。在制備納米水凝膠的同時完成了藥物的負載,不僅簡化了實驗步驟,而且有利于改善藥物在載體內部的分布情況。通過TEM觀察該載藥納米水凝膠的形貌和粒徑,發(fā)現鈣交聯OSA-mPEG載藥納米水凝膠的形貌為近似球形且粒徑約為50 nm,經DLS測得該納米水凝膠在水中的流體力學直徑為135 nm,該尺寸的載體在體內傳送過程中具有很大的優(yōu)勢。該天然多糖類納米水凝膠載藥量大于26%,載藥效率高達90%。在不同的pH條件下,考察組成不同的鈣交聯納米水凝膠的釋放行為。研究發(fā)現,在釋放過程中該類納米水凝膠均顯示出了一定的pH響應性。其中OSA-mPEG載藥納米水凝膠的pH響應性最為明顯,pH為5.0時可持續(xù)穩(wěn)定地釋放DOX,釋放過程可持續(xù)三天以上。
[Abstract]:For a long time, researchers have been working on the research and development of biocompatible and biodegradable stimulative responsive drug delivery systems, in order to realize the active or passive targeting and release of drugs at the lesion sites, thus reducing the toxic and side effects of drugs, improving the biological distribution of drugs in the human body and the effect of disease treatment. Mica hydrogel has shown great potential in the application of drug transport system with its many advantages. It has attracted more and more attention. The biocompatibility of nano hydrogels is very good, the larger specific surface area can be diversified and bioconjugation. Complex internal networks help the load and hydrophilicity of drug molecules. The surface and stable cross-linking structure can increase the cycle time in vivo. The slow biodegradability and low biocompatibility of the synthetic nanosels are the main impediments to use as drug carriers. The biocompatible natural polysaccharide materials have low drug loading efficiency and poor biodegradability in the body. In this paper, the main materials of this thesis are synthetic methacrylic acid (MAA) and natural sodium alginate (SA), and a good biocompatible polyethylene glycol (PEG) molecule is used to modify. The single or dual stimulus response of biocompatible and biodegradable materials is prepared by different synthetic methods. The structure was characterized by infrared spectroscopy (FTIR). The morphology and particle size were investigated by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The cell compatibility of the carrier was investigated by four methyl azazolazolium salt Microenzyme reaction Colorimetry (MTT), and the load and control release of the anticancer drug adriamycin (DOX) were studied. The research work and the main achievements of this dissertation include the following three aspects: 1. using MAA and polyethylene glycol monomethyl ether methacrylate (PEGMA) as monomers, N, N'- double (BACy) as crosslinker, and the preparation of biocompatible and biodegradable nano hydrogel (PMP) by AIBN B). The structure of PMPB nano hydrogels with different crosslinking degrees was characterized by FTIR. The response of the nano hydrogels with high crosslinking degree was studied. The degradation behavior of the nano hydrogel was investigated by TEM. The experiment showed that the PMPB nanosels were degraded and degraded under the action of 10 mM GSH or DTT. The adriamycin load efficiency of the.PMPB nano hydrogel which was basically invisible under transmission electron microscopy could be as high as 95%. The subsequent release experiments showed that the PMPB nano hydrogel had very obvious pH and redox responsiveness. Finally, the cell compatibility of the PMPB nano hydrogel was evaluated by the MTT method, and the experimental result table was evaluated. The bright PMPB nano hydrogel has good cytocompatibility.2. using carbon two imide (EDCI) catalyzed homogeneous cystamine crosslinking method to prepare PEG oxidized sodium alginate nano hydrogel (OSA-mPEG). This kind of natural polysaccharide nano hydrogel shows good biocompatibility and other outstanding advantages compared with synthetic hydrogel. In TEM observation The morphology of the high oxidation degree OSA-mPEG nano hydrogel (DO%=20%) was relatively regular. The average particle size was about 45 nm.DLS showed that the mono dispersibility of the nano hydrogel was good. After the load DOX, the particle size of the gel was reduced to 170nm., and the proportion of solvent, the amount of acetic acid and the amount of DOX added to the drug loading process of the OSA-mPEG nano hydrogel were investigated. The carrier is loaded mainly through the Schiff base bond generated by the drug DOX reaction. The high oxidation degree nano hydrogel has a good load result, the load and the encapsulation efficiency are 22.7 + 0.4% and 59.4 + 1.9%. respectively in the controlled release experiment of the nano hydrogel. The higher oxygen degree nano hydrogel shows a better pH response. The cytotoxicity and cell intake experiments showed that the high oxidation degree of the nano hydrogel had good cytocompatibility, and the nano hydrogel loaded with DOX showed a certain killing force and could be internalized by the cell and released the DOX.3. by the simple and easy calcium crosslinking method to prepare the SA of the in situ loaded drug DOX respectively. OSA, OSA-mPEG nanosels were used for the load and controlled release of DOX. The loading of the nano hydrogels was completed while preparing the nano hydrogel, which not only simplified the experimental procedure, but also improved the distribution of the drug in the carrier. The morphology and particle size of the nano hydrogel were observed by TEM, and the calcium crosslinked OSA-mPEG drug was found. The morphology of the nano hydrogel is approximately spherical and the particle size is about 50 nm, and the hydrogel diameter of the nano hydrogel is 135 nm in water by DLS. The size of the carrier has a great advantage in the transmission process in the body. The natural polysaccharide nano hydrogel contains more than 26%, and the drug loading efficiency is up to 90%. under the different pH conditions. The release behavior of different calcium crosslinked nanosels was formed. It was found that the nano hydrogels showed a certain pH responsiveness during the release process, of which the pH responsiveness of the OSA-mPEG nanoparticles was the most obvious, and the DOX was released steadily and steadily when pH was 5, and the release process lasted for more than three days.

【學位授予單位】：蘭州大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：TQ460.1;O648.17

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