本文選題：透明質(zhì)酸 + 量子點　； 參考：《武漢理工大學(xué)》2014年碩士論文

【摘要】：本文成功制備了一種具有智能示蹤，受體介導(dǎo)靶向性的美法侖（MEL）前藥透明質(zhì)酸（HA）-量子點（QDs）-美法侖（HA-QDs-MEL）。該給藥系統(tǒng)是將具有細胞毒性的美法侖藥物選擇性導(dǎo)向至特定的腫瘤細胞（卵巢癌、乳腺癌等），使藥物在腫瘤細胞部位釋放并達到較高的藥物濃度，在提高藥物生物利用度的同時增加了藥物對腫瘤的選擇殺傷性，因此本給藥系統(tǒng)可以很好地解決化療藥物普遍存在毒副作用大、不良反應(yīng)嚴重等問題，并可以對藥物的運轉(zhuǎn)進行示蹤研發(fā)。 本文進行了HA-QDs-MEL給藥系統(tǒng)的合成。采用水熱法制備了CdTe/CdS量子點。并用L-半胱氨酸對量子點的表面官能團化。制備了L-半胱氨酸修飾的CdTe/CdS量子點。其次制備了透明質(zhì)酸與L-Cys-CdTe/CdS量子點交聯(lián)反應(yīng)產(chǎn)物，作為美法侖藥物的載體。利用透明質(zhì)酸上的羧基和量子點上的氨基進行酰胺縮合。對各步驟實驗產(chǎn)物進行傅里葉紅外和核磁氫譜等表征，結(jié)果證明合成成功。再次，以HA-QDs作為載體，通過酰胺縮合反應(yīng)制備得到HA-QDs-MEL。利用所合成的載體HA-QDs和藥物美法侖芐酯，美法侖芐酯在酸性條件下水解后，得到最終合成產(chǎn)物HA-QDs-MEL。利用HA-QDs上部分空位游離的羧基，用1-乙基-3-（3-二甲基氨基丙基）-碳化二亞胺(EDC)活化羧基，并且在NHS作用下與美法侖芐酯上游離的氨基縮合生成酰胺鍵連接的HA-QDs-MEL酯，然后在酸性條件下水解得到產(chǎn)物HA-QDs-MEL。對HA-QDs-MEL進行紅外核磁等表征，結(jié)果證明成功載藥美法侖，對HA-QDs-MEL進行粒徑分析，，粒徑均一分散，在200到500nm左右。 本文再對所制備的的HA-QDs-MEL給藥系統(tǒng)的藥物釋放，HA-QDs-MEL的釋放有一定的pH選擇性，在模擬腫瘤細胞酸性條件下釋放較好，并且同時具有一定的緩釋作用，釋藥的曲線較平緩，說明有緩釋作用并且，證明該載藥系統(tǒng)有緩控釋并且具有pH敏感性。 本文還對載藥系統(tǒng)進行了細胞評價，對其進行毒性試驗，攝取試驗，定位實驗和受體競爭抑制實驗。結(jié)果表明HA-QDs-MEL的毒性有極大的改善，減少其對正常細胞的殺傷力。藥物內(nèi)吞到溶酶體，由溶酶體傳遞至細胞核，從而殺死腫瘤細胞。由HA受體競爭抑制性實驗表明，HA受體對HA-QDs-MEL有抑制作用，說明CD44受體對給藥系統(tǒng)有靶向作用。
[Abstract]:In this paper, an intelligent tracer and receptor-mediated targeting meflon (Mel) prodrug hyaluronic acid (HA) -quantum dot (QDs) -mefacalen (HA-QDs-MEL) has been successfully prepared. The drug delivery system is to selectively target cytotoxic mefalen drugs to specific tumor cells (ovarian cancer, breast cancer, etc.), allowing the drug to be released at tumor cell sites and reach higher drug concentrations. In addition to increasing the bioavailability of drugs, it also increases the choice of drugs for tumor killing. Therefore, this drug delivery system can solve the common problems of large side effects and serious adverse reactions of chemotherapeutic drugs. And can carry on the tracer research and development to the operation of the drug. The HA-QDs-MEL drug delivery system was synthesized. CdTe / CDs quantum dots were prepared by hydrothermal method. The surface functionalization of quantum dots with L-cysteine was investigated. L- cysteine modified CdTe / CDs quantum dots were prepared. Secondly, the crosslinking products of hyaluronic acid and L-Cys-CdTe-CdS quantum dots were prepared, which were used as the carrier of mefalen. Amides were condensed from carboxyl groups on hyaluronic acid and amino groups on quantum dots. The products were characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic hydrogen spectroscopy (NMR). The results show that the synthesis is successful. Thirdly, using HA-QDs as carrier, HA-QDs-MEL was prepared by amide condensation reaction. The final product HA-QDs-MELL was obtained by hydrolysis of the synthesized carrier HA-QDs and the drug mefallen benzyl ester under acidic conditions. Using partially vacant carboxyl groups on HA-QDs, 1-ethyl-3- (3-dimethyl aminopropyl) -carbodiimide (EDC) was used to activate carboxyl groups and to form amide-bonded HA-QDs-MEL esters by condensation of amphalentyl esters with free amino groups under the action of NHS. The product HA-QDs-MEL was obtained by hydrolysis under acidic conditions. The HA-QDs-MEL was characterized by IR NMR. The results showed that the drug was successfully loaded with mefacalen. The particle size of HA-QDs-MEL was analyzed and the particle size was uniformly dispersed, ranging from 200 to 500nm. In this paper, the release of HA-QDs-MEL from HA-QDs-MEL delivery system was pH selective, and the release of HA-QDs-MEL was better under the simulated acidic condition of tumor cells. At the same time, the release curve of HA-QDs-MEL was smooth, and the release curve of HA-QDs-MEL was smooth. The results show that the drug delivery system has slow and controlled release and pH sensitivity. The cytotoxicity, uptake, localization and competitive inhibition of the drug delivery system were evaluated. The results showed that the toxicity of HA-QDs-MEL was greatly improved and the cytotoxicity of HA-QDs-MEL to normal cells was reduced. Drugs endocytosis to lysosomes, from lysosomes to the nucleus, killing tumor cells. The competitive inhibition of HA receptor showed that HA-QDs-MEL was inhibited by HA-QDs-MEL, indicating that CD44 receptor could target the drug delivery system.
【學(xué)位授予單位】：武漢理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914

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