發(fā)布時間：2018-03-03 12:45

  本文選題：pH敏感　切入點：光敏感　出處：《湖南大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：某些病變組織（如炎癥、感染、惡性腫瘤等）與人體正常組織相比pH偏低呈弱酸性，使pH敏感的前藥能夠在病理部位實現(xiàn)定點釋放；光作為一種外部刺激因子，可以同時實現(xiàn)時、空控制，不需要依賴機體內(nèi)部化學(xué)環(huán)境的變化，能夠在特定時間、特定部位促使藥物釋放，因此可以降低藥物的毒副作用，提高療效。 靶向給藥系統(tǒng)能夠使藥物濃集定位于病變部位，減小用藥量及降低藥物對全身的毒副作用。生物素與其受體的結(jié)合具有特異性和選擇性，利用生物素受體在腫瘤細胞表面過度表達的特點，將生物素作為靶向分子與載體或藥物連接可實現(xiàn)對腫瘤的診斷和靶向治療。 本文主要開展了以下工作： 1.選擇生物素作為腫瘤靶向分子，合成了基于酰腙結(jié)構(gòu)的pH敏感阿霉素前藥（化合物4）和作為對照的非pH敏感阿霉素前藥（化合物6），采用HPLC分析了藥物體外釋放情況。結(jié)果表明：化合物4具有理想的酸敏性，在pH5.0，5.5的緩沖液中靜置24h，阿霉素的累積釋放量分別為87.0%和53.7%；而在pH7.4的緩沖液中性質(zhì)穩(wěn)定，無明顯藥物釋放。通過觀察SMMC-7721細胞和Hela細胞對目標產(chǎn)物的攝取，驗證了生物素的腫瘤靶向性。通過MTT比色法考察化合物4、6對腫瘤細胞的增殖抑制作用，結(jié)果表明化合物4對上述腫瘤細胞的增殖抑制作用明顯優(yōu)于化合物6，其體內(nèi)抗腫瘤活性以及靶向性還需進一步研究。 2.制備了一種基于鄰硝基芐醇的光敏感氮芥前藥（化合物10）。GC-MS檢測結(jié)果表明：化合物10經(jīng)312nm的紫外光照射2h后，氮芥的釋放量為10.1%。 3.選擇生物素作為腫瘤靶向分子，合成了一種基于鄰硝基芐醇的光敏感布洛芬前藥（化合物16）。ON-OFF光控制釋放實驗表明：在暗場中化合物16性質(zhì)穩(wěn)定，312nm的紫外光照射2h后，布洛芬的累計釋放量為42.2%。 4.合成了一種新的四苯乙烯衍生物（化合物22）,通過測定不同比例DMSO-H2O混合溶劑中化合物22的熒光強度，驗證了其聚集誘導(dǎo)發(fā)光性質(zhì)。然后將其與阿霉素通過酰腙鍵連接制備了一種pH敏感的阿霉素前藥（化合物23）。藥物釋放實驗表明：隨化合物23在pH5.5，，6.5緩沖液中靜置時間的延長，所測得的熒光強度逐漸增強，這一性質(zhì)可用于監(jiān)測阿霉素的釋放情況。
[Abstract]:Some pathological tissues (such as inflammation, infection, malignant tumor, etc.) are weakly acidic compared with normal tissues, so that the pH sensitive prodrug can be released at the pathological site. At the same time, air control can be achieved at the same time, without depending on the changes of the internal chemical environment, and can promote the release of drugs at a specific time and at a specific site, so it can reduce the toxic side effects of drugs and improve the efficacy. The targeting drug delivery system can make the drug concentrate in the lesion, reduce the dosage of the drug and reduce the toxicity and side effect of the drug on the whole body. The binding of biotin to its receptor is specific and selective. Based on the over-expression of biotin receptor on the surface of tumor cells, using biotin as a target molecule or drug can be used to diagnose and treat tumor. The main work of this paper is as follows:. 1. Choose biotin as tumor target molecule, Ph sensitive adriamycin prodrug (compound 4) and non pH sensitive adriamycin prodrug (compound 6) based on acylhydrazone structure were synthesized and their release in vitro was analyzed by HPLC. The results showed that compound 4 had ideal acid-sensitivity. The accumulative release of adriamycin was 87.0% and 53.7 respectively in pH 5.0 ~ 5.5 buffer solution for 24 h, while in the buffer solution of pH7.4, the properties of adriamycin were stable and there was no obvious drug release. The uptake of target products by SMMC-7721 cells and Hela cells was observed. MTT colorimetric assay was used to investigate the inhibitory effect of compound 4H6 on the proliferation of tumor cells. The results showed that the inhibitory effect of compound 4 on the proliferation of the above tumor cells was obviously superior to that of compound 6, and its antitumor activity and targeting need further study. 2. A photosensitive nitrogen mustard prodrug based on o-nitrobenzyl alcohol was prepared. The results showed that the release amount of compound 10 was 10.1 after 312nm UV irradiation for 2h. 3. A photosensitive ibuprofen prodrug based on o-nitrobenzyl alcohol was synthesized by using biotin as a tumor target molecule. The photocontrolled release experiments of compound 16N off showed that compound 16 was stable in UV irradiation at 312nm for 2 h in dark field. The cumulative release of ibuprofen was 42.2%. 4. A new tetrastyrene derivative (compound 22) was synthesized. The fluorescence intensity of compound 22 was determined by measuring the fluorescence intensity of compound 22 in different ratios of DMSO-H2O mixed solvents. The aggregation induced luminescence property was verified. Then, a pH sensitive prodrug (compound 23) was prepared by linking it with adriamycin by acyl Hydrazone bond. The drug release experiment showed that with the prolongation of the static time of compound 23 in pH 5.5 ~ 6.5 buffer solution, The fluorescence intensity is gradually increasing, which can be used to monitor the release of adriamycin.
【學(xué)位授予單位】：湖南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914

【參考文獻】

相關(guān)期刊論文 前10條

1 屈小中;楊振忠;;苯甲酰亞胺動態(tài)化學(xué)鍵在構(gòu)筑pH響應(yīng)藥物載體中的應(yīng)用[J];高分子學(xué)報;2011年10期

2 廖列文;龔濤;周靜;周新華;崔英德;;DMAEMA系列智能水凝膠的研究進展[J];化工進展;2011年02期

3 余麗麗;姚琳;楊黎燕;;光響應(yīng)型藥物釋放體系(Pr-DDS)的研究進展[J];化工進展;2012年05期

4 張海群;張旭;;pH響應(yīng)性可控釋放材料[J];化工新型材料;2011年10期

5 張雙;秦安軍;孫景志;唐本忠;;聚集誘導(dǎo)發(fā)光機理研究[J];化學(xué)進展;2011年04期

6 卜站偉,劉大新,劉洋,趙瑾,王超杰;茄呢基胺-氮芥衍生物的合成[J];化學(xué)研究;2005年01期

7 閆繼明;秦安軍;孫景志;唐本忠;;聚集誘導(dǎo)發(fā)光分子在生物檢測領(lǐng)域的應(yīng)用[J];科學(xué)通報;2010年13期

8 趙雯;張宏;盧婷利;陳濤;;RP-HPLC法測定鹽酸阿霉素磁性脂質(zhì)體的藥物含量[J];藥物分析雜志;2010年02期

9 許金霞;唐建斌;趙魯杭;申有青;;腫瘤pH響應(yīng)的聚合物膠束用于腫瘤藥物靶向輸送的研究進展[J];藥學(xué)學(xué)報;2009年12期

10 王曉蕾;劉晨光;;pH響應(yīng)性聚合物膠束及其在抗癌藥物給藥系統(tǒng)中的研究進展[J];中國新藥雜志;2010年21期

本文編號：1561095