新型pH敏感和光敏感前药的合成及其释放特性研究

发布时间：2018-03-03 12:45

本文选题：pH敏感　切入点：光敏感　出处：《湖南大学》2014年硕士论文　论文类型：学位论文

【摘要】：某些病变组织（如炎症、感染、恶性肿瘤等）与人体正常组织相比pH偏低呈弱酸性，使pH敏感的前药能够在病理部位实现定点释放；光作为一种外部刺激因子，可以同时实现时、空控制，不需要依赖机体内部化学环境的变化，能够在特定时间、特定部位促使药物释放，因此可以降低药物的毒副作用，提高疗效。靶向给药系统能够使药物浓集定位于病变部位，减小用药量及降低药物对全身的毒副作用。生物素与其受体的结合具有特异性和选择性，利用生物素受体在肿瘤细胞表面过度表达的特点，将生物素作为靶向分子与载体或药物连接可实现对肿瘤的诊断和靶向治疗。本文主要开展了以下工作： 1.选择生物素作为肿瘤靶向分子，合成了基于酰腙结构的pH敏感阿霉素前药（化合物4）和作为对照的非pH敏感阿霉素前药（化合物6），采用HPLC分析了药物体外释放情况。结果表明：化合物4具有理想的酸敏性，在pH5.0，5.5的缓冲液中静置24h，阿霉素的累积释放量分别为87.0%和53.7%；而在pH7.4的缓冲液中性质稳定，无明显药物释放。通过观察SMMC-7721细胞和Hela细胞对目标产物的摄取，验证了生物素的肿瘤靶向性。通过MTT比色法考察化合物4、6对肿瘤细胞的增殖抑制作用，结果表明化合物4对上述肿瘤细胞的增殖抑制作用明显优于化合物6，其体内抗肿瘤活性以及靶向性还需进一步研究。 2.制备了一种基于邻硝基苄醇的光敏感氮芥前药（化合物10）。GC-MS检测结果表明：化合物10经312nm的紫外光照射2h后，氮芥的释放量为10.1%。 3.选择生物素作为肿瘤靶向分子，合成了一种基于邻硝基苄醇的光敏感布洛芬前药（化合物16）。ON-OFF光控制释放实验表明：在暗场中化合物16性质稳定，312nm的紫外光照射2h后，布洛芬的累计释放量为42.2%。 4.合成了一种新的四苯乙烯衍生物（化合物22）,通过测定不同比例DMSO-H2O混合溶剂中化合物22的荧光强度，验证了其聚集诱导发光性质。然后将其与阿霉素通过酰腙键连接制备了一种pH敏感的阿霉素前药（化合物23）。药物释放实验表明：随化合物23在pH5.5，，6.5缓冲液中静置时间的延长，所测得的荧光强度逐渐增强，这一性质可用于监测阿霉素的释放情况。
[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.
【学位授予单位】：湖南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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