基于吡咯并吡咯二酮衍生物的光敏剂设计合成及其光动力治疗肿瘤的性能研究

发布时间：2018-05-13 15:34

本文选题：光动力疗法 + 吡咯并吡咯二酮　；参考：《南京邮电大学》2017年硕士论文

【摘要】：理论计算发现,减少光敏剂单重态和三重态能级间的能级差(△EST)可大大促进系间窜越(ISC)的速率。通过增加系间窜越的速率可增强光敏剂产生单线态氧的能力,进而增强其抗肿瘤性能。基于此,本文设计并合成了两种吡咯并吡咯二酮(DPP)衍生物——苯基取代型吡咯并吡咯二酮(PDPP)和噻吩取代型吡咯并吡咯二酮(TDPP)。通过理论计算和实验研究发现,TDPP比PDPP拥有更低能极差(△EST),具有更高的产生单线态氧的效率。随后,我们对产生单线态氧效率更高的TDPP进行化学修饰,通过共价键将聚乙二醇羧酸(mPEGCOOH)接到其侧链得到TDPP-mPEG。进一步实验发现TDPP-mPEG具有良好的水溶性、生理稳定性以及光稳定性。在此基础上,我们将TDPP-mPEG与Hela细胞进行培养后,通过荧光共聚焦显微镜可以看到TDPP-mPEG很容易被Hela细胞吞噬并分散在其细胞质中。在特定波长的光的照射下,Hela细胞的细胞核开始起泡、变圆,说明TDPP-mPEG有良好的生物相容性,光照条件下,在细胞内具有较好的抗肿瘤性能。我们还将TDPP-mPEG用于裸鼠体内,周期性的对比治疗观察发现,光照情况下,TDPPmPEG可以显著抑制肿瘤组织的生长,切片发现肿瘤组织已经坏死,同时,裸鼠体重在正常范围内变化,亦无其他不良反应,表明TDPP-mPEG对正常组织几乎无损伤,且具有很好的光动力治疗效果。
[Abstract]:It is found by theoretical calculation that reducing the energy level difference (est) between the single and triplet states of Guang Min can greatly promote the rate of intersystem crossover. The ability of Guang Min agent to produce singlet oxygen can be enhanced by increasing the rate of interline crossover, and then its anti-tumor performance can be enhanced. Based on this, two derivatives, phenyl substituted pyrrolidine-pyrrolidinone (PDPPP) and thiophene substituted pyrrolidine-pyrrolidinone (TDPPN), have been designed and synthesized. Through theoretical calculation and experimental study, it is found that TDP has lower energy difference than PDPP, and has higher efficiency of producing singlet oxygen. Then we chemically modified the TDPP with higher singlet oxygen efficiency and connected the poly (ethylene glycol) carboxylic acid mPEGCOOH to the side chain to obtain TDPP-mPEG. Further experiments showed that TDPP-mPEG had good water solubility, physiological stability and photostability. On this basis, TDPP-mPEG and Hela cells were cultured and TDPP-mPEG was easily swallowed and dispersed in the cytoplasm of Hela cells by confocal fluorescence microscopy. The nuclei of Hela cells began to bubble and became round under the irradiation of specific wavelengths of light, which indicated that TDPP-mPEG had good biocompatibility and had better anti-tumor properties in the cells under light irradiation. We also used TDPP-mPEG in nude mice. Periodic comparative observation showed that TDPP mPEG could significantly inhibit the growth of tumor tissue, and the tumor tissue was necrotic, and the body weight of nude mice changed within normal range. There were no other adverse reactions, indicating that TDPP-mPEG had almost no damage to normal tissue and had good photodynamic therapy effect.
【学位授予单位】：南京邮电大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

【参考文献】