光敏感型盐酸多柔比星脂质体逆转乳腺癌耐药

发布时间：2018-11-17 08:38

【摘要】：本文旨在构建一种新型光敏感共输送脂质体,联合光动力学治疗与化疗,逆转乳腺癌耐药。采用薄膜水化挤出-硫酸铵主动载药法制备共输送光敏剂二氢卟吩e6三甲酯(chlorin e6 trimethyl ester,Ce6t M)与盐酸多柔比星(doxorubicin hydrochloride,DOX)的脂质体(liposomes loaded with Ce6t M and DOX,CDL),对CDL的粒径、zeta电位、光敏感释药行为及释药机制进行了研究。在此基础上,进一步考察该脂质体对人乳腺癌耐阿霉素MCF7/ADR细胞的细胞毒性、摄取、胞内三磷酸腺苷(adenosine triphosphate,ATP)水平和细胞周期的影响。最后探究了CDL中DOX在荷MCF7/ADR肿瘤裸鼠中的组织分布和抗肿瘤效果。结果表明,CDL具有良好的光敏感释药特性,在671 nm(2 W·cm~(-2))激光照射过程中,2 min内DOX的累积释放就达到(96.52±0.11)%。低功率、短时间(15 s,0.25 W·cm~(-2))光照后,CDL中DOX仍可继续快速释放。这种光敏感释药行为有助于增加DOX在MCF7/ADR细胞中的蓄积。与未光照组比较,光照CDL组中DOX对MCF7/ADR细胞的半数抑制浓度(inhibitory concentration 50,IC_(50))降低了601.9倍,这可能与肿瘤细胞内DOX的蓄积增加、单线态氧(singlet oxygen,~1O_2)产生、ATP水平下降以及细胞周期的阻滞有关。药效学实验结果表明,光照CDL组的肿瘤抑制率达到(94.7±6.2)%。光敏感CDL在逆转乳腺癌耐药治疗方面具有明显的潜在应用价值。
[Abstract]:The aim of this study was to construct a novel photo-sensitive co-delivery liposome combined with photodynamic therapy and chemotherapy to reverse drug resistance in breast cancer. The liposome (liposomes loaded with Ce6t M and DOX,CDL, a liposome containing Guang Min (chlorin e6 trimethyl ester,Ce6t M) and doxorubicin hydrochloride (doxorubicin hydrochloride,DOX), was prepared by membrane hydration extrusion and active drug loading with ammonium sulfate. Zeta potential, light-sensitive drug release behavior and drug release mechanism were studied. On this basis, the effects of liposome on cytotoxicity, uptake, intracellular adenosine triphosphate (adenosine triphosphate,ATP) level and cell cycle of human breast cancer adriamycin resistant MCF7/ADR cells were further investigated. Finally, the tissue distribution and anti-tumor effect of DOX in MCF7/ADR bearing nude mice were investigated. The results showed that CDL had good photo-sensitive release properties, and the cumulative release of DOX in 2 min was (96.52 卤0.11)% during 671 nm (2 W cm~ (-2) laser irradiation. After low power and short time (15 sL 0.25 W cm~ (-2), DOX in CDL could be released rapidly. This photo-sensitive drug release behavior helps to increase the accumulation of DOX in MCF7/ADR cells. Compared with the unirradiated group, the half inhibitory concentration of DOX on MCF7/ADR cells in CDL group was decreased by 601.9 times, which may be related to the increase of DOX accumulation in tumor cells and the production of single linear oxygen (singlet oxygen,~1O_2). The decrease of ATP level is related to cell cycle arrest. The results of pharmacodynamics test showed that the tumor inhibition rate of CDL group was (94.7 卤6.2)%. Photosensitive CDL has obvious potential value in reversing drug resistance in breast cancer.
【作者单位】：中国科学院上海药物研究所;中国科学院大学;
【基金】：国家自然科学基金创新研究群体项目(81521005)
【分类号】：R979.1

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