中文摘要：

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。

英文摘要：

This study was aimed to build a new photo-sensitive co-delivery liposomes which combine photodynamic therapy with chemotherapy to reverse drug resistance of breast cancer. Photodynamic photosen- sitizer chlorin e6 trimethyl ester （Ce6tM） and chemotherapeutic drug doxorubicin hydrochloride （DOX） were loaded into the liposomes （liposomes loaded with Ce6tM and DOX, CDL） by thin-film hydration extrusion and ammonium sulfate active loading methods. CDL was characterized with cryo-transmission electron microscopy （Cryo-TEM）, dynamic light scattering particle size, zeta potentials and photo-sensitive DOX release behaviors in vitro. CDL cytotoxicity, singlet oxygen production, DOX accumulation, intracellular ATP level and cell cycle analysis in MCF7/ADR cells were evaluated. Finally, the tissue distribution of DOX and antitumor effects of CDL in BALB/c-nu nude mice bearing MCF7/ADR tumor were investigated. The results showed that the parti- cle size of obtained CDL was 90.7 ± 1.1 nm and distributed uniformly. CDL possessed outstanding properties ofphoto-sensitive drug release profile. The accumulated release of DOX reached （96.52 ± 0.11） % in 2 min under 671 nm laser irradiation （2 W·cm-2）. Interestingly, DOX in CDL could maintain rapid release after 671 nm laser irradiation with low power and short time （15 s, 0.25 W ·cm-2）. This phenomenon was caused by oxidation of unsaturated phospholipids in CDL under 671 nm laser irradiation and had nothing to do with the slightly elevated temperature. Photo-sensitive drug release behavior contributed to increased DOX accumulation in MCF7/ADR cells. The half inhibition concentration （IC so） of DOX in CDL laser group in MCF7/ADR cells was decreased by 601.9-fold compared with no laser group, which could be related to increased accumulation of DOX, decreased ATP levels and cell cycle arrest in MCF7/ADR cells. With the help of CDL, DOX accumulation in tumor was increased and in cardiac toxicity was reduced in vivo. CDL laser group showed a good anti