药学学报, 2017, 52(5): 809-820
引用本文:
孟庆硕, 张鹏程, 尹琦, 张志文, 于海军, 李亚平. 光敏感型盐酸多柔比星脂质体逆转乳腺癌耐药[J]. 药学学报, 2017, 52(5): 809-820.
MENG Qing-shuo, ZHANG Peng-cheng,YIN Qi, ZHANG Zhi-wen, YU Hai-jun, LI Ya-ping. Photo-sensitive liposomes loading doxorubicin hydrochloride reverse drug resistance of breast cancer[J]. Acta Pharmaceutica Sinica, 2017, 52(5): 809-820.

光敏感型盐酸多柔比星脂质体逆转乳腺癌耐药
孟庆硕1,2, 张鹏程1, 尹琦1, 张志文1, 于海军1, 李亚平1
1. 中国科学院上海药物研究所, 上海 201203;
2. 中国科学院大学, 北京 100049
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,Ce6tM)与盐酸多柔比星(doxorubicin hydrochloride,DOX)的脂质体(liposomes loaded with Ce6tM 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671nm(2W·cm-2)激光照射过程中,2min内DOX的累积释放就达到(96.52±0.11)%。低功率、短时间(15s,0.25W·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,IC50)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,1O2)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。
关键词:   
Photo-sensitive liposomes loading doxorubicin hydrochloride reverse drug resistance of breast cancer
MENG Qing-shuo1,2, ZHANG Peng-cheng1, YIN Qi1, ZHANG Zhi-wen1, YU Hai-jun1, LI Ya-ping1
1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
2. University of Chinese Academy of Sciences, Beijing 100049, China
Abstract:
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 particle size of obtained CDL was 90.7 ± 1.1 nm and distributed uniformly. CDL possessed outstanding properties of photo-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 (IC50) 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-tumor effect. The tumor inhibition rate was (94.7 ± 6.2)%. These results suggest that CDL has a promising potential in reversing drug resistance of breast cancer.
Key words:   
收稿日期: 2017-02-03
DOI: 10.16438/j.0513-4870.2017-0105
基金项目: 国家自然科学基金创新研究群体项目(81521005).
通讯作者: 李亚平,Tel:86-21-20231979,E-mail:ypli@simm.ac.cn
Email: ypli@simm.ac.cn
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参考文献:
[1] Chen WQ. Cancer statistics: updated cancer burden in China [J]. Chin J Cancer Res, 2015, 27: 1.
[2] Chen WQ, Zheng RS, Baade PD, et al. Cancer statistics in China, 2015 [J]. CA Cancer J Clin, 2016, 66: 115-132.
[3] Yin Q, Shen JN, Zhang ZW, et al. Reversal of multidrug resistance by stimuli-responsive drug delivery systems for therapy of tumor [J]. Adv Drug Deliv Rev, 2013, 65: 1699-1715.
[4] He QY. Tumor heterogeneity and drug resistance of targeted antitumor agents [J]. Acta Pharm Sin (药学学报), 2016, 51: 197-201.
[5] Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer [J]. N Engl J Med, 2015, 372: 724-734.
[6] Lucena SR, Salazar N, Gracia-Cazaña T, et al. Combined treatments with photodynamic therapy for non-melanoma skin cancer [J]. Int J Mol Sci, 2015, 16: 25912-25933.
[7] Tang S, Yin Q, Zhang ZW, et al. Co-delivery of doxorubicin and RNA using pH-sensitive poly (β-amino ester) nanoparti-cles for reversal of multidrug resistance of breast cancer [J]. Biomaterials, 2014, 35: 6047-6059.
[8] Wang TT, Wang DG, Yu HJ, et al. Intracellularly acid-switchable multifunctional micelles for combinational photo/chemotherapy of the drug-resistant tumor [J]. ACS Nano, 2016, 10: 3496-3508.
[9] Park SJ, Park W, Na K. Tumor intracellular-environment responsive materials shielded nano-complexes for highly efficient light-triggered gene delivery without cargo gene damage [J]. Adv Funct Mater, 2015, 25: 3472-3482.
[10] Hu YP, Zhou HY, Shen S. Preparation of doxorubicin-loaded Fe3O4-TiO2 nanoparticles and evaluation of chemo-photody-namic therapy in vivo [J]. Acta Pharm Sin (药学学报), 2016, 51: 1340-1344.
[11] Gao GY, Chen ML, Li MY, et al. Current status and prospect of translational medicine in nanotechnology [J]. Acta Pharm Sin (药学学报), 2015, 50: 919-924.
[12] Lucky SS, Soo KC, Zhang Y. Nanoparticles in photodynamic therapy [J]. Chem Rev, 2015, 115: 1990-2042.
[13] Manzoor AA, Lindner LH, Landon CD, et al. Overcoming limitations in nanoparticle drug delivery: triggered, intravas-cular release to improve drug penetration into tumors [J]. Cancer Res, 2012, 72: 5566-5575.
[14] Kong G, Anyarambhatla G, Petros WP, et al. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release [J]. Cancer Res, 2000, 60: 6950-6957.
[15] Frangioni JV. In vivo near-infrared fluorescence imaging [J]. Curr Opin Chem Biol, 2003, 7: 626-634.
[16] Saad SY, Najjar TA, Al-Rikabi AC. The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats [J]. Pharmacol Res, 2001, 43: 211-218.