聚L-谷氨酸-γ-苄酯纳米粒子提高耐药细胞药物累积的研究

华东师范大学学报(自然科学版) ›› 2013, Vol. 2013 ›› Issue (6): 141-149.

聚L-谷氨酸-γ-苄酯纳米粒子提高耐药细胞药物累积的研究

刘凯，陈静，王镜，俞磊，朱建中，王依婷

华东师范大学跨学科高等研究院, 上海 200062

收稿日期:2013-01-01 修回日期:2013-04-01 出版日期:2013-11-25 发布日期:2014-01-13

Poly (L-γ-glutamylglutamine) nanoparticles enhance drug accumulation in resistant cells

LIU Kai, CHEN Jing, WANG Jing, YU Lei, ZHU Jian-zhong, WANG Yi-ting

Institutes for Advanced interdisciplinary Research, East China Normal University, Shanghai 200062, China

Received:2013-01-01 Revised:2013-04-01 Online:2013-11-25 Published:2014-01-13

摘要/Abstract

摘要： 研究PGG载体在耐药肿瘤细胞中的作用. 通过诱导A549细胞产生多药耐药性,评估在耐药肿瘤细胞中PGG对抗癌药物多柔比星胞内累积和驻留的影响. 证明PGG药物输送系统能够增加耐药细胞株中的药物累积. 利用内吞抑制试验和透射电镜试验阐明细胞通过胞饮方式摄取PGG载体药物,该方式提高了药物的细胞摄取,增加了药物的细胞累积. 并利用激光共聚焦显微术确认了药物的细胞累积. PGG-Dox同游离Dox相比,通过胞饮作用进入细胞后,可以显著增加药物处理细胞内的Dox累积和驻留. Dox与PGG药物输送系统连接后,具有显著的抗耐药效果. PGG药物输送系统具备应用于耐药型肿瘤治疗的潜力.

关键词: 多药耐药性, 多聚体药物输送系统, 纳米技术, 纳米药物

Abstract: This work investigated the antitumor efficacy of poly (L-γ-glutamylglutamine) (PGG) prodrug in multidrug resistant (MDR) cancer cells and the possible mechanisms. The A549 cell line was induced to become multidrug resistant. A549 was applied to evaluate the effect of PGG-Dox on intracellular accumulation and retention of Dox. Endocytosis inhibition studies and transmission electron microscope assay were used to investigate the mechanisms of cellular PGG-Dox uptake. Confocal laser scanning microscopy was performed to confirm the drug accumulation. Treatment of MDR cells with PGG-Dox resulted in significantly enhanced drug accumulation and retention after the end of treatment compared with free Dox. Endocytosis inhibition studies showed pinocytosis is the mainly pathway in the elevated membrane permeability of the PGG-Dox. These demonstrated that Dox conjugate with PGG NPs effectively bypass the multidrug resistance. Our PGG DDS may be considered as an attractive and promising delivery system to overcome multidrug resistance.

Key words: multidrug resistance, polymer drug delivery system, nanotechnology, nanomedicine

中图分类号:

刘凯，陈静，王镜，俞磊，朱建中，王依婷. 聚L-谷氨酸-γ-苄酯纳米粒子提高耐药细胞药物累积的研究[J]. 华东师范大学学报(自然科学版), 2013, 2013(6): 141-149.

LIU Kai, CHEN Jing, WANG Jing, YU Lei, ZHU Jian-zhong, WANG Yi-ting. Poly (L-γ-glutamylglutamine) nanoparticles enhance drug accumulation in resistant cells[J]. Journal of East China Normal University(Natural Sc, 2013, 2013(6): 141-149.

参考文献

［1］ MINOTTI G, MENNA P, SALVATORELLI E, et al. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity［J］. Pharmacological Reviews, 2004,56: 185-229. 

［2］ DAVE B, CHANG J. Treatment resistance in stem cells and breast cancer［J］. Journal of Mammary Gland Biology and Neoplasia, 2009,14: 79-82. 

［3］ BORST P, ELFERINK R O. Mammalian ABC transporters in health and disease［J］. Annual Review of Biochemistry, 2002,71: 537-592. 

［4］ BROXTERMAN H J, GOTINK K J, VERHEUL H M. Understanding the causes of multidrug resistance in cancer: A comparison of doxorubicin and sunitinib［J］. Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy, 2009(12): 114-126. 

［5］ AMBUDKAR S V, KIMCHI-SARFATY C, SAUNA Z E, et al. P-glycoprotein: From genomics to mechanism. Oncogene［J］. 2003,22: 7468-7485. 

［6］ GOTTESMAN M M, FOJO T, BATES S E. Multidrug resistance in cancer: Role of ATP-dependent transporters［J］. Nature Reviews. Cancer, 2002(2): 48-58. 

［7］ MISRA R, ACHARYA S, SAHOO S K. Cancer nanotechnology: Application of nanotechnology in cancer therapy［J］. Drug Discovery Today, 2010,15: 842-850. 

［8］ SHAPIRA A, LIVNEY Y D, BROXTERMAN H J, et al. Nanomedicine for targeted cancer therapy: Towards the overcoming of drug resistance［J］. Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy, 2011,14: 150-163. 

［9］ DUNCAN R. Polymer conjugates as anticancer nanomedicines［J］. Nature Reviews Cancer. 2006(6): 688-701. 

［10］ CHITHRANI B D, GHAZANI A A, CHAN W C. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells［J］. Nano Letters, 2006(6): 662-668. 

［11］ CHITHRANI B D, CHAN W C. Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes［J］. Nano Letters, 2007(7): 1542-1550. 

［12］ WONG H L, BENDAYAN R, RAUTH A M, et al. A mechanistic study of enhanced doxorubicin uptake and retention in multidrug resistant breast cancer cells using a polymer-lipid hybrid nanoparticle system［J］. The Journal of Pharmacology and Experimental Therapeutics, 2006,317: 1372-1381. 

［13］ BONOMI P. Paclitaxel poliglumex (PPX, CT-2103): macromolecular medicine for advanced non-small-cell lung cancer［J］. Expert Review of Anticancer Therapy, 2007(7): 415-422. 

［14］ DUNCAN R, VICENT M J. Do HPMA copolymer conjugates have a future as clinically useful nanomedicines? A critical overview of current status and future opportunities［J］. Advanced Drug Delivery Reviews, 2010,62: 272-282. 

［15］ ETRYCH T, SIROVA M, STAROVOYTOVA L, et al. HPMA copolymer conjugates of paclitaxel and docetaxel with pH-controlled drug release［J］. Molecular Pharmaceutics, 2010(7): 1015-1026. 

［16］ MILLER K, ELDAR-BOOCK A, POLYAK D, et al. Antiangiogenic antitumor activity of HPMA copolymer-paclitaxel-alendronate conjugate on breast cancer bone metastasis mouse model［J］. Molecular Pharmaceutics, 2011(8): 1052-1062. 

［17］ VAN S, DAS S K, WANG X, et al. Synthesis, characterization, and biological evaluation of poly(L-gamma-glutamyl-glutamine)- paclitaxel nanoconjugate［J］. International Journal of Nanomedicine, 2010(5): 825-837. 

［18］ WANG X, ZHAO G, VAN S, et al. Pharmacokinetics and tissue distribution of PGG-paclitaxel, a novel macromolecular formulation of paclitaxel, in nu/nu mice bearing NCI-460 lung cancer xenografts［J］. Cancer Chemotherapy and Pharmacology, 2010,65: 515-526. 

［19］ YANG D, VAN S, JIANG X, et al. Novel free paclitaxel-loaded poly(L-gamma-glutamylglutamine)-paclitaxel nanoparticles［J］. International Journal of Nanomedicine, 2011(6): 85-91. 

［20］ YANG D, VAN S, SHU Y, et al. Synthesis, characterization, and in vivo efficacy evaluation of PGG-docetaxel conjugate for potential cancer chemotherapy［J］. International Journal of Nanomedicine, 2012(7): 581-589. 

［21］ PAJIC M, IYER J K, KERSBERGEN A, et al. Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer［J］. Cancer Research, 2009,69: 6396-6404. 

［22］ DUNCAN R. Polymer therapeutics as nanomedicines: New perspectives ［J］. Current Opinion in Biotechnology, 2011,22: 492-501. 

［23］ WAN C P, LETCHFORD K, JACKSON J K, et al. The combined use of paclitaxel-loaded nanoparticles with a low-molecular-weight copolymer inhibitor of P-glycoprotein to overcome drug resistance［J］. Int J Nanomedicine, 2013(8): 379-391. 

［24］ CASCORBI I. P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations［J］. Handb Exp Pharmacol, 2011,201: 261-283.