药学学报, 2014, 49(8): 1188-1193
引用本文:
顾卓珺, 王萌, 方琼艳, 王成润, 郑怀宇. 载阿霉素普朗尼克化聚酰胺-胺树状聚合物对乳腺癌多药耐药细胞株MCF-7/ADR的抑制作用[J]. 药学学报, 2014, 49(8): 1188-1193.
GU Zhuo-jun, WANG Meng, FANG Qiong-yan, WANG Cheng-run, ZHENG Huai-yu. Inhibition of MCF-7/ADR cells by DOX-loaded pluronic-attached PAMAM dendrimer conjugate[J]. Acta Pharmaceutica Sinica, 2014, 49(8): 1188-1193.

载阿霉素普朗尼克化聚酰胺-胺树状聚合物对乳腺癌多药耐药细胞株MCF-7/ADR的抑制作用
顾卓珺1, 王萌2, 方琼艳1, 王成润2, 郑怀宇1
1. 舟山医院, 浙江 舟山 316021;
2. 浙江大学药学院, 浙江 杭州 310058
摘要:
本文合成了普朗尼克修饰的聚酰胺-胺聚合物(PF127-PAMAM),以阿霉素(DOX) 为模型药物,考察了该载药复合物对乳腺癌多药耐药细胞株MCF-7/ADR的抑制作用。核磁共振图谱及红外图谱表明聚合物成功合成,元素分析法测得每个聚酰胺-胺分子伯氨基的普朗尼克化程度为27.63%(PAMAM:PF127,1:35.37,摩尔比)。PF127-PAMAM较PAMAM水合粒径增大,zeta电位有所降低。较低的电位及PF127的保护作用使得PF127-PAMAM有较低的溶血性和细胞毒性。每个PF127-PAMAM分子可以负载19.58个DOX分子,载药复合物的释放具有缓慢释放及pH敏感的特性。对于乳腺癌细胞株MCF-7,PF127-PAMAM/DOX的细胞毒性较游离DOX稍弱;而对于乳腺癌多药耐药细胞株MCF-7/ADR,PF127-PAMAM/DOX则表现出较强的逆转耐药性的效果,其耐药逆转指数(RRI) 高达33.15。
关键词:    聚酰胺-胺      普朗尼克      阿霉素      多药耐药     
Inhibition of MCF-7/ADR cells by DOX-loaded pluronic-attached PAMAM dendrimer conjugate
GU Zhuo-jun1, WANG Meng2, FANG Qiong-yan1, WANG Cheng-run2, ZHENG Huai-yu1
1. Zhoushan Hospital, Zhoushan 316021, China;
2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Abstract:
Pluronic modified polyamidoamine (PAMAM) conjugate (PF127-PAMAM) was prepared and the inhibiting effect of MDR against MCF-7/ADR was investigated with doxorubicin (DOX) as model drug. 1H NMR and FTIR spectra showed that the conjugate was synthesized successfully. Element analysis accu-rately measured that 27.63% amino of per PAMAM was modified by pluronic (PAMAM:PF127, 1:35.37 mole ratio). PF127-PAMAM showed an increased size and a reduced zeta potential compared to PAMAM. PF127-PAMAM had lower hemolytic toxicity and cytotoxicity due to the reduced zeta potential and the protection of PF127. Each PF127-PAMAM molecular could load 19.58 DOX molecules, and the complex exhibited sustained and pH-sensitive release behavior. PF127-PAMAM/DOX exhibited weaker cytotoxicity than free DOX in MCF-7 cells; while the complex showed much stronger reverse effect of drug resistance in MCF-7/ADR cells, and resistance reversion index (RRI) was as high as 33.15.
Key words:    polyamidoamine    pluronic    doxorubicin    multidrug resistance   
收稿日期: 2014-04-09
基金项目: 浙江省医学会临床科研专项资助项目(2011ZYC-A95).
通讯作者: 顾卓珺 Tel:86-580-2292847,Fax:86-580-2292992,E-mail:gzj0063@126.com
Email: gzj0063@126.com
相关功能
PDF(628KB) Free
打印本文
0
作者相关文章
顾卓珺  在本刊中的所有文章
王萌  在本刊中的所有文章
方琼艳  在本刊中的所有文章
王成润  在本刊中的所有文章
郑怀宇  在本刊中的所有文章

参考文献:
[1] Naito S, Yokomizo A, Koga H. Mechanisms of drug resis-tance in chemotherapy for urogenital carcinoma [J]. Int J Urol, 1999, 6: 427-439.
[2] Chen AM, Zhang M, Wei DG, et al. Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells [J]. Small, 2009, 5: 2673-2677.
[3] Kröger N, Achterrath W, Hegewisch-Becker S, et al. Cur-rent options in treatment of anthracycline-resistant breast cancer [J]. Cancer Treat Rev, 1999, 25: 279-291.
[4] Wang YZ, Hao JG, Li YJ, et al. Poly(caprolactone)-modified Pluronic P105 micelles for re-versal of paclitaxcel-resistance in SKOV-3 tumors [J]. Biomaterials, 2012, 33: 4741-4751.
[5] Wu J, Yan X, Shao R, et al. Study of co-encapsulated doxorubicin and curcumin poly(butyl cyanoacrylate) nanoparticles and reversion of multidrug resistance in MCF/ADR cell line [J]. China Biotechnol (中国生物工程杂志), 2013, 33: 35-43.
[6] Zhou WJ, Zhou W, Jia SW, et al. Cytological study on the effect of overcoming multidrug resistance of liposomal doxorubicin in vitro [J]. Chin J Hosp Pharm (中国医院药学杂志), 2012, 32: 1349-1352.
[7] Liu Y, Huang L, Liu F. Paclitaxel nanocrystals for overcoming multidrug resistance in cancer [J]. Mol Pharm, 2010, 7: 863-869.
[8] Xiao L, Xiong XQ, Sun XH, et al. Role of cellular uptake in the reversal of multidrug resistance by PEG-b-PLA poly-meric micelles [J]. Biomaterials, 2011, 32: 5148-5157.
[9] Hong S, Leroueil PR, Majoros IJ, et al. The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform [J]. Chem Biol, 2007, 14: 107-115.
[10] Ma K, Hu MX, Qi Y, et al. PAMAM-triamcinolone aceton-ide conjugate as a nucleus-targeting gene carrier for enhanced transfer activity [J]. Biomaterials, 2009, 30: 6109-6118.
[11] Jang SH, Choi SJ, Oh JH, et al. Nonviral gene delivery to human ovarian cancer cells using arginine-grafted PAMAM dendrimer [J]. Drug Dev Ind Pharm, 2001, 37: 41-46.
[12] Jevprasesphant R, Penny J, Attwood D, et al. Engineering of dendrimer surfaces to enhance transepithelial transport and reduce cytotoxicity [J]. Pharm Res, 2003, 20: 1543-1550.
[13] Majoros IJ, Thomas TP, Mehta CB, et al. Poly-(ami-doamine) dendrimer-based multifunctional engineered nanodevice for cancer therapy [J]. J Med Chem, 2005, 48: 5892-5899.
[14] Zhuo RX, Du B, Lu ZR. In vitro release of 5-fluorouracil with cyclic core dendritic polymer [J]. J Control Release, 1999, 57: 249-257.
[15] Han M, Lv Q, Tang XJ, et al. Overcoming drug resistance of MCF-7/ADR cells by altering intracellular distribution of doxorubicin via MVP knockdown with a novel siRNA polyamidoamine-hyaluronic acid complex [J]. J Control Release, 2012, 163: 136-144.
[16] Zhu SJ, Hong MH, Zhang LH, et al. PEGylated PAMAM dendrimer-doxorubicin conjugates: in vitro evaluation and in vivo tumor accumulation [J]. Pharm Res, 2010, 27: 161-174.
[17] Yu PL, Li ST, Ye L, et al. Synthesis of PEGylated PAMAM dendrimer as a drug carrier [J]. Chin J Biomed Eng (中国生物医学工程学报), 2007, 26: 921-925.
[18] Zhang W, Shi Y, Chen YZ, et al. Enhanced antitumor efficacy by paclitaxel-loaded pluronic P123/F127 mixed micelles against non-small cell lung cancer based on passive tumor targeting and modulation of drug resistance [J]. Eur J Pharm Biopharm, 2010, 75: 341-353.
[19] Wang YZ, Fang XL, Li YJ, et al. Preparation, characteriza-tion of paclitaxel loaded Pluronic P105 polymeric micelles and in vitro reversal of multidrug resistant tumor [J]. Acta Pharm Sin (药学学报), 2008, 43: 640-646.
[20] Wei Z, Hao JG, Yuan S, et al. Paclitaxel-loaded Pluronic P123/F127 mixed polymeric micelles: formulation, optimization and in vitro characterization [J]. Int J Pharm, 2009, 376: 176-185.
[21] Batrakova EV, Kabanov AV. Pluronic block copolymers: evolution of drug delivery concept from inert nanocarriers to biological response modifiers [J]. J Control Release, 2008, 130: 98-106.
[22] Dung TH, Kim J, Kim MS, et al. Preparation and bio-physical characterization of pluronic F127-dendrimer conjugate as a delivery agent of antisense oligonucleotides [J]. J Nanosci Nanotechnol, 2008, 8: 5326-5330.
[23] Kojima C, Kono K, Maruyama K, et al. Synthesis of polyamidoamine dendrimers having poly(ethyleneglycol) grafts and their ability to encapsulate anticancer drugs [J]. Bioconjug Chem, 2000, 11: 910-917.
[24] Qi R, Gao Y, Tang Y, et al. PEG-conjugated PAMAM dendrimers mediate efficient intramuscular gene expression [J]. AAPS J, 2009, 11: 395-405.
[25] Twyman LJ, Beezer AE, Esfand R, et al. The synthesis of water soluble dendrimers, and their application as possible drug delivery systems [J]. Tetrahedron Lett, 1999, 40: 1743-1746.
相关文献:
1.王坚成;刘晓岩;吕万良;How-Sung;Lee;Boon-Cher;Goh;张强.新型阿霉素抗耐药性隐形脂质体的体外细胞毒和体内毒性研究[J]. 药学学报, 2005,40(5): 475-480
2.祝浩杰;吴玉林;刘国卿.洛美利嗪逆转K562/ADM细胞多药耐药性[J]. 药学学报, 2004,39(5): 333-337