药学学报, 2015, 50(8): 1038-1044
引用本文:
邓春月, 龙莹莹, 刘厦, 陈章宝, 李翀. 生物素介导的胰腺癌靶向聚合物胶束制备及其用于光动力治疗的初步研究[J]. 药学学报, 2015, 50(8): 1038-1044.
DENG Chun-yue, LONG Ying-ying, LIU Sha, CHEN Zhang-bao, LI Chong. Construction of biotin-modified polymeric micelles for pancreatic cancer targeted photodynamic therapy[J]. Acta Pharmaceutica Sinica, 2015, 50(8): 1038-1044.

生物素介导的胰腺癌靶向聚合物胶束制备及其用于光动力治疗的初步研究
邓春月, 龙莹莹, 刘厦, 陈章宝, 李翀
西南大学药学院, 重庆 400716
摘要:
本文探索以生物素为导向分子介导纳米载体靶向胰腺癌并开展光动力治疗的可行性。以聚乙二醇-磷脂酰乙醇胺 [poly (ethylene glycol)-distearoyl phosphatidyl ethanolamine, mPEG2000-DSPE] 为载体材料, 生物素-聚乙二醇-磷脂酰乙醇胺 [biotin-poly(ethylene glycol)-distearoyl phosphatidyl ethanolamine, Biotin-PEG3400-DSPE] 为功能材料, 通过薄膜水化法制备生物素修饰的聚合物胶束。通过体外细胞摄取实验和体内荧光活体成像实验考察其靶向性并对导向分子的比例进行优选。在此基础上, 以新型光动力药物竹红菌乙素为光敏剂, 制备载药胶束制剂并对其体内外药效进行系统评价。结果表明, 5% (mol/mol) 比例的生物素修饰具有相对较好的体内外靶向 性, 其载药制剂粒径较小 [(36.74 ± 2.16) nm] 且分布较均一, 药物的包封率较高, 达到 (80.06 ± 0.19) %。药效评价显示, 经生物素介导能提高光敏剂对 BxPC-3细胞的光毒性, 在体内则表现为显著抑制裸鼠皮下瘤生长。本研究成功地将生物素介导主动靶向的“抑瘤谱”扩大至胰腺癌, 所得载光敏剂胶束的制剂学性质较好, 为胰腺癌尤其是部分难渗透、放化疗不敏感的胰腺癌治疗研究提供了有益的思路。
关键词:   
Construction of biotin-modified polymeric micelles for pancreatic cancer targeted photodynamic therapy
DENG Chun-yue, LONG Ying-ying, LIU Sha, CHEN Zhang-bao, LI Chong
College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China
Abstract:
In this study, we explored the feasibility of biotin-mediated modified polymeric micelles for pancreatic cancer targeted photodynamic therapy. Poly (ethylene glycol)-distearoyl phosphatidyl ethanolamine (mPEG2000-DSPE) served as the drug-loaded material, biotin-poly(ethylene glycol)-distearoyl phosphatidyl ethanolamine (Biotin-PEG3400-DSPE) as the functional material and the polymeric micelles were prepared by a thin-film hydration method. The targeting capability of micelles was investigated by cell uptake assay in vitro and fluorescence imaging in vivo and the amounts of Biotin-PEG-DSPE were optimized accordingly. Hypocrellin B (HB), a novel photosensitizer was then encapsulated in biotinylated polymeric micelles and the anti-tumor efficacy was evaluated systemically in vitro and in vivo. The results showed that micelles with 5 mol % Biotin-PEG-DSPE demonstrated the best targeting capability than those with 20 mol % or 0.5 mol % of corresponding materials. This formulation has a small particle size [mean diameter of (36.74 ± 2.16) nm] with a homogeneous distribution and high encapsulation efficiency (80.06 ± 0.19) %. The following pharmacodynamics assays showed that the biotinylated micelles significantly enhanced the cytotoxicity of HB against tumor cells in vitro and inhibited tumor growth in vivo, suggesting a promising potential of this formulation for treatment of pancreatic cancer, especially those poorly permeable, or insensitive to radiotherapy and chemotherapy.
Key words:   
收稿日期: 2015-04-28
基金项目: 国家自然科学基金资助项目 (21272187); 中央高校基本科研业务费资助项目 (XDJK2013A015).
通讯作者: 李翀
Email: chongli2009@gmail.com
相关功能
PDF(9312KB) Free
打印本文
0
作者相关文章

参考文献:
[1] Zhang L, Wei G, Lu WY. Application of activatable cell-penetrating peptide in the field of tumor therapy [J]. Acta Pharm Sin (药学学报), 2014, 49: 1639-1643.
[2] Torchilin VP. Drug targeting [J]. Eur J Pharm Sci, 2000, 11: 81-91.
[3] Tripodo G, Mandracchia D, Collina S, et al. New perspectives in cancer therapy: the biotin-antitumor molecule conjugates [J]. Angew Chem Int Ed, 2014, 8: 1-4.
[4] Shi JF, Wu P, Jiang ZH, et al. Synthesis and tumor cell growth inhibitory activity of biotinylated annonaceous acetogenins [J]. Eur J Med Chem, 2014, 71: 219-228.
[5] Chen S, Zhao X, Chen J, et al. Mechanism-based tumor-targeting drug delivery system. Validation of efficient vitamin receptor-mediated endocytosis and drug release [J]. Bioconjug Chem, 2010, 21: 979-987.
[6] Vadlapudi AD, Vadlapatla RK, Pal D, et al. Functional and molecular aspects of biotin uptake via SMVT in human corneal epithelial (HCEC) and retinal pigment epithelial (D407) cells [J]. AAPS J, 2012, 14: 832-842.
[7] Russell-Jones G, McTavish K, McEwan J, et al. Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours [J]. J Inorg Biochem, 2004, 98: 1625- 1633.
[8] Shi JF, Wu P, Jiang ZH, et al. Synthesis and tumor cell growth inhibitory activity of biotinylated annonaceous acetogenins [J]. Eur J Med Chem, 2014, 71: 219-228.
[9] Vrouenraets MB, Visser GW, Snow GB, et al. Basic principles, applications in oncology and improved selectivity of photodynamic therapy [J]. Anticancer Res, 2002, 23: 505-522.
[10] Nyman ES, Hynninen PH. Research advances in the use of tetrapyrrolic photosensitizers for photodynamic therapy [J]. J Photochem Photobiol B, 2004, 73: 1-28.
[11] Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour immunity [J]. Nat Rev Cancer, 2006, 6: 535-545.
[12] Dougherty TJ, Gomer CJ, Henderson BW, et al. Photodynamic therapy [J]. J Natl Cancer Inst, 1998, 90: 889-905.
[13] Robertson CA, Evans DH, Abrahamse H. Photodynamic therapy (PDT): a short review on cellular mechanisms and cancer research applications for PDT [J]. J Photochem Photobiol B, 2009, 96: 1-8.
[14] Hidalgo M. Pancreatic cancer [J]. N Engl J Med, 2010, 362: 1605-1617.
[15] Ikeda N, Adachi M, Taki T, et al. Prognostic significance of angiogenesis in human pancreatic cancer [J]. Br J Cancer, 1999, 79: 1553.
[16] Stathis A, Moore MJ. Advanced pancreatic carcinoma: nilrent treatment and future challenges [J]. Nat Rev Clin Oncol, 2010, 7: 163-172.
[17] Wang P, Xu C, Xu J, et al. Hypocrellin B enhances ultrasound-induced cell death of nasopharyngeal carcinoma cells [J]. Ultrasound Med Biol, 2010, 36: 336-342.
[18] Mulrooney CA, O'Brien EM, Morgan BJ, et al. Perylenequinones: isolation, synthesis, and biological activity [J]. Eur J Org Chem, 2012, 21: 3887-3904.
[19] Song L, Zhao B, Xie J, et al. Interactions of hypocrellin B with hyaluronan and photo-induced interactions [J]. Biochim Biophys Acta, 2006, 1760: 333-339.
[20] Ma G, Khan SI, Jacob MR, et al. Antimicrobial and antileishmanial activities of hypocrellin A and B [J]. Antimicrob Agents Chemother, 2004, 48: 4450-4452.
[21] Toffoli DJ, Gomes L, Vieira Jr ND, et al. Photodynamic potentiality of hypocrellin B and its lanthanide complexes [J]. J Opt A Pure Appl Opt, 2008, 10: 687-688.
[22] Cetin Y, Bullerman LB. Cytotoxicity of Fusarium mycotoxins to mammalian cell cultures as determined by the MTT bioassay [J]. Food Chem Toxicol, 2005, 43: 755-764.
[23] Tang N, Du G, Wang N, et al. Improving penetration in tumors with nanoassemblies of phospholipids and doxorubicin [J]. J Natl Cancer Inst, 2007, 99: 1004-1015.
[24] Cabral H, Matsumoto Y, Mizuno K, et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size [J]. Nat Nanotechnol, 2011, 6: 815-823.