超顺磁性紫杉醇纳米微粒对脑胶质细胞瘤体内外抑制作用的实验研究
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摘要
目的研究超顺磁性紫杉醇纳米微粒对恶性脑胶质细胞瘤细胞的抑制作用。
方法利用纳米技术制作出超顺磁性紫杉醇纳米微粒,并观察其粒径、磁响应性和缓控释药速度。将其与人恶性脑胶质瘤细胞系U251共同孵育后观察纳米微粒在细胞内的分布,并用CCK-8法和流式细胞法检测不同浓度紫杉醇纳米微粒对U251细胞的细胞毒性作用和诱导凋亡作用。立体定向向SD大鼠脑内基底节区种植C6恶性胶质瘤细胞,建立荷胶质瘤大鼠模型,对比静脉注射超顺磁性紫杉醇纳米微粒和单纯紫杉醇后大鼠的生存时间。
结果超顺磁性紫杉醇纳米微粒粒径约20nm,具备超顺磁性,体外可持续释药15天以上。其能有效进入肿瘤细胞内部并释放药物,诱导肿瘤细胞发生凋亡,其细胞毒性作用与紫杉醇相近。荷瘤大鼠注射超顺磁性紫杉醇纳米微粒并用0.5T磁场进行磁靶向治疗后生存期较紫杉醇治疗组延长1倍。
结论超顺磁性紫杉醇纳米微粒改变了紫杉醇的弱水溶性,并且安全稳定,能持续缓慢释放药物。因其粒径小,能顺利进入肿瘤细胞内部发挥显著抗肿瘤作用。同时,在外磁场引导下能聚集于磁靶向区域,提高肿瘤局部药物浓度,达到杀灭肿瘤、延长生存期的作用。
Objective:The inhibitive effects of superparamagnetic paclitaxel nanoparticles to the malignant glioma growth were studied both in vivo and in vitro.
Methods:Superparamagnetic paclitaxel nanoparticles were fabricated by nanotechnology before their diameters, magnetism as well as drug release rate were tested. After incubation with human malignant glioma cell line U251, the intracellular distribution of nanoparticles was observed. Afterwards the cytotoxicity and apoptosis-inducing capacity of superparamagnetic paclitaxel nanoparticles at different concentrations to U251 were tested by CCK-8 kit and flow cytometry. Rat malignant glioma cell line C6 was implanted into SD rats' head stereotactically to obtain the glioma-bearing rats. After intravenous administration of superparamagnetic paclitaxel nanoparticles and magnetic targeting, the rats'survival was recorded and compared with that after pure paclitaxel injection.
Results:Superparamagnetic paclitaxel nanoparticles had a mean diameter of 20 nm with a narrow distribution. They were superparamagnetic and released drugs for more than 15 days constantly. Besides they could enter the glioma cells effectively and inducing apoptosis with a similar cytotoxicity with paclitaxel. After intravenous injection of superparamagnetic paclitaxel nanoparticles and magnetic targeting with a 0.5T magnet, the survival of glioma-bearing rats were prolonged for 1 fold compared to rats treated with paclitaxel.
Conclusion:Superparamagnetic paclitaxel nanoparticles converted the poor solubility of paclitaxel. They are safe and stable with a long release of loaded drugs. The superparamagnetic paclitaxel nanoparticles can enter the glioma cells to inhibit their growth because of their ultrasmall size. Besides, they can accumulate in magnetic targeted area and result in a high local drug concentration to inhibit the tumor growth and prolong the glioma-bearing rats'survival.
方法利用纳米技术制作出超顺磁性紫杉醇纳米微粒,并观察其粒径、磁响应性和缓控释药速度。将其与人恶性脑胶质瘤细胞系U251共同孵育后观察纳米微粒在细胞内的分布,并用CCK-8法和流式细胞法检测不同浓度紫杉醇纳米微粒对U251细胞的细胞毒性作用和诱导凋亡作用。立体定向向SD大鼠脑内基底节区种植C6恶性胶质瘤细胞,建立荷胶质瘤大鼠模型,对比静脉注射超顺磁性紫杉醇纳米微粒和单纯紫杉醇后大鼠的生存时间。
结果超顺磁性紫杉醇纳米微粒粒径约20nm,具备超顺磁性,体外可持续释药15天以上。其能有效进入肿瘤细胞内部并释放药物,诱导肿瘤细胞发生凋亡,其细胞毒性作用与紫杉醇相近。荷瘤大鼠注射超顺磁性紫杉醇纳米微粒并用0.5T磁场进行磁靶向治疗后生存期较紫杉醇治疗组延长1倍。
结论超顺磁性紫杉醇纳米微粒改变了紫杉醇的弱水溶性,并且安全稳定,能持续缓慢释放药物。因其粒径小,能顺利进入肿瘤细胞内部发挥显著抗肿瘤作用。同时,在外磁场引导下能聚集于磁靶向区域,提高肿瘤局部药物浓度,达到杀灭肿瘤、延长生存期的作用。
Objective:The inhibitive effects of superparamagnetic paclitaxel nanoparticles to the malignant glioma growth were studied both in vivo and in vitro.
Methods:Superparamagnetic paclitaxel nanoparticles were fabricated by nanotechnology before their diameters, magnetism as well as drug release rate were tested. After incubation with human malignant glioma cell line U251, the intracellular distribution of nanoparticles was observed. Afterwards the cytotoxicity and apoptosis-inducing capacity of superparamagnetic paclitaxel nanoparticles at different concentrations to U251 were tested by CCK-8 kit and flow cytometry. Rat malignant glioma cell line C6 was implanted into SD rats' head stereotactically to obtain the glioma-bearing rats. After intravenous administration of superparamagnetic paclitaxel nanoparticles and magnetic targeting, the rats'survival was recorded and compared with that after pure paclitaxel injection.
Results:Superparamagnetic paclitaxel nanoparticles had a mean diameter of 20 nm with a narrow distribution. They were superparamagnetic and released drugs for more than 15 days constantly. Besides they could enter the glioma cells effectively and inducing apoptosis with a similar cytotoxicity with paclitaxel. After intravenous injection of superparamagnetic paclitaxel nanoparticles and magnetic targeting with a 0.5T magnet, the survival of glioma-bearing rats were prolonged for 1 fold compared to rats treated with paclitaxel.
Conclusion:Superparamagnetic paclitaxel nanoparticles converted the poor solubility of paclitaxel. They are safe and stable with a long release of loaded drugs. The superparamagnetic paclitaxel nanoparticles can enter the glioma cells to inhibit their growth because of their ultrasmall size. Besides, they can accumulate in magnetic targeted area and result in a high local drug concentration to inhibit the tumor growth and prolong the glioma-bearing rats'survival.
引文
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[29]Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature,1979,277:665-667.
[30]Sakamoto J, Annapragada A, Decuzzi P, Ferrari M:Antibiological barrier nanovector technology for cancer applications. Expert Opin Drug Deliv, 2007,4:359-369.
[31]Roiter Y, Ornatska M, Rammohan AR, Balakrishnan J, Heine DR, Minko S. Interaction of lipid membrane with nanostructured surfaces. Langmuir, 2009,25:6287-6299.
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[33]Laquintana V, Trapani A, Denora N, Wang F, Gallo JM, Trapani G:New strategies to deliver anticancer drugs to brain tumors. Expert Opin Drug Deliv,2009,6:1017-1032.
[34]Liang XF, Wang HJ, Luo H, Tian H, Zhang BB, Hao LJ, Teng JI, Chang J: Characterization of novel multifunctional cationic polymeric liposomes formed from octadecyl quaternized carboxymethyl chitosan/cholesterol and drug encapsulation. Langmuir,2008,24:7147-7153.
1. Helson L, Helson C, Malik S, et al. A saturation threshold for taxol cytotoxicity in human glial and neuroblastoma cells[J]. Anticancer Drugs, 1993,4(4):487-490.
2. Liebmann JE, Cook JA, Lipschultz C, et al. Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines[J]. Br J Cancer,1993,68(6):1104-1109.
3. Chamberlain MC, Kormanik P. Salvage chemotherapy with taxol for recurrent anaplastic astrocytomas[J]. J Neurooncol,1999,43(1):71-78.
4. Chamberlain MC, Kormanik PA. Salvage chemotherapy with paclitaxel for recurrent oligodendrogliomas[J]. J Clin Oncol,1997,15(12):3427-3432.
5. Gannett DE, Hill D, Hamilton AJ, et al. Paclitaxel as a radiosensitizer combined with fractionated stereotactic radiotherapy in the treatment of recurrent medulloblastoma[J]. Am J Clin Oncol,1997,20(3):233-226.
6. Postma TJ, Heimans JJ, Luykx SA, et al. A phase II study of paclitaxel in chemonaive patients with recurrent high-grade glioma[J]. Ann Oncol,2000, 11(4):409-413.
7. Tishler RB, Geard CR, Hall EJ, et al. Taxol sensitizes human astrocytoma cells to radiation[J]. Cancer Res,1992,52(12):3495-3497.
8. Glantz MJ, Choy H, Kearns CM, et al. Weekly, outpatient paclitaxel and concurrent cranial irradiation in adults with brain tumors:preliminary results and promising directions[J]. Semin Oncol,1995,22(5 Suppl 12):26-32.
9. Lederman G, Wronski M, Arbit E, et al. Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel[J]. Am J Clin Oncol,2000,23(2):155-159.
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[2]DeAngelis LM, Burger PC, Green SB, et al. Malignant glioma: who benefits from adjuvant chemotherapy [J]? Ann Neurol,1998,44(4): 691-695.
[3]Stere JI, Raizer JJ. Chemotherapy in the treatment of malignant gliomas[J]. Expert Rev Anticancer Ther,2006,6(5):755-767.
[4]Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a medical research council trial [J]. J Clin Oncol, 2001,19(2):509-518.
[5]Stupp R, DietrichPY, Ostermann Kraljevic S, et al. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide[J]. J Clin Oncol,2002,20(5):1375-1382.
[6]Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma[J]. N Engl J Med,2005,352(10):987-996.
[7]刘金龙,陈硕朗,林佳平,等.胶质瘤显微手术切除加术中间质化疗的临床效果[J].中华显微外科杂志,2003,26(2)：156-158.
[8]李安民,章翔,易声禹,等.恶性脑胶质细胞瘤的间质化疗[J].中国临床神经外科杂志,1999,4(3)：24-26.
[9]于耀宇,马廉亭,秦尚振,等.脑胶质瘤术后间质化疗联合同步放疗的临床研究[J].中国临床神经外科杂志,2005,25：342-344.
[10]Mykhaylyk OM, Dudchenko NO, Dudchenko AK. Pharmacokinetics of the doxorubicin magnetic nanoconjugate in mice. Effects of the nonuniform stationary magnetic field [J]. Ukr Biokhim Zh,2005, 77(5):80-92.
[11]李安民,张传秀,傅相平,等.磁导向下磁性化疗药物脑内定位分布的实验研究[J].中国微创外科杂志,2005,5(5)：409-411.
[12]李安民,张传秀,傅相平,等.磁导向下磁性化疗药物对肝、肾及骨髓的影响[J].中国微创外科杂志,2005,5(11)：943-946.
[13]Helson L, Helson C, Malik S, et al. A saturation threshold for taxol cytotoxicity in human glial and neuroblastoma cells [J]. Anticancer Drugs, 1993,4(4):487-490.
[14]Liebmann JE, Cook JA, Lipschultz C, et al. Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines[J]. Br J Cancer,1993, 68(6):1104-1109.
[15]Chamberlain MC, Kormanik P. Salvage chemotherapy with taxol for recurrent anaplastic astrocytomas[J]. J Neurooncol,1999,43(1):71-78.
[16]Chamberlain MC, Kormanik PA. Salvage chemotherapy with paclitaxel for recurrent oligodendrogliomas[J]. J Clin Oncol,1997,15(12): 3427-3432.
[17]Gannett DE, Hill D, Hamilton AJ, et al. Paclitaxel as a radiosensitizer combined with fractionated stereotactic radiotherapy in the treatment of recurrent medulloblastoma[J]. Am J Clin Oncol,1997,20(3):233-226.
[18]Postma TJ, Heimans JJ, Luykx SA, et al. A phase Ⅱ study of paclitaxel in chemonaive patients with recurrent high-grade glioma[J]. Ann Oncol, 2000, 11(4):409-413.
[19]Glantz MJ, Choy H, Kearns CM, et al. Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors [J]. J Natl Cancer Inst,1995,87(14):1077-1081.
[20]Janes KA, Fresneau MP, Marazuela A, et al. Chitosan nanoparticles as delivery systems for doxorubicin [J]. J Control Release,2001,73(2-3): 255-267.
[21]Mitra S, Gaur U, Ghosh PC, et al. Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier[J]. J Control Release,2001,74(1-3):317-323.
[22]马金阳,黄书岚,何文,等。壳聚糖颅内局部缓释化疗载体的初步研究[J].中国临床神经外科杂志,2005,10(2)：127-128.
[23]常津.具有复合靶向抗癌功能的纳米高分子材料——阿霉素免疫性毫微粒的制备及体外试验[J].中国生物医学工程学报,1996,15：97.
[24]张景劝,张志荣,谭群友.磁靶向给药系统的研究进展[J].中国医药工业杂志,2001,32(12)：564-567.
[25]向艳,杨红.壳聚糖在药物缓释载体中的应用[J].中国生化药物杂志,2005,26(1)：62-64.
[26]Wiegand S, Heinen T, Ramaswamy A, et al. Evaluation of the tolerance and distribution of intravenously applied ferrofluid particles of 250 and 500 nm size in an animal model[J]. J Drug Target,2008,17:1.
[27]Koenig S H, Kellar K E. Theory of proton relaxation in solutions of magnetic nanoparticles,including the superparamagnetic size range [J]. Acad Radiol 1996; 3 (Suppl 2):S273-S276.
[28]林爱华,平其能.壳聚糖载药纳米粒研究进展[J].中国药业,2006,15(21) ： 25-27.
[29]Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature,1979,277:665-667.
[30]Sakamoto J, Annapragada A, Decuzzi P, Ferrari M:Antibiological barrier nanovector technology for cancer applications. Expert Opin Drug Deliv, 2007,4:359-369.
[31]Roiter Y, Ornatska M, Rammohan AR, Balakrishnan J, Heine DR, Minko S. Interaction of lipid membrane with nanostructured surfaces. Langmuir, 2009,25:6287-6299.
[32]McBain SC, Yiu HH, Dobson J. Magnetic nanoparticles for gene and drug delivery. Int J Nanomedicine,2008,3:169-180.
[33]Laquintana V, Trapani A, Denora N, Wang F, Gallo JM, Trapani G:New strategies to deliver anticancer drugs to brain tumors. Expert Opin Drug Deliv,2009,6:1017-1032.
[34]Liang XF, Wang HJ, Luo H, Tian H, Zhang BB, Hao LJ, Teng JI, Chang J: Characterization of novel multifunctional cationic polymeric liposomes formed from octadecyl quaternized carboxymethyl chitosan/cholesterol and drug encapsulation. Langmuir,2008,24:7147-7153.
1. Helson L, Helson C, Malik S, et al. A saturation threshold for taxol cytotoxicity in human glial and neuroblastoma cells[J]. Anticancer Drugs, 1993,4(4):487-490.
2. Liebmann JE, Cook JA, Lipschultz C, et al. Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines[J]. Br J Cancer,1993,68(6):1104-1109.
3. Chamberlain MC, Kormanik P. Salvage chemotherapy with taxol for recurrent anaplastic astrocytomas[J]. J Neurooncol,1999,43(1):71-78.
4. Chamberlain MC, Kormanik PA. Salvage chemotherapy with paclitaxel for recurrent oligodendrogliomas[J]. J Clin Oncol,1997,15(12):3427-3432.
5. Gannett DE, Hill D, Hamilton AJ, et al. Paclitaxel as a radiosensitizer combined with fractionated stereotactic radiotherapy in the treatment of recurrent medulloblastoma[J]. Am J Clin Oncol,1997,20(3):233-226.
6. Postma TJ, Heimans JJ, Luykx SA, et al. A phase II study of paclitaxel in chemonaive patients with recurrent high-grade glioma[J]. Ann Oncol,2000, 11(4):409-413.
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