-
胶质瘤是成人最常见的原发性脑肿瘤之一,占恶性脑肿瘤的70%以上,具有恶性程度高、侵袭性强、治疗效果及预后差等特点,临床主要治疗手段为手术切除、放化疗或两者联合治疗[1]。然而,血脑屏障(BBB)的选择通透性以及肿瘤细胞的多药耐药(MDR)特点给胶质瘤的治疗带来了挑战[2]。
BBB指的是位于中枢神经系统的一种无孔微血管结构,主要由血管内皮细胞以及位于内皮细胞层囊腔表面的壁细胞组成[3]。BBB的主要功能是维护大脑内环境的稳态,严格管控物质进出大脑,保障大脑功能的正常运行。然而,这种保护作用限制了很多药物进入脑内,使得一些治疗脑部疾病的药物难以在病灶部位达到有效药物浓度,成为药物治疗脑部疾病的重要制约因素[3-4]。
冰片属芳香开窍类中药,又名2-茨醇,属于小分子脂溶性双环单萜类物质,其主要有效成分为龙脑。在《中国药典》2020版中,收录的冰片有两种:一种通过人工合成而得,名为冰片,又名合成龙脑;另一种为经樟科植物樟[Cinnamomum cam phora(L.)Presl]的新鲜枝、叶提取加工而得的天然冰片,又名右旋龙脑[5]。现代药理学研究表明冰片具有促进药物透过各种体内外屏障,抗菌、保护心脑血管、镇痛抗炎以及防止血栓等多种药理作用[6-7]。近年来,许多研究表明冰片与抗胶质瘤的化疗药物联合应用,可以明显提高化疗药物的生物利用度和治疗疗效,本文就近年来冰片对胶质瘤化疗的辅助治疗临床前研究作一综述,以期为胶质瘤的临床治疗提供新的思路。
Advances in preclinical studies on borneol as an adjuvant for glioma
-
摘要: 胶质瘤是一种常见的原发性恶性脑肿瘤,目前临床主要治疗手段为手术切除联合放化疗,但由于血脑屏障的选择通透性和肿瘤细胞的多药耐药性特点,使得治疗效果并不理想。近年来,研究发现冰片具有开放血脑屏障以及促进化疗药物渗透的作用,冰片与化疗药物联用或共载,化疗药物能更多地靶向胶质瘤组织,增加疗效。本文就近年来冰片与化疗药物联合应用的临床前研究进行综述,以期为胶质瘤的治疗提供有益参考。Abstract: Glioma is a common primary malignant brain tumor. At present, the main clinical treatment is surgical resection combined with radiotherapy and chemotherapy. Due to the selective permeability of the blood-brain barrier and the characteristics of multi-drug resistance of tumor cells, the therapeutic effect is not ideal. In recent years, studies have found that borneol could open the blood-brain barrier and promote the infiltration of chemotherapy drugs. When borneol is combined with or co-carried with chemotherapy drugs, chemotherapy drugs could target more glioma tissues and increase efficacy. The preclinical studies on the combination of borneol and chemotherapy drugs in recent years were reviewed in this article, in order to provide useful reference for the treatment of glioma.
-
Key words:
- glioma /
- borneol /
- chemotherapy /
- blood-brain barrier
-
[1] OSTROM Q T, CIOFFI G, WAITE K, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018[J]. Neuro Oncol, 2021, 23(12 Suppl 2): iii1-iii105. [2] 汪超甲, 王辉. 脑胶质瘤化疗现状及耐药机制的研究进展[J]. 中国临床神经外科杂志, 2017, 22(11):791-794. doi: 10.13798/j.issn.1009-153X.2017.11.023 [3] ABBOTT N J, PATABENDIGE A A K, DOLMAN D E M, et al. Structure and function of the blood-brain barrier[J]. Neurobiol Dis,2010,37(1):13-25. doi: 10.1016/j.nbd.2009.07.030 [4] 董小平, 喻斌, 金路, 等. 血脑屏障细胞组成研究进展[J]. 中国实验方剂学杂志, 2012, 18(8):281-284. doi: 10.3969/j.issn.1005-9903.2012.08.083 [5] 国家药典委员会. 中华人民共和国药典2020版第一部[S]. 北京: 中国医药科技出版社, 2020: 52, 61. [6] LI J X, XIE Q, MA R, et al. Recent progress on the synergistic antitumor effect of a borneol-modified nanocarrier drug delivery system[J]. Front Med (Lausanne), 2021, 8: 750170. [7] 高雅, 李友明, 罗燕, 等. 右旋龙脑的药理作用研究进展[J]. 现代药物与临床, 2021, 36(7):1537-1540. [8] 段美美, 曾武, 陈浩, 等. 天然冰片对顺铂在C6脑胶质瘤模型大鼠体内的药动学及脑组织分布的影响[J]. 中药药理与临床, 2013, 29(5):24-27. doi: 10.13412/j.cnki.zyyl.2013.05.009 [9] 郭军洽, 张荣, 段美美, 等. 天然冰片对甲氨蝶呤透过血肿瘤屏障的影响[J]. 中药新药与临床药理, 2015, 26(1):73-77. doi: 10.3969/j.issn.1003-9783.2015.01.018 [10] 崔爱玲, 王巍东, 赵松鹤, 等. 瘤内注射吉西他滨治疗大鼠脑胶质瘤的效果观察[J]. 肿瘤研究与临床, 2013, 25(12):796-798. doi: 10.3760/cma.j.issn.1006-9801.2013.12.002 [11] 张帆, 房绍英, 印晓星. 冰片对吉西他滨在脑胶质瘤模型大鼠体内药动学的影响[J]. 徐州医科大学学报, 2021, 41(5):324-327. doi: 10.3969/j.issn.2096-3882.2021.05.003 [12] 范成普, 陈才红, 杜杭根, 等. 冰片对替莫唑胺抗大鼠脑胶质瘤促进作用的研究[J]. 浙江医学, 2019, 41(18):1956-1958,1963,1913. doi: 10.12056/j.issn.1006-2785.2019.41.18.2019-1186 [13] HU Q Y, GAO X L, KANG T, et al. CGKRK-modified nanoparticles for dual-targeting drug delivery to tumor cells and angiogenic blood vessels[J]. Biomaterials,2013,34(37):9496-9508. doi: 10.1016/j.biomaterials.2013.09.001 [14] LV L Y, LI X R, QIAN W, et al. Enhanced anti-glioma efficacy by borneol combined with CGKRK-modified paclitaxel self-assembled redox-sensitive nanoparticles[J]. Front Pharmacol,2020,11:558. doi: 10.3389/fphar.2020.00558 [15] REDDY S, TATIPARTI K, SAU S, et al. Recent advances in nano delivery systems for blood-brain barrier (BBB) penetration and targeting of brain tumors[J]. Drug Discov Today,2021,26(8):1944-1952. doi: 10.1016/j.drudis.2021.04.008 [16] MENG L W, CHU X Y, XING H Y, et al. Improving glioblastoma therapeutic outcomes via doxorubicin-loaded nanomicelles modified with borneol[J]. Int J Pharm, 2019, 567: 118485. [17] LU Y, CHEN X L, DU S Y, et al. The in situ and in vivo study on enhancing effect of borneol in nasal absorption of Geniposide in rats[J]. Arch Pharm Res,2010,33(5):691-696. doi: 10.1007/s12272-010-0507-8 [18] 赵霄, 余双文, 杜俊锋, 等. 冰片/RGD双修饰多烯紫杉醇纳米粒经鼻给药抗脑胶质瘤作用研究[J]. 药学学报, 2021, 56(12):3233-3242. doi: 10.16438/j.0513-4870.2021-1193 [19] SRINIVAS U S, TAN B W Q, VELLAYAPPAN B A, et al. ROS and the DNA damage response in cancer[J]. Redox Biol, 2019, 25: 101084. [20] PRASAD S, GUPTA S C, TYAGI A K. Reactive oxygen species (ROS) and cancer: role of antioxidative nutraceuticals[J]. Cancer Lett,2017,387:95-105. doi: 10.1016/j.canlet.2016.03.042 [21] 李文明, 吴琦, 朱彧. 异硫氰酸苄酯对脑胶质瘤U-87 MG细胞活性氧的诱导作用及其机制研究[J]. 中国现代应用药学, 2014, 31(8):938-942. [22] 邹林樾, 徐晓雪, 户乃丽. 雷公藤甲素对脑胶质瘤细胞凋亡的影响及机制探讨[J]. 继续医学教育, 2018, 32(9):145-147. doi: 10.3969/j.issn.1004-6763.2018.09.080 [23] 蔡紫微, 蒋佩文, 张丹莹, 等. 活性氧介导重楼皂苷诱导脑胶质瘤细胞凋亡的研究[J]. 成都医学院学报, 2021, 16(4):419-423. [24] CAO W Q, ZHAI X Q, MA J W, et al. Natural borneol sensitizes human glioma cells to cisplatin-induced apoptosis by triggering ROS-mediated oxidative damage and regulation of MAPKs and PI3K/AKT pathway[J]. Pharm Biol,2020,58(1):72-79. doi: 10.1080/13880209.2019.1703756 [25] 郭源源, 王鹏云. 冰片联合紫杉醇对脑胶质瘤细胞的化疗增效作用[J]. 亚太传统医药, 2018, 14(9):9-11. [26] LIU W J, YIN Y B, SUN J Y, et al. Natural borneol is a novel chemosensitizer that enhances temozolomide-induced anticancer efficiency against human glioma by triggering mitochondrial dysfunction and reactive oxide species-mediated oxidative damage[J]. Onco Targets Ther,2018,11:5429-5439. doi: 10.2147/OTT.S174498 [27] HASELOFF R F, DITHMER S, WINKLER L, et al. Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects[J]. Semin Cell Dev Biol,2015,38:16-25. doi: 10.1016/j.semcdb.2014.11.004 [28] 陈艳明, 王宁生. 冰片对血脑屏障体外模型细胞间紧密连接和细胞吞饮囊泡的影响[J]. 中国中西医结合杂志, 2004, 24(7):632-634. doi: 10.3321/j.issn:1003-5370.2004.07.014 [29] DUAN M M, XING Y M, GUO J Q, et al. Borneol increases blood-tumour barrier permeability by regulating the expression levels of tight junction-associated proteins[J]. Pharm Biol,2016,54(12):3009-3018. doi: 10.1080/13880209.2016.1199044 [30] MILLER D S, BAUER B, HARTZ A M S. Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy[J]. Pharmacol Rev,2008,60(2):196-209. doi: 10.1124/pr.107.07109 [31] PATHAN N, SHENDE P. Tailoring of P-glycoprotein for effective transportation of actives across blood-brain-barrier[J]. J Control Release,2021,335:398-407. doi: 10.1016/j.jconrel.2021.05.046 [32] 朱国栋. 冰片开放血脑屏障及通过P糖蛋白介导的机制研究[D]. 广州: 广州医学院, 2009. [33] WANG L J, SUN Y. Efflux mechanism and pathway of verapamil pumping by human P-glycoprotein[J]. Arch Biochem Biophys, 2020, 696: 108675. [34] 陈艳明, 王宁生. 冰片对P-糖蛋白的影响[J]. 中药新药与临床药理, 2003, 14(2):96-99. doi: 10.19378/j.issn.1003-9783.2003.02.011 [35] TANG B, FANG G H, GAO Y, et al. Lipid-albumin nanoassem-blies co-loaded with borneol and paclitaxel for intracellular drug delivery to C6 glioma cells with P-gp inhibition and its tumor targeting[J]. Asian J Pharm Sci,2015,10(5):363-371. doi: 10.1016/j.ajps.2015.04.004 [36] WANG S X, TAN N, MA C C, et al. Inhibitory effects of benzaldehyde, vanillin, muscone and borneol on P-glycoprotein in caco-2 cells and everted gut sac[J]. Pharmacology,2018,101(5-6):269-277. doi: 10.1159/000487144 [37] YU B, RUAN M, DONG X P, et al. The mechanism of the opening of the blood-brain barrier by borneol: a pharmacodynamics and pharmacokinetics combination study[J]. J Ethnopharmacol,2013,150(3):1096-1108. doi: 10.1016/j.jep.2013.10.028 [38] GABRIELY G, WHEELER M A, TAKENAKA M C, et al. Role of AHR and HIF-1α in glioblastoma metabolism[J]. Trends Endocrinol Metab,2017,28(6):428-436. doi: 10.1016/j.tem.2017.02.009 [39] WANG Z, LI Q L, XIA L, et al. Borneol promotes apoptosis of Human Glioma Cells through regulating HIF-1a expression via mTORC1/eIF4E pathway[J]. J Cancer,2020,11(16):4810-4822. doi: 10.7150/jca.45304
计量
- 文章访问数: 4616
- HTML全文浏览量: 1176
- PDF下载量: 20
- 被引次数: 0