抗HER2/neu受体拟肽修饰的紫杉醇白蛋白纳米粒的血液毒性和病理学毒性研究

doi:10.5246/jcps.2013.05.065

摘要/Abstract

摘要：

纳米制剂具备高载药量、靶向性积聚以及表面修饰性质, 被广泛应用于临床诊断和治疗, 但是相关的毒性研究很少。为了研究白蛋白纳米制剂静脉注射后对正常组织的毒性, 我们先通过高压均质法制备稳定、均一的紫杉醇白蛋白纳米粒, 通过共价键将靶向肿瘤细胞HER2/neu受体的拟肽AHNP结合于纳米粒表面得到靶向修饰的纳米粒, 并考察其理化性质。建立HER2受体过表达的荷瘤裸小鼠模型, 静脉注射纳米制剂和紫杉醇传统注射液后取血进行血常规比较分析, 发现紫杉醇白蛋白纳米粒和AHNP靶向修饰的紫杉醇白蛋白纳米粒均避免了传统注射液引起的粒细胞减少症和贫血作用。对动物肿瘤和重要组织进行病理切片、H&E染色分析, 发现AHNP靶向修饰显著提高紫杉醇白蛋白纳米粒的抗肿瘤效果。紫杉醇白蛋白纳米粒和紫杉醇溶液均引起严重的肝损伤, AHNP靶向修饰能显著降低纳米粒对于肝脏的损伤, 但可能增加个别动物的肺部损伤。

关键词: 白蛋白纳米粒, 抗HER2/neu受体拟肽, 靶向输送系统, 毒性, 紫杉醇

Abstract:

Nanoparticles have been widely applied in diagnosis and therapy due to the high loading of insoluble drug, increased target accumulation and interaction with biological tissues. Recently, severe side effects of nanoparticles have been reported, but the underlying mechanism remains largely unknown. In our study, we aim to understand the safety of paclitaxel (PTX) loaded bovine albumin nanoparticles (BNPs) and active targeted PTX loaded BNPs to normal vital organ or tissue in vivo. The anti-human epidermal growth factor receptor 2 (HER2/neu) peptide mimetic (AHNP) was covalent bound to surface of BNPs (AHNP-BNPs) to exert selected delivery to HER2⁺ cells. In HER2⁺ tumor xenographs, saline (control), PTX traditional formula (medium of Cremophor EL-ethanol), BNPs, and AHNP-BNPs were administrated to evaluate the toxicity. There is no severe neutropenia or anemia with treatment of BNPs and AHNP-BNPs compared with traditional PTX injection. We also evaluated their damage on normal organs, including liver, kidney, spleen, lung and heart to fully estimate the safety of AHNP-BNPs and BNPs delivery systems. We observed similar toxicity in liver and lung in mice treated with BNPs or PTX injection, but decreased liver damage in mice treated with AHNP-BNPs. Further studies are required to confirm our conclusion.

Key words: Albumin nanoparticle, Anti-HER2/neu peptide mimetic, Target delivery, Toxicity, Paclitaxel

中图分类号:

R994

Supporting: Foundation items: the National Natural Science Foundation of China (Grant No. 30970785, 81273454), Beijing Natural Science Foundation (Grant No. 7132113), National Basic Research Program (Grant No. 2009CB930303, 2013CB932501), Doctoral Foundation of the Ministry of Education (Grant No. 20100001110056), and Innovation Team of Ministry of Education (Grant No. BMU20110263).
^*Corresponding author. Tel.: 86-10-82801584; Fax: 86-10-82801584

王占璋, 仰浈臻, 齐宪荣^*. 抗HER2/neu受体拟肽修饰的紫杉醇白蛋白纳米粒的血液毒性和病理学毒性研究[J]. , DOI: 10.5246/jcps.2013.05.065.

Zhanzhang Wang, Zhenzhen Yang, Xianrong Qi^*. Hematological and pathological toxicity of anti-HER2/neu peptide mimetic modified paclitaxel bovine serum albumin nanoparticles[J]. , DOI: 10.5246/jcps.2013.05.065.

参考文献

[1] Crosasso, P.; Ceruti, M.; Brusa, P.; Arpicco, S.; Dosio, F.; Cattel, L. J. Control. Release. 2000, 63, 19-30.
[2] Li, C.; Milas, L.; Hunter, N.R.; Ke, S.; Yu, D.F.; Charnsangavej, C.; Wallace, S. Clin. Cancer Res. 1999, 5, 891-897.
[3] Sparreboom, A.; Scripture, C.D.; Trieu, V.; Williams, P.J.; De, T.; Yang, A.; Beals, B.; Figg, W.D.; Hawkins, M.; Desai, N. Clin. Cancer Res. 2005, 11, 4136-4143.
[4] Kim, T.Y.; Kim, D.W.; Chung, J.Y.; Shin, S.G.; Kim, S.C.; Heo, D.S.; Kim, N.K.; Bang, Y.J. Clin. Cancer Res. 2004, 10, 3708-3716.
[5] Zheng, H.; Hou, W.J.; Wang, J.C.; Zhang, Q. J. Chin. Pharm. Sci. 2012, 21, 591-597.
[6] Madaan, A.; Singh, P.; Awasthi, A.; Verma, R.; Singh, A.T.; Jaggi, M.; Mishra, S.K.; Kulkarni, S.; Kulkarni, H. Clin. Transl. Oncol. 2013, 15, 26-32.
[7] Hoffman, A.S. J. Control. Release. 2008, 132, 153-163.
[8] Azarmi, S.; Roa, W.H.; Löbenberg, R. Adv. Drug Deliv. Rev. 2008, 60, 863-875.
[9] Owens, D.E.; Peppas, N.A. Int. J. Pharm. 2006, 307, 93-102.
[10] Aqil, F.; Munagala, R.; Jeyabalan, J.; Vadhanam, M.V. Cancer Lett. 2013, 334, 133-141.
[11] Desai, N.P.; Louie, L.; Soon-Shiong, P.; Tao, C.L.; Yang, A. U.S. Pat. 8137684, 2006; A61K31/337.
[12] Park, B.W.; Zhang, H.T.; Wu, C.; Berezov, A.; Zhang, X.; Dua, R.; Wang, Q.; Kao, G.; O' Rourke, D.M.; Greene, M.I.; Murali, R. Nat. Biotechnol. 2000, 18, 194-198.
[13] Weber, C.; Coester, C.; Kreuter, J.; Langer, K. Int. J. Pharm. 2000, 194, 91-102.
[14] Langer, K.; Balthasar, S.; Vogel, V.; Dinauer, N.; von Briesen, H.; Schubert, D. Int. J. Pharm. 2003, 257, 169-180.
[15] Orsi, I.A.; Andrade, V.G.; Bonato, P.S.; Raimundo, L.B.; Herzog, D.S.; Borie, E. Braz. Dent. J. 2011, 22, 490-496.
[16] Guillemard, V.; Nedev, H.N.; Berezov, A.; Murali, R.; Saragovi, H.U. DNA Cell Biol. 2005, 24, 351-358.
[17] Dunphy, F.R.; Dunleavy, T.L.; Harrison, B.R.; Boyd, J.H.; Varvares, M.A.; Dunphy, C.H.; Rodriguez, J.J.; McDonough, E.M.; Minster, J.R.; McGrady, M.D. Cancer. 1997, 79, 1623-1628.
[18] Fetterly, G.J.; Tamburlin, J.M.; Straubinger, R.M. Biopharm. Drug Dispos. 2001, 22, 251-261.
[19] Groopman, J.E.; Itri, L.M. J. Natl. Cancer Inst. Monographs. 1999, 91, 1616-1634.
[20] Arunachalam, B.; Phan, U.T.; Geuze, H.J.; Cresswell, P. Proc. Natl. Acad. Sci. USA. 2000, 97, 745-750.
[21] Desai, N.; Trieu, V.; Yao, Z.; Louie, L.; Ci, S.; Yang, A.; Tao, C.; De, T.; Beals, B.; Dykes, D.; Noker, P.; Yao, R.; Labao, E.; Hawkins, M.; Soon-Shiong, P. Clin. Cancer Res. 2006, 12, 1317-1324.
[22] Marceau, P.; Biron, S.; Hould, F.S.; Marceau, S.; Simard, S.; Thung, S.N.; Kral, J.G. J. Clin. Endocrinol. Metab. 1999, 84, 1513-1517.
[23] Gwinn, M.R.; Vallyathan, V. Environ. Health Perspect. 2006, 114, 1818-1825.
[24] Pourmand, A.; Abdollahi, M. Daru. 2012, 20, 95.
[25] Mostafalou, S.; Mohammadi, H.; Ramazani, A.; Abdollahi, M. Daru. 2013, 21, 1-4.
[26] Hagens, W.I.; Oomen, A.G.; de Jong, W.H.; Cassee, F.R.; Sips, A.J. Regul. Toxicol. Pharmacol. 2007, 49, 217-229.