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不同聚乙二醇（PEG）修饰的多肽HM-3的体内抗肿瘤活性

In vivo anti-tumor activity of polypeptide HM-3 modified by different polyethylene glycols (PEG).

作者信息

Liu Zhendong, Ren Yinling, Pan Li, Xu Han-Mei

机构信息

Department of Marine Pharmacy, College of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China; E-Mails:

出版信息

Int J Mol Sci. 2011;12(4):2650-63. doi: 10.3390/ijms12042650. Epub 2011 Apr 19.

DOI:10.3390/ijms12042650
PMID:21731464
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3127140/
Abstract

HM-3, designed by our laboratory, is a polypeptide composed of 18 amino acids. Pharmacodynamic studies in vivo and in vitro indicated that HM-3 could inhibit endothelial cell migration and angiogenesis, thereby inhibiting tumor growth. However, the half-life of HM-3 is short. In this study, we modified HM-3 with different polyethylene glycols (PEG) in order to reduce the plasma clearance rate, extend the half-life in the body, maintain a high concentration of HM-3 in the blood and increase the therapeutic efficiency. HM-3 was modified with four different types of PEG with different molecular weights (ALD-mPEG(5k), ALD-mPEG(10k), SC-mPEG(10k) and SC-mPEG(20k)), resulting in four modified products (ALD-mPEG(5k)-HM-3, ALD-mPEG(10k)-HM-3, SC-mPEG(10k)-HM-3 and SC-mPEG(20k)-HM-3, respectively). Anti-tumor activity of these four modified HM-3 was determined in BALB/c mice with Taxol as a positive control and normal saline as a negative control. Tumor weight inhibition rates of mice treated with Taxol, HM-3, ALD-mPEG(5k)-HM-3, ALD-mPEG(10k)-HM-3, SC-mPEG(10k)-HM-3 and SC-mPEG(20k)-HM-3 were 44.50%, 43.92%, 37.95%, 31.64%, 20.27% and 50.23%, respectively. Tumor inhibition rates in the Taxol, HM-3 and SC-mPEG(20k)-HM-3 groups were significantly higher than that in the negative control group. The efficiency of tumor inhibition in the SC-mPEG(20k)-HM-3 group (drug treatment frequency: once per two days) was better than that in the HM-3 group (drug treatment frequency: twice per day). In addition, tumor inhibition rate in the SC-mPEG(20k)-HM-3 group was higher than that in the taxol group. We conclude that SC-mPEG(20k)-HM-3 had a low plasma clearance rate and long half-life, resulting in high anti-tumor therapeutic efficacy in vivo. Therefore, SC-mPEG(20k)-HM-3 could be potentially developed as new anti-tumor drugs.

摘要

HM-3由本实验室设计，是一种由18个氨基酸组成的多肽。体内和体外药效学研究表明，HM-3可抑制内皮细胞迁移和血管生成，从而抑制肿瘤生长。然而，HM-3的半衰期较短。在本研究中，我们用不同的聚乙二醇（PEG）修饰HM-3，以降低血浆清除率，延长体内半衰期，维持血液中HM-3的高浓度并提高治疗效果。用四种不同分子量的PEG（ALD-mPEG(5k)、ALD-mPEG(10k)、SC-mPEG(10k)和SC-mPEG(20k)）修饰HM-3，得到四种修饰产物（分别为ALD-mPEG(5k)-HM-3、ALD-mPEG(10k)-HM-3、SC-mPEG(10k)-HM-3和SC-mPEG(20k)-HM-3）。以紫杉醇为阳性对照、生理盐水为阴性对照，在BALB/c小鼠中测定这四种修饰HM-3的抗肿瘤活性。用紫杉醇、HM-3、ALD-mPEG(5k)-HM-3、ALD-mPEG(10k)-HM-3、SC-mPEG(10k)-HM-3和SC-mPEG(20k)-HM-3处理的小鼠的肿瘤重量抑制率分别为44.50%、43.92%、37.95%、31.64%、20.27%和50.23%。紫杉醇、HM-3和SC-mPEG(20k)-HM-3组的肿瘤抑制率显著高于阴性对照组。SC-mPEG(20k)-HM-3组（给药频率：每两天一次）的肿瘤抑制效果优于HM-3组（给药频率：每天两次）。此外，SC-mPEG(20k)-HM-3组的肿瘤抑制率高于紫杉醇组。我们得出结论，SC-mPEG(20k)-HM-3具有低血浆清除率和长半衰期，在体内具有高抗肿瘤治疗效果。因此，SC-mPEG(20k)-HM-3有可能被开发为新型抗肿瘤药物。

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