Abstract
HM-3, An RGD (Arg-Gly-Asp)-modified polypeptide derived from endostatin, is a potent angiogenesis inhibitor. Its robust inhibitory effects on endothelial cell migration and tumor growth have been demonstrated by activity assay both in vitro and in vivo. However, HM-3 has relatively short half-life in vivo. In order to prolong its half-life and retain its safety and efficacy, previous studies modified HM-3 with four types of PEG (site-specific N-terminal modification), and the results showed that mPEG-SC20k-HM-3 was the most ideal modification product via activity evaluation in vivo. In the present study, we determined the pharmacokinetic properties, immunogenicity and binding targets of mPEG-SC20k-HM-3. The results showed that mPEG-SC20k-HM-3 had good linear pharmacokinetic properties in SD rats. The half-life of mPEG-SC20k-HM-3 was 43.76-fold longer than that of unmodified HM-3 after intravenous injection in SD rats. The administration frequency of the modified product (mPEG-SC20k-HM-3) was reduced from twice a day to once every 2 days, while the safety and efficacy were retained. The immunogenicity of mPEG-SC20k-HM-3 was significantly lower than that of HM-3 in BALB/c mice. Histochemical and immunohistochemical results showed that mPEG-SC20k-HM-3 could significantly inhibit angiogenesis and tumor growth, induce continuous necrosis, and reduce vessel density within tumor tissues. Furthermore, mPEG-SC20k-HM-3 could bind multi-target αvβ3 and α5β1 of integrin, and the major binding target was integrin αvβ3. All of these results indicated that PEGylated HM-3 had a good application prospect.
Keywords: PEGylation, anti-tumor, integrin, polypeptide, pharmacokinetics, immunogenicity, targets, mechanism, endostatin, angiogenesis inhibitor
Current Pharmaceutical Design
Title:In Vivo Pharmacokinetics, Immunogenicity and Mechanism of PEGylated Antitumor Polypeptide
Volume: 18 Issue: 12
Author(s): Zhendong Liu, Weiguang Li, Han-Mei Xu, Xiaofeng Huang, Li Pan, Yinling Ren, Yongjing Yang, Yongbing Li, Chunyan Pu and Chi Zhang
Affiliation:
Keywords: PEGylation, anti-tumor, integrin, polypeptide, pharmacokinetics, immunogenicity, targets, mechanism, endostatin, angiogenesis inhibitor
Abstract: HM-3, An RGD (Arg-Gly-Asp)-modified polypeptide derived from endostatin, is a potent angiogenesis inhibitor. Its robust inhibitory effects on endothelial cell migration and tumor growth have been demonstrated by activity assay both in vitro and in vivo. However, HM-3 has relatively short half-life in vivo. In order to prolong its half-life and retain its safety and efficacy, previous studies modified HM-3 with four types of PEG (site-specific N-terminal modification), and the results showed that mPEG-SC20k-HM-3 was the most ideal modification product via activity evaluation in vivo. In the present study, we determined the pharmacokinetic properties, immunogenicity and binding targets of mPEG-SC20k-HM-3. The results showed that mPEG-SC20k-HM-3 had good linear pharmacokinetic properties in SD rats. The half-life of mPEG-SC20k-HM-3 was 43.76-fold longer than that of unmodified HM-3 after intravenous injection in SD rats. The administration frequency of the modified product (mPEG-SC20k-HM-3) was reduced from twice a day to once every 2 days, while the safety and efficacy were retained. The immunogenicity of mPEG-SC20k-HM-3 was significantly lower than that of HM-3 in BALB/c mice. Histochemical and immunohistochemical results showed that mPEG-SC20k-HM-3 could significantly inhibit angiogenesis and tumor growth, induce continuous necrosis, and reduce vessel density within tumor tissues. Furthermore, mPEG-SC20k-HM-3 could bind multi-target αvβ3 and α5β1 of integrin, and the major binding target was integrin αvβ3. All of these results indicated that PEGylated HM-3 had a good application prospect.
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Cite this article as:
Liu Zhendong, Li Weiguang, Xu Han-Mei , Huang Xiaofeng , Pan Li, Ren Yinling, Yang Yongjing, Li Yongbing, Pu Chunyan and Zhang Chi, In Vivo Pharmacokinetics, Immunogenicity and Mechanism of PEGylated Antitumor Polypeptide , Current Pharmaceutical Design 2012; 18 (12) . https://dx.doi.org/10.2174/138161212799958620
DOI https://dx.doi.org/10.2174/138161212799958620 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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