Pharmacokinetics of PEGylated recombinant human endostatin (M2ES) in rats

Zuo-gang, LI; Jia, Lin; Guo, Lei; Yu, Min; Sun, Xu Guo; Nie, Wen; Fu, Yan; Chun-ming, Rao; Wang, Junzhi; Luo, Yongzhang

doi:10.1038/aps.2015.16

Cited by 11 publications

(12 citation statements)

References 28 publications

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“…We next screened the EOMA‐secreted pro‐angiogenic factor(s) that is specifically disrupted by thalidomide. As reported , EOMA secretes angiogenesis factors including ADAMTS1, angiogenin, Cyr61, endostatin, endothelin‐1, HB‐EGF, CXCL1, PDGF‐AA, PDGF‐AB, PlGF‐2, SDF‐1, Serpin E1, and TIMP‐1. We therefore examine whether thalidomide can repress the transcription of the aforementioned factors by qRT‐PCR.…”

Section: Resultsmentioning

confidence: 63%

“…To examine whether thalidomide can also inhibit hemangioendothelioma, we first performed in vivo study by utilizing mouse EOMA, which exhibits endothelial cell properties. EOMA cells were subcutaneously injected into in nude mice and formed tumors after 7 days as reported [17,18]. As shown in Figure 1a-c, hemangioendothelioma growth was inhibited by thalidomide administration.…”

Section: R E S U L T Smentioning

confidence: 72%

“…Contrary to our assumption, thalidomide treatment showed marginally effect on the proliferation of EOMA cells in vitro (Figure 1h). Endostatin and angiostatin, endogenous antiangiogenic factors that are derived from the cleavage of collagens and plasminogen, respectively, also had little effect on the proliferation EOMA cells [17,18]. These findings may indicate that mutations in EOMA cells significantly alter patterns of cell mitosis, thereby increasing the risk of malignancy.…”

Section: Discussionmentioning

confidence: 99%

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Blockade of angiogenin by thalidomide inhibits the tumorigenesis of murine hemangioendothelioma

Guo

Wan

et al. 2019

Fundamemntal Clinical Pharma

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Thalidomide, a well‐known immunomodulatory compound, has an anti‐angiogenic activity, which may be utilized for the treatment of angiogenesis‐related diseases such as hemangioendothelioma. The aim of the present study was to investigate both the antitumor role of thalidomide on hemangioendothelioma and the underlying mechanism. By using the xenograft mouse model, we found that thalidomide can inhibit the progression of hemangioendothelioma in vivo. Moreover, thalidomide shows no effect on the proliferation of hemangioendothelioma endothelial cell (EOMA), but significantly impairs the pro‐angiogenic capacity of the EOMA cells in vitro. By qRT‐PCR screening, we observed that the expression of angiogenin was downregulated by thalidomide treatment. We next performed tissue array analysis and found a positive correlation between angiogenin expression level and hemangioendothelioma occurrence in patients. Moreover, we confirmed that the antitumoral role of thalidomide is dependent on angiogenin expression both in vivo and in vitro. Taken together, we concluded that thalidomide can inhibit the progression of hemangioendothelioma by downregulating the expression of pro‐angiogenic factor angiogenin and therefore can be used as a potent therapeutic to treat hemangioendothelioma.

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Section: Resultsmentioning

confidence: 63%

Section: R E S U L T Smentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Blockade of angiogenin by thalidomide inhibits the tumorigenesis of murine hemangioendothelioma

Guo

Wan

et al. 2019

Fundamemntal Clinical Pharma

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“…Since the intrinsic labeling does not alter the structure of the molecule and possesses fast identical physicochemical property to analytes, it can represent the pharmacokinetic behavior of the analytes precisely. Radiolabeling is commonly used in the studies of the in vivo absorption, distribution, metabolism, and excretion (ADME) processes of PEG [62,78,79], PEGylated small molecules [80], PEGylated peptides [81–83], PEGylated proteins [84–86], and PEGylated nanoparticles [10,87–93], which will be discussed in the following parts respectively.…”

Section: Bioanalytical Methods For Polyethylene Glycols and Pegylatedmentioning

confidence: 99%

Recent advances in the bioanalytical methods of polyethylene glycols and PEGylated pharmaceuticals

Zhang

Song

et al. 2020

J of Separation Science

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Polyethylene glycols are synthetic polymers composed of repeating oxyethylene subunits, which have been known for non-toxic, non-immunogenic, non-antigenic, good solubility in water and therefore approved for pharmaceutical applications. Recently, attachment or amalgamation of polyethylene glycols to therapeutic small molecules, peptides, proteins, or nanoparticles has become a mature technology for the sake of improving their pharmacokinetic and pharmacological profiles, also referred to as PEGylation. By comparison, there are only a few PEGylated pharmaceuticals have been registered for further clinical trials and even less was approved for marketing. High failure rate of PEGylated pharmaceuticals in pre-clinical and clinical trials could be majorly attributed to their unclear pharmacokinetic behaviors. Therefore, the in vivo fate of the PEGylated pharmaceuticals for the various routes of administration needs to be thoroughly investigated An accurate in vivo pharmacological study thereof highly depends on the precise detection of polyethylene glycols as well as their fragments in biological matrixes. The goal of this review is to highlight the analytical methods that were developed and applied to evaluate the polyethylene glycols in pharmaceutical ingredients and excipients, which bring us closer to bridging

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“…To prolong the circulating half‐life of endostatin and reduce its dosing frequency, PEG was applied to produce an N‐terminal mono‐PEGylated recombinant human endostatin . Li et al reported that PEG modification substantially prolongs the circulation time of MES; the half‐life of MES (3 mg/kg) and M 2 ES (3 mg/kg) were 3.9 and 60.1 hours, respectively. In addition, M 2 ES can significantly reduce dosing frequency compared with other similar products in the market .…”

Section: Introductionmentioning

confidence: 99%

Biophysical and biological characterization of PEGylated recombinant human endostatin

Guo

Zhou

et al. 2019

Clin Exp Pharma Physio

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Endostatin, a 20 kDa C-terminal fragment digested from collagen XVIII, is an endogenous angiogenesis inhibitor, which inhibits the migration and proliferation of endothelial cells, and potently suppresses tumour growth without inducing toxicity and acquired drug resistance. [1][2][3] Our studies proved that endostatin inhibits angiogenesis, lymphangiogenesis, and tumour progression, and also demonstrated that the molecular mechanism of endostatin is dependent on the internalization through the cell surface receptor nucleolin and integrins. [4][5][6] Thus, endostatin appears to be an ideal candidate for tumour therapy; then, the anti-tumour activity of endostatin was assessed in preclinical and clinical trials. However, there are some obstacles for getting endostatin with high quality and activity, which affects the application of endostatin for extensive clinical evaluation. 7 ZBPendostatin, an N-terminal modified recombinant human endostatin, was approved by the State Food and Drug Administration of China in 2005 for the treatment of non-small cell lung cancer. 8 Our studies Abstract Recombinant human endostatin (MES), showing potent inhibition on angiogenesis and tumour growth, has great potential as a therapeutic agent for tumours. The aim of this study was to evaluate the biophysical and biological characterization of PEGylated recombinant human endostatin (M 2 ES). Recombinant human endostatin was mono-PEGylated by conjugation with methoxy polyethylene glycol aldehyde (mPEG-ALD), and the modification site was identified by digested peptide mapping and matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS). The purity was assessed by SDS-PAGE, high-performance liquid chromatography (HPLC), and capillary zone electrophoresis. The physicochemical property was analyzed through fluorescence spectroscopy, and circular dichroism. The bioactivity and anti-tumour efficacy of M 2 ES were evaluated using an in vitro endothelial cell migration model and a null-mouse xenograft model of a prostatic cancer, respectively. M 2 ES molecules contain a single 20 kDa mPEG-ALD molecule conjugated at the N-terminal portion of MES. The purity of M 2 ES was greater than 98%. The physicochemical analysis demonstrated that PEGylation does not change the secondary and tertiary structure of MES. Notably, M 2 ES retards endothelial cell migration and tumour growth when compared to control group. These biophysical and biological characterization study data contribute to the initiation of the ongoing clinical study. K E Y W O R D S M 2 ES, PEGylation, recombinant human endostatin Capillary zone electrophoresis (CZE) was performed on a P/ ACE 5000 instrument (Beckman). Samples were injected using nitrogen pressure and peaks were detected on-column with a UV detector operating at 214 nm. Data were analyzed using the P/ACE Gold data analysis software. CZE electropherogram obtained on a fused-silica capillary at 15 kV, 20°C, 10 seconds pressure injection with detection at 214 nm. The electrophoretic buffer ...

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Pharmacokinetics of PEGylated recombinant human endostatin (M2ES) in rats

Cited by 11 publications

References 28 publications

Blockade of angiogenin by thalidomide inhibits the tumorigenesis of murine hemangioendothelioma

Blockade of angiogenin by thalidomide inhibits the tumorigenesis of murine hemangioendothelioma

Recent advances in the bioanalytical methods of polyethylene glycols and PEGylated pharmaceuticals

Biophysical and biological characterization of PEGylated recombinant human endostatin

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