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Li Z.-G.,Chinas National Center for Safety Evaluation of Drugs | Jia L.,National Engineering Laboratory for Anti Tumor Protein Therapeutics | Jia L.,Beijing Key Laboratory for Protein Therapeutics | Jia L.,Tsinghua University | And 13 more authors.
Acta Pharmacologica Sinica | Year: 2015

Aim:M2ES is PEGylated recombinant human endostatin. In this study we investigated the pharmacokinetics, tissue distribution, and excretion of M2ES in rats.Methods: 125I-radiolabeled M2ES was administered to rats by intravenous bolus injection at 3 mg/kg. The pharmacokinetics, tissue distribution and excretion of M2ES were investigated using the trichloroacetic acid (TCA) precipitation method. Results:The serum M2ES concentration-time curve after a single intravenous dose of 3 mg/kg in rats was fitted with a non-compartment model. The pharmacokinetic parameters were evaluated as follows: Cmax =28.3 μg·equ/mL, t1/2 =71.5 h, AUC(0-∞) =174.6 μg·equ·h/mL, Cl=17.2 mL·h-1 ·kg-1, MRT=57.6 h, and Vss =989.8 mL/kg for the total radioactivity; Cmax =30.3 μg·equ/mL, t 1/2 =60.1 h, AUC(0-∞) =146.2 μg·equ·h/mL, Cl=20.6 mL·h-1 ·kg-1, MRT=47.4 h, and Vss =974.6 mL/kg for the TCA precipitate radioactivity. M2ES was rapidly and widely distributed in various tissues and showed substantial deposition in kidney, adrenal gland, lung, spleen, bladder and liver. The radioactivity recovered in the urine and feces by 432 h post-dose was 71.3% and 8.3%, respectively. Only 0.98% of radioactivity was excreted in the bile by 24 h post-dose. Conclusion: PEG modification substantially prolongs the circulation time of recombinant human endostatin and effectively improves its pharmacokinetic behavior. M2ES is extensively distributed in most tissues of rats, including kidney, adrenal gland, lung, spleen, bladder and liver. Urinary excretion was the major elimination route for M2ES. © 2015 CPS and SIMM. Source

Zhuo W.,National Engineering Laboratory for Anti Tumor Protein Therapeutics | Zhuo W.,Beijing Key Laboratory for Protein Therapeutics | Zhuo W.,Tsinghua University | Chen Y.,National Engineering Laboratory for Anti Tumor Protein Therapeutics | And 8 more authors.
Frontiers of Medicine in China | Year: 2011

Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, was first identified as a potent angiogenic inhibitor. The anti-angiogenic function of endostatin has been well documented during the past decade. Recently, several studies demonstrated that endostatin also inhibits tumor lymphangiogenesis and lymphatic metastasis. However, the exact mechanism that endostatin executes its anti-angiogenic and anti-lymphangiogenic functions remains elusive. In the current mini-review, we briefly summarize recent novel findings, including the functions of endostatin targeting not only angiogenesis but also lymphangiogenesis, and the underlying mechanism by which endostatin internalization regulates its biological functions. © 2011 Higher Education Press and Springer-Verlag Berlin Heidelberg. Source

Guo L.,Lanzhou University | Guo L.,National Engineering Laboratory for Anti Tumor Protein Therapeutics | Guo L.,Beijing Key Laboratory for Protein Therapeutics | Guo L.,Tsinghua University | And 21 more authors.
Molecular Medicine Reports | Year: 2015

Hypoxia-inducible factor-1α (HIF-1α) is key in tumor progression and aggressiveness as it regulates a series of genes involved in angiogenesis and anaerobic metabolism. Previous studies have shown that the transcriptional levels of HIF-1α may be downregulated by endostatin. However, the molecular mechanism by which endostatin represses HIF-1α expression remains unknown. The current study investigated the mechanism by which nuclear-translocated endostatin suppresses HIF-1α activation by disrupting Zn(II) homeostasis. Endostatin was observed to downregulate HIF-1α expression at mRNA and protein levels. Blockage of endostatin nuclear translocation by RNA interference of importin α1/β1 or ectopic expression of NLS-deficient mutant nucleolin in human umbilical vein endothelial cells co-transfected with small interfering (si)-nucleolin siRNA compromises endostatin-reduced HIF-1α expression. Nuclear-translocated apo-endostatin, but not holo-endostatin, significantly disrupts the interaction between CBP/p300 and HIF-1α by disturbing Zn(II) homeostasis, which leads to the transcriptional inactivation of HIF-1α. The results reveal mechanistic insights into the method by which nuclear-translocated endostatin downregulates HIF-1α activation and provides a novel way to investigate the function of endostatin in endothelial cells. Source

Wang J.,Tsinghua University | Wang J.,Beijing Key Laboratory for Protein Therapeutics | Wang J.,Protein Science Laboratory of MOE | Xu L.,Tsinghua University | And 8 more authors.
Vaccine | Year: 2011

Induction of mucosal antibodies to prevent HIV infection is an important strategy for the HIV-1 prophylaxis. Here we report an epitope-vaccine based antigen that was able to elicit mucosal antibodies capable of blocking HIV-1 transcytosis. Because the ELDKWA epitope of neutralizing antibody 2F5 plays a crucial role in transcytosis, a series of immunogens that contain tandem copies of ELDKWA were prepared. Mice were immunized with these immunogens intranasally, and received intraperitoneal. +. intranasal boosters. The immunogens that contained more ELDKWA epitopes elicited higher level of mucosal ELDKWA-epitope specific IgAs and systemic IgGs. Although the antisera from the immunized mice exhibited mild neutralizing potency to HIV-1 isolates HXB2 and JRFL, the affinity purified mucosal ELDKWA-epitope specific antibodies could block the transcytosis of cell-free CNE3 (a primary isolate of subtype CRF01_AE) in human tight epithelial models. © 2011 Elsevier Ltd. Source

Chen Y.,National Engineering Laboratory for Anti Tumor Protein Therapeutics | Chen Y.,Beijing Key Laboratory for Protein Therapeutics | Chen Y.,Tsinghua University | Wang S.,National Engineering Laboratory for Anti Tumor Protein Therapeutics | And 14 more authors.
Blood | Year: 2011

Specific internalization of endostatin into endothelial cells has been proved to be important for its biologic functions. However, the mechanism of endostatin internalization still remains elusive. In this study, we report for the first time that both caveolae/lipid rafts and clathrin-coated pits are involved in endostatin internalization. Inhibition of either the caveolae pathway or the clathrin pathway with the use of chemical inhibitors, small interfering RNAs, or dominant-negative mutants alters endostatin internalization in vitro. Intriguingly, cholesterol sequestration by nystatin, a polyene antifungal drug, significantly enhances endostatin uptake by endothelial cells through switching endostatin internalization predominantly to the clathrin-mediated pathway. Nystatinenhanced internalization of endostatin also increases its inhibitory effects on endothelial cell tube formation and migration. More importantly, combined treatment with nystatin and endostatin selectively enhances endostatin uptake and biodistribution in tumor blood vessels and tumor tissues but not in normal tissues of tumor-bearing mice, ultimately resulting in elevated antiangiogenic and antitumor efficacies of endostatin in vivo. Taken together, our data show a novel mechanism of endostatin internalization and support the potential application of enhancing the uptake and therapeutic efficacy of endostatin via regulating distinct endocytic pathways with cholesterolsequestering agents. © 2011 by The American Society of Hematology. Source

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