Background: Endostatin (ES) is a promising anti-angiogenesis protein and has been approved
for the treatment of non-small cell lung cancer, but short half-life, poor stability and nonspecific
delivery caused great pain to patients and produced unsatisfactory treatment effectiveness.
Objective: In this work, in order to overcome these disadvantages, ES was covalently modified by
polysulfated heparin (PSH) with the expectancy of longer half-life, higher anti-angiogenesis activity
and better cellular uptake.
Methods: To characterize the cellular uptake, flow cytometry and confocal laser scanning microscopy
were used to study the intracellular localization of fluorescein isothiocyanate-labeled ES and PSH-ES
in EAhy926 endothelial cells. Zebrafish model was used to study the anti-angiogenesis activities of ES
and its derivatives in vivo. The 125I-radiolabeled ES and PSH-ES were administered to healthy BALC/c
mice for the pharmacokinetics study.
Results: Compared with ES, better cellular uptake effects were detected in PSH-ES group. Both ES
and PSH-ES showed inhibition on the intersegmental vessels formation, while PSH-ES displayed a
higher one. The half-life of PSH-ES was lengthened and area under the curve (AUC) was increased. At
the same time, ES and PSH-ES were both widely and rapidly distributed in the lungs, livers, kidneys
and hearts with little difference.
Conclusion: The results indicated that PSH displayed good properties as a novel glyco-modifier for
protein and peptide. The results also showed that PSH-ES displayed better cellular uptake, higher antiangiogenesis
activity and prolonged half-life, which would lead to better anti-tumour effects.