Therapeutic Potential of Anti-Angiogenic Multitarget N,O-Sulfated E. Coli K5 Polysaccharide in Diabetic Retinopathy. 
Vascular endothelial growth factor (VEGF) blockers have been developed for the treatment of proliferative diabetic retinopathy (PDR), the leading cause of visual impairments in the working-age population in the Western world.  However, limitations to anti-VEGF therapies may exist because of the local production of other proangiogenic factors that may cause resistance to anti-VEGF interventions.  Thus, novel therapeutic approaches targeting additional pathways are required.  Here, we identified a sulfated derivative of the Escherichia coli polysaccharide K5 [K5-N,OS(H)] as a multitarget molecule highly effective in inhibiting VEGF-driven angiogenic responses in different in vitro, ex vivo, and in vivo assays, including a murine model of oxygen-induced retinopathy.  Furthermore, K5-N,OS(H) binds a variety of heparin-binding angiogenic factors upregulated in PDR vitreous humor besides VEGF, thus inhibiting their biological activity.  Finally, K5-N,OS(H) hampers the angiogenic activity exerted in vitro and in vivo by human vitreous fluid samples collected from patients with PDR.  Together, the data provide compelling experimental evidence that K5-N,OS(H) represents an antiangiogenic multitarget molecule with potential implications for the therapy of pathologic neovessel formation in the retina of patients with PDR.