title: sFlt Multivalent Conjugates Inhibit Angiogenesis and Improve Half-Life In Vivo.
abstract: Current anti-VEGF drugs for patients with diabetic retinopathy suffer from short residence time in the vitreous of the eye. In order to maintain biologically effective doses of drug for inhibiting retinal neovascularization, patients are required to receive regular monthly injections of drug, which often results in low patient compliance and progression of the disease. To improve the intravitreal residence time of anti-VEGF drugs, we have synthesized multivalent bioconjugates of an anti-VEGF protein, soluble fms-like tyrosine kinase-1 (sFlt) that is covalently grafted to chains of hyaluronic acid (HyA), conjugates that are termed mvsFlt. Using a mouse corneal angiogenesis assay, we demonstrate that covalent conjugation to HyA chains does not decrease the bioactivity of sFlt and that mvsFlt is equivalent to sFlt at inhibiting corneal angiogenesis. In a rat vitreous model, we observed that mvsFlt had significantly increased intravitreal residence time compared to the unconjugated sFlt after 2 days. The calculated intravitreal half-lives for sFlt and mvsFlt were 3.3 and 35 hours, respectively. Furthermore, we show that mvsFlt is more effective than the unconjugated form at inhibiting retinal neovascularization in an oxygen-induced retinopathy model, an effect that is most likely due to the longer half-life of mvsFlt in the vitreous. Taken together, our results indicate that conjugation of sFlt to HyA does not affect its affinity for VEGF and this conjugation significantly improves drug half-life. These in vivo results suggest that our strategy of multivalent conjugation could substantially improve upon drug half-life, and thus the efficacy of currently available drugs that are used in diseases such as diabetic retinopathy, thereby improving patient quality of life.
authors.affiliation: Department of Bioengineering, University of California, Berkeley, California, United States of America.
authors.forename: Eda I
authors.initials: EI
authors.lastname: Altiok
authors.affiliation: Department of Bioengineering, University of California, Berkeley, California, United States of America.|Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Galway, Ireland.
authors.forename: Shane
authors.initials: S
authors.lastname: Browne
authors.affiliation: Department of Ophthalmology, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Khuc
authors.affiliation: Department of Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Moran
authors.affiliation: Department of Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Kelu
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California, United States of America.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Santiago-Ortiz
authors.affiliation: Department of Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
authors.affiliation: Department of Ophthalmology, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Matilda F
authors.initials: MF
authors.lastname: Chan
authors.affiliation: Department of Bioengineering, University of California, Berkeley, California, United States of America.|Department of Materials Science and Engineering, University of California, Berkeley, California, United States of America.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Healy
mesh_terms: D000818:Animals; D016510:Corneal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000473:pathology; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D006820:Hyaluronic Acid; D040281:Vascular Endothelial Growth Factor Receptor-1