title: Sustained delivery of a HIF-1 antagonist for ocular neovascularization.
abstract: Doxorubicin (DXR) and daunorubicin (DNR) inhibit hypoxia-inducible factor-1 (HIF-1) transcriptional activity by blocking its binding to DNA. Intraocular injections of DXR or DNR suppressed choroidal and retinal neovascularization (NV), but also perturbed retinal function as demonstrated by electroretinograms (ERGs). DXR was conjugated to novel copolymers of branched polyethylene glycol and poly(sebacic acid) (DXR-PSA-PEG3) and formulated into nanoparticles that when placed in aqueous buffer, slowly released small DXR-conjugates. Intraocular injection of DXR-PSA-PEG3 nanoparticles (1 or 10 μg DXR content) reduced HIF-1-responsive gene products, strongly suppressed choroidal and retinal NV, and did not cause retinal toxicity. In transgenic mice that express VEGF in photoreceptors, intraocular injection of DXR-PSA-PEG3 nanoparticles (10 μg DXR content) suppressed NV for at least 35 days. Intraocular injection of DXR-PSA-PEG3 nanoparticles (2.7 mg DXR content) in rabbits resulted in sustained DXR-conjugate release with detectable levels in aqueous humor and vitreous for at least 105 days. This study demonstrates a novel HIF-1-inhibitor-polymer conjugate formulated into controlled-release particles that maximizes efficacy and duration of activity, minimizes toxicity, and provides a promising new chemical entity for treatment of ocular NV.
authors.affiliation: Department of Ophthalmology, Baltimore, USA; Department of Neuroscience, Baltimore, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwase
authors.forename: Jie
authors.initials: J
authors.lastname: Fu
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Muramatsu
authors.forename: Akiko
authors.initials: A
authors.lastname: Miki
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Hashida
authors.forename: Lili
authors.initials: L
authors.lastname: Lu
authors.forename: Brian
authors.initials: B
authors.lastname: Oveson
authors.forename: Raquel
authors.initials: R
authors.lastname: Lima e Silva
authors.forename: Christopher
authors.initials: C
authors.lastname: Seidel
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Sheila
authors.initials: S
authors.lastname: Connelly
authors.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.forename: Mingsheng
authors.initials: M
authors.lastname: Wu
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003630:Daunorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011817:Rabbits; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D051793:Hypoxia-Inducible Factor 1; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003630:Daunorubicin
keywords: Age-related macular degeneration; Angiogenesis; Diabetic retinopathy; Nanoparticles