Sustained delivery of a HIF-1 antagonist for ocular neovascularization

Takeshi Iwase, Jie Fu, Tsunehiko Yoshida, Daisuke Muramatsu, Akiko Miki, Noriyasu Hashida, Lili Lu, Brian Oveson, Raquel Formica, Christopher Seidel, Ming Yang, Sheila Connelly, Jikui Shen, Bing Han, Mingsheng Wu, Gregg L Semenza, Justin S Hanes, Peter A Campochiaro

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)625-633
Number of pages9
JournalJournal of Controlled Release
Volume172
Issue number3
DOIs
StatePublished - 2013

Fingerprint

Hypoxia-Inducible Factor 1
Doxorubicin
Intraocular Injections
Nanoparticles
Retinal Neovascularization
Choroidal Neovascularization
Daunorubicin
Aqueous Humor
Vascular Endothelial Growth Factor A
Transgenic Mice
Buffers
Polymers

Keywords

  • Age-related macular degeneration
  • Angiogenesis
  • Diabetic retinopathy
  • Nanoparticles

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Sustained delivery of a HIF-1 antagonist for ocular neovascularization. / Iwase, Takeshi; Fu, Jie; Yoshida, Tsunehiko; Muramatsu, Daisuke; Miki, Akiko; Hashida, Noriyasu; Lu, Lili; Oveson, Brian; Formica, Raquel; Seidel, Christopher; Yang, Ming; Connelly, Sheila; Shen, Jikui; Han, Bing; Wu, Mingsheng; Semenza, Gregg L; Hanes, Justin S; Campochiaro, Peter A.

In: Journal of Controlled Release, Vol. 172, No. 3, 2013, p. 625-633.

Research output: Contribution to journalArticle

Iwase, T, Fu, J, Yoshida, T, Muramatsu, D, Miki, A, Hashida, N, Lu, L, Oveson, B, Formica, R, Seidel, C, Yang, M, Connelly, S, Shen, J, Han, B, Wu, M, Semenza, GL, Hanes, JS & Campochiaro, PA 2013, 'Sustained delivery of a HIF-1 antagonist for ocular neovascularization', Journal of Controlled Release, vol. 172, no. 3, pp. 625-633. https://doi.org/10.1016/j.jconrel.2013.10.008
Iwase, Takeshi ; Fu, Jie ; Yoshida, Tsunehiko ; Muramatsu, Daisuke ; Miki, Akiko ; Hashida, Noriyasu ; Lu, Lili ; Oveson, Brian ; Formica, Raquel ; Seidel, Christopher ; Yang, Ming ; Connelly, Sheila ; Shen, Jikui ; Han, Bing ; Wu, Mingsheng ; Semenza, Gregg L ; Hanes, Justin S ; Campochiaro, Peter A. / Sustained delivery of a HIF-1 antagonist for ocular neovascularization. In: Journal of Controlled Release. 2013 ; Vol. 172, No. 3. pp. 625-633.
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AU - Miki, Akiko

AU - Hashida, Noriyasu

AU - Lu, Lili

AU - Oveson, Brian

AU - Formica, Raquel

AU - Seidel, Christopher

AU - Yang, Ming

AU - Connelly, Sheila

AU - Shen, Jikui

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AU - Wu, Mingsheng

AU - Semenza, Gregg L

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N2 - 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.

AB - 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.

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