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Sustained delivery of a HIF-1 antagonist for ocular neovascularization
Takeshi Iwase1, Jie Fu, Tsunehiko Yoshida
1Department of Ophthalmology, Baltimore, USA; Department of Neuroscience, Baltimore, USA.
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.
Insights
A new doxorubicin (DXR) nanoparticle formulation effectively inhibits hypoxia-inducible factor-1 (HIF-1) to treat eye diseases like neovascularization (NV) without causing retinal toxicity.
Area of Science:
- Ophthalmology
- Nanotechnology
- Molecular Biology
Background:
- Hypoxia-inducible factor-1 (HIF-1) plays a critical role in neovascularization (NV).
- Doxorubicin (DXR) and daunorubicin (DNR) inhibit HIF-1 but cause retinal toxicity upon intraocular injection.
- Novel drug delivery systems are needed to improve the safety and efficacy of ocular NV treatments.
Purpose of the Study:
- To develop and evaluate a novel nanoparticle formulation of doxorubicin (DXR) conjugated to polyethylene glycol and poly(sebacic acid) (DXR-PSA-PEG3) for treating ocular neovascularization (NV).
- To assess the efficacy, duration of activity, and retinal toxicity of the DXR-PSA-PEG3 nanoparticles.
- To investigate the potential of this formulation as a new chemical entity for ocular NV treatment.
Main Methods:
- Doxorubicin (DXR) was conjugated to branched polyethylene glycol and poly(sebacic acid) copolymers (PSA-PEG3) and formulated into nanoparticles.
- The DXR-PSA-PEG3 nanoparticles were administered via intraocular injection in mouse models of NV and in rabbits.
- HIF-1-responsive gene products, NV suppression, retinal function (via electroretinograms), and drug release kinetics were evaluated.
Main Results:
- Intraocular injection of DXR-PSA-PEG3 nanoparticles significantly reduced HIF-1-responsive gene products and suppressed choroidal and retinal NV.
- The nanoparticles demonstrated no retinal toxicity in treated animals.
- Sustained release of DXR conjugates was observed in rabbits for at least 105 days, with NV suppression lasting at least 35 days in mice.
Conclusions:
- The novel DXR-PSA-PEG3 nanoparticle formulation is a potent HIF-1 inhibitor that effectively suppresses ocular NV.
- This controlled-release formulation maximizes efficacy and duration of activity while minimizing toxicity.
- DXR-PSA-PEG3 nanoparticles represent a promising new therapeutic approach for ocular neovascularization.
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