Sustained delivery of a HIF-1 antagonist for ocular neovascularization.
Sustained delivery of a HIF-1 antagonist for ocular neovascularization.
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DOI：
10.1016/j.jconrel.2013.10.008
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发表时间：
2013-12-28
期刊：
影响因子：
--
通讯作者：
Campochiaro PA
中科院分区：
文献类型：
--
作者：
Iwase T;Fu J;Yoshida T;Muramatsu D;Miki A;Hashida N;Lu L;Oveson B;Lima e Silva R;Seidel C;Yang M;Connelly S;Shen J;Han B;Wu M;Semenza GL;Hanes J;Campochiaro PA
阿霉素（DXR）和柔红霉素（DNR）通过阻断缺氧诱导因子-1 （HIF-1）与DNA的结合抑制其转录活性。眼内注射DXR或DNR可抑制脉络膜和视网膜新生血管（NV），但视网膜电图（ERGs）显示也会干扰视网膜功能。DXR与支链聚乙二醇和聚癸二酸的新型共聚物（DXR- psa - peg3）偶联，并配制成纳米颗粒，当置于水缓冲液中时，缓慢释放小的DXR偶联物。眼内注射DXR- psa - peg3纳米颗粒（DXR含量为1或10 μg）可降低hif -1应答基因产物，强烈抑制脉络膜和视网膜NV，且无视网膜毒性。在光感受器中表达VEGF的转基因小鼠中，眼内注射DXR- psa - peg3纳米颗粒（10 μg DXR含量）抑制NV至少35天。兔眼内注射DXR- psa - peg3纳米颗粒（含2.7 mg DXR）可使DXR偶联物在房水和玻璃体中持续释放至少105天。本研究展示了一种新型的hif -1抑制剂-聚合物缀合物，它被配制成控释颗粒，最大限度地提高了疗效和活性持续时间，最大限度地降低了毒性，为治疗眼部NV提供了一种有前途的新化学实体。
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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影响因子：
5.6
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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