Sustained delivery of a HIF-1 antagonist for ocular neovascularization

被引：62

作者：

Iwase, Takeshi ^{[1
,2
]}

Fu, Jie ^{[1
,3
,4
]}

Yoshida, Tsunehiko ^{[1
,2
]}

Muramatsu, Daisuke ^{[1
,2
]}

Miki, Akiko ^{[1
,2
]}

Hashida, Noriyasu ^{[1
,2
]}

Lu, Lili ^{[1
,2
]}

Oveson, Brian ^{[1
,2
]}

Lima e Silva, Raquel ^{[1
,2
]}

Seidel, Christopher ^{[1
,2
]}

Yang, Ming ^{[5
]}

Connelly, Sheila ^{[5
]}

Shen, Jikui ^{[1
,2
]}

Han, Bing ^{[1
,3
]}

Wu, Mingsheng ^{[1
,3
]}

Semenza, Gregg L. ^{[6
,7
,8
,9
,10
,11
,12
]}

Hanes, Justin ^{[1
,3
,4
,9
,13
,14
,15
]}

Campochiaro, Peter A. ^{[1
,2
,3
]}

机构：

[1] Univ Maryland, Dept Ophthalmol, Baltimore, MD 21201 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[3] Ctr Nanomed, Baltimore, MD USA

[4] Dept Chem & Biomol Engn, Baltimore, MD USA

[5] GrayBug LLC, Baltimore, MD USA

[6] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Vasc Program, Baltimore, MD USA

[7] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[9] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[10] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD USA

[11] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA

[12] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA

[13] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA

[14] Johns Hopkins Univ, Sch Med, Dept Environm Hlth Sci, Baltimore, MD USA

[15] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21205 USA

来源：

JOURNAL OF CONTROLLED RELEASE | 2013年 / 172卷 / 03期

关键词：

Age-related macular degeneration; Angiogenesis; Diabetic retinopathy; Nanoparticles; ENDOTHELIAL GROWTH-FACTOR; CHOROIDAL NEOVASCULARIZATION; CELL-DEATH; FACTOR-B; IN-VIVO; RETINAL NEOVASCULARIZATION; DIABETIC-RETINOPATHY; INCREASED EXPRESSION; VEGF; BEVACIZUMAB;

D O I：

10.1016/j.jconrel.2013.10.008

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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-PEG(3)) and formulated into nanoparticles that when placed in aqueous buffer, slowly released small DXR-conjugates. Intraocular injection of DXR-PSA-PEG(3) nanoparticles (1 or 10 mu g 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-PEG(3) nanoparticles (10 mu g DXR content) suppressed NV for at least 35 days. Intraocular injection of DXR-PSA-PEG(3) 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. (C) 2013 Elsevier B.V. All rights reserved.

引用

页码：625 / 633

页数：9

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