TY - JOUR
T1 - Sustained delivery of a HIF-1 antagonist for ocular neovascularization
AU - Iwase, Takeshi
AU - Fu, Jie
AU - Yoshida, Tsunehiko
AU - Muramatsu, Daisuke
AU - Miki, Akiko
AU - Hashida, Noriyasu
AU - Lu, Lili
AU - Oveson, Brian
AU - Lima E Silva, Raquel
AU - Seidel, Christopher
AU - Yang, Ming
AU - Connelly, Sheila
AU - Shen, Jikui
AU - Han, Bing
AU - Wu, Mingsheng
AU - Semenza, Gregg L.
AU - Hanes, Justin
AU - Campochiaro, Peter A.
PY - 2013
Y1 - 2013
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.
KW - Age-related macular degeneration
KW - Angiogenesis
KW - Diabetic retinopathy
KW - Nanoparticles
UR - http://www.scopus.com/inward/record.url?scp=84887159636&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887159636&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2013.10.008
DO - 10.1016/j.jconrel.2013.10.008
M3 - Article
C2 - 24126220
AN - SCOPUS:84887159636
SN - 0168-3659
VL - 172
SP - 625
EP - 633
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 3
ER -