TY - JOUR
T1 - Dendrimer-Triamcinolone Acetonide Reduces Neuroinflammation, Pathological Angiogenesis, and Neuroretinal Dysfunction in Ischemic Retinopathy
AU - Cho, Hongkwan
AU - Kambhampati, Siva P.
AU - Lai, Michael J.
AU - Zhou, Lingli
AU - Lee, Grace
AU - Xie, Yangyiran
AU - Hui, Qiaoyan
AU - Kannan, Rangaramanujam M.
AU - Duh, Elia J.
N1 - Funding Information:
This work was supported by the National Institutes of Health (EY022383 and EY022683 to E.J.D.; R01HD076901 and RO1EY025304 to R.M.K.), and Core Grant P30EY001765, Imaging and Microscopy Core Module.
Publisher Copyright:
© 2020 Wiley-VCH GmbH
PY - 2021/2
Y1 - 2021/2
N2 - Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Severe visual loss in DR is primarily due to proliferative diabetic retinopathy, characterized by pathologic preretinal angiogenesis driven by retinal ischemia. Microglia, the resident immune cells of the retina, have emerged as a potentially important regulator of pathologic retinal angiogenesis. Corticosteroids including triamcinolone acetonide (TA), known for their antiangiogenic effects, are used in treating retinal diseases, but their use is significantly limited by side effects including cataracts and glaucoma. Generation-4 hydroxyl polyamidoamine dendrimer nanoparticles are utilized to deliver TA to activated microglia in the ischemic retina in a mouse model of oxygen-induced retinopathy (OIR). Following intravitreal injection, dendrimer-conjugated TA (D-TA) exhibits selective localization and sustained retention in activated microglia in disease-associated areas of the retina. D-TA, but not free TA, suppresses inflammatory cytokine production, microglial activation, and preretinal neovascularization in OIR. In addition, D-TA, but not free TA, ameliorates OIR-induced neuroretinal and visual dysfunction. These results indicate that activated microglia are a promising therapeutic target for retinal angiogenesis and neuroprotection in ischemic retinal diseases. Furthermore, dendrimer-based targeted therapy and specifically D-TA constitute a promising treatment approach for DR, offering increased and sustained drug efficacy with reduced side effects.
AB - Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Severe visual loss in DR is primarily due to proliferative diabetic retinopathy, characterized by pathologic preretinal angiogenesis driven by retinal ischemia. Microglia, the resident immune cells of the retina, have emerged as a potentially important regulator of pathologic retinal angiogenesis. Corticosteroids including triamcinolone acetonide (TA), known for their antiangiogenic effects, are used in treating retinal diseases, but their use is significantly limited by side effects including cataracts and glaucoma. Generation-4 hydroxyl polyamidoamine dendrimer nanoparticles are utilized to deliver TA to activated microglia in the ischemic retina in a mouse model of oxygen-induced retinopathy (OIR). Following intravitreal injection, dendrimer-conjugated TA (D-TA) exhibits selective localization and sustained retention in activated microglia in disease-associated areas of the retina. D-TA, but not free TA, suppresses inflammatory cytokine production, microglial activation, and preretinal neovascularization in OIR. In addition, D-TA, but not free TA, ameliorates OIR-induced neuroretinal and visual dysfunction. These results indicate that activated microglia are a promising therapeutic target for retinal angiogenesis and neuroprotection in ischemic retinal diseases. Furthermore, dendrimer-based targeted therapy and specifically D-TA constitute a promising treatment approach for DR, offering increased and sustained drug efficacy with reduced side effects.
KW - angiogenesis
KW - dendrimer nanoparticle
KW - microglia
KW - neuroinflammation
KW - oxygen-induced retinopathy (OIR)
KW - targeted drug delivery
KW - triamcinolone acetonide
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U2 - 10.1002/adtp.202000181
DO - 10.1002/adtp.202000181
M3 - Article
C2 - 34527806
AN - SCOPUS:85103743772
SN - 2366-3987
VL - 4
JO - Advanced Therapeutics
JF - Advanced Therapeutics
IS - 2
M1 - 2000181
ER -