TY - JOUR
T1 - Systemic dendrimer nanotherapies for targeted suppression of choroidal inflammation and neovascularization in age-related macular degeneration
AU - Kambhampati, Siva P.
AU - Bhutto, Imran A.
AU - Wu, Tony
AU - Ho, Katie
AU - McLeod, D. Scott
AU - Lutty, Gerard A.
AU - Kannan, Rangaramanujam M.
N1 - Funding Information:
This work was supported by National Eye Institute [NEI-R01EY025304 (RMK); NEI-RO1EY016151 (GL), EY01765 (Wilmer)], unrestricted funds from Research to Prevent Blindness, and a grant from the Altsheler Durell foundation (GL and RMK). The authors would like to acknowledge the Wilmer Eye Institute NEI-sponsored CORE imaging facility for the access to LSM 710 confocal microscopy and Woods animal facility for animal housing and procedures.
Funding Information:
This work was supported by National Eye Institute [NEI-R01EY025304 (RMK); NEI-RO1EY016151 (GL), EY01765 (Wilmer)], unrestricted funds from Research to Prevent Blindness , and a grant from the Altsheler Durell foundation (GL and RMK). The authors would like to acknowledge the Wilmer Eye Institute NEI-sponsored CORE imaging facility for the access to LSM 710 confocal microscopy and Woods animal facility for animal housing and procedures.
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/7/10
Y1 - 2021/7/10
N2 - Inflammation and neovascularization are key pathological events in human age-related macular degeneration (AMD). Activated microglia/macrophages (mi/ma) and retinal pigmented epithelium (RPE) play an active role in every stage of disease progression. Systemic therapies that can target these cells and address both inflammation and neovascularization will broaden the impact of existing therapies and potentially open new avenues for early AMD where there are no viable therapies. Utilizing a clinically relevant rat model of AMD that mirrors many aspects that of human AMD pathological events, we show that systemic hydroxyl-terminated polyamidoamine dendrimer-triamcinolone acetonide conjugate (D-TA) is selectively taken up by the injured mi/ma and RPE (without the need for targeting ligands). D-TA suppresses choroidal neovascularization significantly (by >80%, >50-fold better than free drug), attenuates inflammation in the choroid and retina, by limiting macrophage infiltration in the pathological area, significantly suppressing pro-inflammatory cytokines and pro-angiogenic factors, with minimal side effects to healthy ocular tissue and other organs. In ex vivo studies on human postmortem diabetic eyes, the dendrimer is also taken up into choroidal macrophages. These results suggest that the systemic hydroxyl dendrimer-drugs can offer new avenues for therapies in treating early/dry AMD and late/neovascular AMD alone, or in combination with current anti-VEGF therapies. This hydroxyl dendrimer platform but conjugated to a different drug is undergoing clinical trials for severe COVID-19, potentially paving the way for faster clinical translation of similar compounds for ocular and retinal disorders.
AB - Inflammation and neovascularization are key pathological events in human age-related macular degeneration (AMD). Activated microglia/macrophages (mi/ma) and retinal pigmented epithelium (RPE) play an active role in every stage of disease progression. Systemic therapies that can target these cells and address both inflammation and neovascularization will broaden the impact of existing therapies and potentially open new avenues for early AMD where there are no viable therapies. Utilizing a clinically relevant rat model of AMD that mirrors many aspects that of human AMD pathological events, we show that systemic hydroxyl-terminated polyamidoamine dendrimer-triamcinolone acetonide conjugate (D-TA) is selectively taken up by the injured mi/ma and RPE (without the need for targeting ligands). D-TA suppresses choroidal neovascularization significantly (by >80%, >50-fold better than free drug), attenuates inflammation in the choroid and retina, by limiting macrophage infiltration in the pathological area, significantly suppressing pro-inflammatory cytokines and pro-angiogenic factors, with minimal side effects to healthy ocular tissue and other organs. In ex vivo studies on human postmortem diabetic eyes, the dendrimer is also taken up into choroidal macrophages. These results suggest that the systemic hydroxyl dendrimer-drugs can offer new avenues for therapies in treating early/dry AMD and late/neovascular AMD alone, or in combination with current anti-VEGF therapies. This hydroxyl dendrimer platform but conjugated to a different drug is undergoing clinical trials for severe COVID-19, potentially paving the way for faster clinical translation of similar compounds for ocular and retinal disorders.
KW - Age-related macular degeneration (AMD)
KW - Choroidal neovascularization
KW - Microglia/macrophages
KW - PAMAM dendrimers
KW - Retinal inflammation
KW - Systemic therapies
KW - Triamcinolone acetonide
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UR - http://www.scopus.com/inward/citedby.url?scp=85108070579&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2021.05.035
DO - 10.1016/j.jconrel.2021.05.035
M3 - Article
C2 - 34058271
AN - SCOPUS:85108070579
SN - 0168-3659
VL - 335
SP - 527
EP - 540
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -