TY - JOUR
T1 - Targeted Microglial Attenuation through Dendrimer-Drug Conjugates Improves Glaucoma Neuroprotection
AU - Pitha, Ian
AU - Kambhampati, Siva
AU - Sharma, Anjali
AU - Sharma, Rishi
AU - McCrea, Liam
AU - Mozzer, Ann
AU - Kannan, Rangaramanujam M.
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/3/13
Y1 - 2023/3/13
N2 - Retinal microglial/macrophage activation and optic nerve (ON) microglial/macrophage activation are glaucoma biomarkers and potential therapeutic targets for this blinding disease. We report targeting of activated microglia by PAMAM dendrimers in a rat glaucoma model and neuroprotection by N-acetylcysteine-conjugated dendrimer (D-NAC) conjugates in a post-injury rescue experiment. Intravitreally delivered fluorescently labeled dendrimer (D-Cy5) conjugates targeted and were retained in Iba-1-positive cells (90% at 7 days and 55% after 28 days) in the retina following intraocular pressure (IOP) elevation, while systemically delivered D-Cy5 targeted ON cells. A single intravitreal D-NAC dose given 1 week after IOP elevation significantly reduced transcription of pro-inflammatory (IL-6, MCP-1, IL-1β) and A1 astrocyte (Serping1, Fkbp5, Amigo2) markers and increased survival of retinal ganglion cells (39 ± 12%) versus BSS- (20 ± 15%, p = 0.02) and free NAC-treated (26 ± 14%, p = 0.15) eyes. These results highlight the potential of dendrimer-targeted microglia and macrophages for early glaucoma detection and as a neuroprotective therapeutic target.
AB - Retinal microglial/macrophage activation and optic nerve (ON) microglial/macrophage activation are glaucoma biomarkers and potential therapeutic targets for this blinding disease. We report targeting of activated microglia by PAMAM dendrimers in a rat glaucoma model and neuroprotection by N-acetylcysteine-conjugated dendrimer (D-NAC) conjugates in a post-injury rescue experiment. Intravitreally delivered fluorescently labeled dendrimer (D-Cy5) conjugates targeted and were retained in Iba-1-positive cells (90% at 7 days and 55% after 28 days) in the retina following intraocular pressure (IOP) elevation, while systemically delivered D-Cy5 targeted ON cells. A single intravitreal D-NAC dose given 1 week after IOP elevation significantly reduced transcription of pro-inflammatory (IL-6, MCP-1, IL-1β) and A1 astrocyte (Serping1, Fkbp5, Amigo2) markers and increased survival of retinal ganglion cells (39 ± 12%) versus BSS- (20 ± 15%, p = 0.02) and free NAC-treated (26 ± 14%, p = 0.15) eyes. These results highlight the potential of dendrimer-targeted microglia and macrophages for early glaucoma detection and as a neuroprotective therapeutic target.
UR - http://www.scopus.com/inward/record.url?scp=85149007901&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85149007901&partnerID=8YFLogxK
U2 - 10.1021/acs.biomac.2c01381
DO - 10.1021/acs.biomac.2c01381
M3 - Article
C2 - 36827603
AN - SCOPUS:85149007901
SN - 1525-7797
VL - 24
SP - 1355
EP - 1365
JO - Biomacromolecules
JF - Biomacromolecules
IS - 3
ER -