Targeted Microglial Attenuation through Dendrimer-Drug Conjugates Improves Glaucoma Neuroprotection
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Published on: March 23, 2016
Ian Pitha1,2,3, Siva Kambhampati1,2, Anjali Sharma1,2
1Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States.
Abstract:
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.
Insights
Dendrimer-drug conjugates target activated microglia in a rat glaucoma model. N-acetylcysteine dendrimers protected retinal ganglion cells and reduced inflammation, showing potential for glaucoma therapy.
Area of Science:
- Ophthalmology
- Neuroscience
- Nanomedicine
Background:
- Microglial/macrophage activation in the retina and optic nerve are key glaucoma biomarkers.
- These activated cells present potential therapeutic targets for this blinding disease.
Purpose of the Study:
- To investigate targeting of activated microglia using polyamidoamine (PAMAM) dendrimers in a rat glaucoma model.
- To evaluate neuroprotection by N-acetylcysteine-conjugated dendrimers (D-NAC) in a post-injury rescue experiment.
Main Methods:
- Intravitreal delivery of fluorescently labeled dendrimer (D-Cy5) to track targeting of Iba-1-positive cells in the retina after intraocular pressure (IOP) elevation.
- Systemic delivery of D-Cy5 to assess targeting of optic nerve (ON) cells.
- Administration of a single intravitreal D-NAC dose 1 week post-IOP elevation to assess anti-inflammatory and neuroprotective effects.
Main Results:
- Intravitreally delivered D-Cy5 showed high retention in retinal microglia/macrophages (90% at 7 days, 55% at 28 days).
- Systemic D-Cy5 targeted optic nerve cells.
- D-NAC treatment significantly reduced pro-inflammatory and A1 astrocyte markers.
- D-NAC increased retinal ganglion cell survival by 39% compared to BSS and free NAC treatments.
Conclusions:
- Dendrimer-based drug delivery systems can effectively target activated microglia and macrophages in the glaucomatous eye.
- D-NAC demonstrates significant neuroprotective effects and reduces inflammation, highlighting its therapeutic potential for glaucoma.
- Targeting microglia/macrophages with dendrimers offers a promising strategy for early glaucoma detection and treatment.
