(65h) Inflammation Targeted Intravenous Dendrimer-Drug Therapy for Age Related Macular Degeneration

Inflammation mediated by activated microglia/macrophages (Mi/ma) is implicated in many ocular posterior segment diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, retinitis pigmentosa (RP) and retinopathy of prematurity (ROP). Mi/ma under normal conditions perform immune surveillance and maintain retinal/choroidal hemostasis, but under disease conditions particularly in AMD, these cells migrate, and take part in intense cross-talk with other cells by secreting inflammatory cytokines, pro-angiogenic factors and influencing disease progression by causing oxidative stress and neovascularization. Current treatments for AMD involve frequent, localized intravitreal injections of anti-VEGF agents to neutralize the soluble VEGF but does not address the underlying inflammation. Further, these therapies doesn’t work in 1/3 of the patients, and often associated with side-effects such as choriocapillaries atrophy, RPE loss and intraocular toxicity and there is no viable therapy for early AMD. Hence, targeting and delivering drugs to the key cells involved in disease progression will highly beneficial for both early and late stages, improve compliance and reduce costs. We have discovered that hydroxyl terminated PAMAM dendrimers when administered intravenously targets, localizes and retained in activated mi/ma, injured RPE and astrocytes in more than 5 ocular disease models [1,2]. We found that this unique intrinsic targeting of dendrimers is attributed to (1) the size, shape and neutral surface functionality of dendrimers, (2) Significantly reduced non-specific tissue interaction and its ability cross impaired blood retinal barrier, and (3) increased phagocytic activity of activated mi/ma [3,4].

In this study, we harnessed the targeting ability of dendrimers to deliver drugs (anti-inflammatory and anti-angiogenic) to the key cells (activated mi/ma and injured RPE) and evaluate is efficacy for early and late AMD in subretinal lipid injected rat AMD model. For early AMD, Dendrimer-N-Acetyl Cysteine (D-NAC) or dendrimer-triamcinolone acetonide (D-TA) monotherapy was utilized. When administered intravenously, D-NAC or D-TA demonstrated pathology dependent biodistribution by co-localizing and retaining in mi/ma and RPE cells for more than 21 days but cleared intact from systemic circulation and off-target organs within 24 hrs [2]. D-NAC or D-TA monotherapy resulted in attenuation for retinal and choroidal inflammation by suppressing inflammatory cytokine expression and promoting macrophage depletion in bleb areas compared to free drug controls. D-NAC or D-TA monotherapy resulted in significantly smaller CNV areas suggesting CNV suppression. D-NAC therapy resulted in phenotype switching of microglia from ‘activated’ to ‘resting’ thereby promoting restoration of retinal health. For late AMD, when a combination therapy of intravenous D-NAC + D-TA at day 10 onwards demonstrated CNV regression (~72%), reduction of oxidative stress, inflammatory and pathological angiogenic markers. Fluorescein angiography demonstrated that combination therapy resulted in reduced vascular leakage compared to free drug and untreated controls. Intravenous dendrimer-drug therapy did not demonstrate elevation of IOP or any signs of ocular and systemic toxicity [2].

Targeting and selectively co-localization of dendrimers, in activated mi/ma and RPE, makes them excellent carriers for systemic drug delivery to specific affected cells in the choroid/retina. Delivering drugs to the key pathological cells via dendrimers without any toxicity effects may provide opportunity to develop dendrimer-based therapies to achieve efficacy at significantly lower concentration with a more amenable and patient friendly delivery route particularly for dry AMD where there are no viable therapies available. The efficacy of D-NAC and D-TA in CNV suppression/regression, attenuation of retinal/choroidal inflammation may offer an effective treatment option for early and late stages of AMD and other ocular diseases where inflammation is involved.

¹ Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

² Department of ophthalmology, Wilmer Eye Institute, Johns Hopkins School of medicine, Baltimore, Maryland, USA.

References:

1. Kambhampati, SP., Clunies-Ross, A.J., Bhutto, I., Mishra, MK., Edwards, M., McLeod, D.S., Kannan, RM., Lutty, GA. Systemic and Intravitreal Delivery of Dendrimers to Activated Microglia/Macrophage in Ischemia/Reperfusion Mouse. IOVS. 2015, 56(8), 4413-4424.
2. Kannan, RM., Lutty, G., Kambhampati, SP., Mishra, Mk., Bhutto. I.A. "Dendrimer compositions and their use in treatment of diseases of the eye." U.S. Patent Application 15/307,284, filed February 16, 2017.
3. Alnasser, Y., Kambhampati, SP., Nance, E., Rajbhandari, L., Shrestha, S., Venkatesan, A., Kannan RM., Kannan, S. Preferential and Increased Uptake of Hydroxyl-Terminated PAMAM Dendrimers by Activated Microglia in Rabbit Brain Mixed Glial Culture. Molecules. 2018, 23(5), 1025-1039.
4. Nance, E., Zhang, F., Mishra, M. K., Zhang, Z., Kambhampati, S. P., Kannan, R. M., & Kannan, S. Nanoscale effects in dendrimer-mediated targeting of neuroinflammation. Biomaterials. 2016, 101, 96-107.