Intracellular delivery of dendrimer triamcinolone acetonide conjugates into microglial and human retinal pigment epithelial cells

Kambhampati, Siva P.; Mishra, Manoj Kumar; Mastorakos, Panagiotis; Oh, You-Take; Lutty, Gerard A.; Kannan, Rangaramanujam M.

doi:10.1016/j.ejpb.2015.02.013

Cited by 60 publications

(51 citation statements)

References 54 publications

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“…With the development of nanoparticles, the possibility of more targeted treatment with sustained release is possible. For example, dendrimers can be formulated to specifically target either RPE cells or macrophages/microglia (Kambhampati et al, 2015). When Triamcinolone acetonide (TA) is incorporated into dendrimers, the anti-inflammatory activity is improved 100-fold more than free TA in macrophages.…”

Section: Therapeutic Considerations: Current Treatment Recommendatmentioning

confidence: 99%

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD

Datta

Cano

Ebrahimi

et al. 2017

Progress in Retinal and Eye Research

591

487

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The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch’s membrane and the choriocapillaris on its basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated.

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Section: Therapeutic Considerations: Current Treatment Recommendatmentioning

confidence: 99%

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD

Datta

Cano

Ebrahimi

et al. 2017

Progress in Retinal and Eye Research

591

487

View full text Add to dashboard Cite

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“…The multiple hydroxyl groups present on the surface can be easily manipulated for introducing drugs, imaging agents or for complexing biologics [11,28–31]. Dendrimer-triamcinolone acetonide (D-TA) conjugates enhances drug solubility and intracellular delivery of TA resulting in improved antiangiogenic and anti-inflammatory activity [32]. Single intravitreal injection of dendrimer-fluocinolone acetonide conjugates attenuates neuroinflammation and provides sufficient neuroprotection for more than 30 days in rat model of retinitis pigmentosa at a 30-fold lower dose than free drug [33].…”

Section: Introductionmentioning

confidence: 99%

Subconjunctival injectable dendrimer-dexamethasone gel for the treatment of corneal inflammation

et al. 2017

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Corneal inflammation is often encountered as a key pathological event in many corneal diseases. Current treatments involve topical corticosteroids which require frequent instillations due to rapid tear turnover, causing side-effects such as corneal toxicity and elevated intraocular pressure (IOP). Hence, new interventions that can reduce side effects, dosing frequency, and increase patient compliance can be highly beneficial. In this study, we explore a subconjunctival injectable gel based on G4-PAMAM dendrimer and hyaluronic acid, cross-linked using thiol-ene click chemistry, incorporated with dendrimer dexamethasone (D-Dex) conjugates as a potential strategy for sustained delivery and enhanced bioavailability of corticosteroids. The efficacy of the injectable gel formulation was evaluated in a rat mild alkali burn model. Fluorescently-labelled dendrimers (D-Cy5) incorporated in the gel release D-Cy5 in vivo. The released D-Cy5 selectively targets and localizes within corneal macrophages in inflamed rat cornea but not in healthy controls. This pathology dependent biodistribution was exploited for drug delivery, by incorporating D-Dex in the injectable gel. The attenuation of corneal inflammation by D-Dex gels was assessed using various clinical and biochemical parameters over a 2-week period. Subconjunctival D-Dex gel treatment resulted in favorable clinically-relevant outcomes with reduced central corneal thickness and improved corneal clarity compared to free-Dex and placebo gel controls. The extent of corneal neovascularization was significantly reduced in the D-Dex group. These findings suggest that D-Dex attenuates corneal inflammation more effectively than free-Dex by attenuating macrophage infiltration and pro-inflammatory cytokines expression. A significant elevation in IOP was not observed in the D-Dex group but was observed in the free-Dex group. This novel injectable D-Dex gel may be a potential drug delivery platform for the treatment of many inflammatory ocular surface disorders such as dry eye, autoimmune keratitis and post-surnical complications where frequent steroid administration is required.

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“…38 In their study, the inhibitory effects of D-TA on microglial cells were studied only in BV-2 cell lines. Our study confirms their results in primary glia.…”

Section: Discussionmentioning

confidence: 99%

Polyamidoamine dendrimer-conjugated triamcinolone acetonide attenuates nerve injury-induced spinal cord microglia activation and mechanical allodynia

et al. 2017

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BackgroundAccumulating evidence on the causal role of spinal cord microglia activation in the development of neuropathic pain after peripheral nerve injury suggests that microglial activation inhibitors might be useful analgesics for neuropathic pain. Studies also have shown that polyamidoamine dendrimer may function as a drug delivery vehicle to microglia in the central nervous system. In this regard, we developed polyamidoamine dendrimer-conjugated triamcinolone acetonide, a previously identified microglial activation inhibitor, and tested its analgesic efficacy in a mouse peripheral nerve injury model.ResultPolyamidoamine dendrimer was delivered selectively to spinal cord microglia upon intrathecal administration. Dendrimer-conjugated triamcinolone acetonide inhibited lipoteichoic acid-induced proinflammatory gene expression in primary glial cells. In addition, dendrimer-conjugated triamcinolone acetonide administration (intrathecal) inhibited peripheral nerve injury-induced spinal cord microglial activation and the expression of pain-related genes in the spinal cord, including Nox2, IL-1β, TNF-α, and IL-6. Dendrimer-conjugated triamcinolone acetonide administration right after nerve injury almost completely reversed peripheral nerve injury-induced mechanical allodynia for up to three days. Meanwhile, dendrimer-conjugated triamcinolone acetonide administration 1.5 days post injury significantly attenuated mechanical allodynia.ConclusionOur data demonstrate that dendrimer-conjugated triamcinolone acetonide inhibits spinal cord microglia activation and attenuates neuropathic pain after peripheral nerve injury, which has therapeutic implications for the treatment of neuropathic pain.

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Intracellular delivery of dendrimer triamcinolone acetonide conjugates into microglial and human retinal pigment epithelial cells

Cited by 60 publications

References 54 publications

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD

Subconjunctival injectable dendrimer-dexamethasone gel for the treatment of corneal inflammation

Polyamidoamine dendrimer-conjugated triamcinolone acetonide attenuates nerve injury-induced spinal cord microglia activation and mechanical allodynia

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