Nanoparticle-based targeting of microglia improves the neural regeneration enhancing effects of immunosuppression in the zebrafish retina.

Retinal Müller glia function as injury-induced stem-like cells in zebrafish but not mammals. However, insights gleaned from zebrafish have been applied to stimulate nascent regenerative responses in the mammalian retina. For instance, microglia/macrophages regulate Müller glia stem cell activity in the chick, zebrafish, and mouse.

Dendrimer-enabled targeted delivery attenuates glutamate excitotoxicity and improves motor function in a rabbit model of cerebral palsy.

Glutamate carboxypeptidase II (GCPII), localized on the surface of astrocytes and activated microglia, regulates extracellular glutamate concentration in the central nervous system (CNS). We have previously shown that GCPII is upregulated in activated microglia in the presence of inflammation. Inhibition of GCPII activity could reduce glutamate excitotoxicity, which may decrease inflammation and promote a 'normal' microglial phenotype.

Dendrimer-2PMPA Delays Muscle Function Loss and Denervation in a Murine Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease where muscle weakness and neuromuscular junction (NMJ) denervation precede motor neuron cell death. Although acetylcholine is the canonical neurotransmitter at the mammalian NMJ synapse, glutamate has recently been identified as a critical neurotransmitter for NMJ development and maintenance. One source of glutamate is through the catabolism of N-acetyl-aspartyl-glutamate (NAAG), which is found in mM concentrations in mammalian motoneurons, where it is released upon stimulation and hydrolyzed to glutamate by the glial enzyme glutamate carboxypeptidase II (GCPII).

Dendrimer-2PMPA selectively blocks upregulated microglial GCPII activity and improves cognition in a mouse model of multiple sclerosis.

Cognitive impairment is a common aspect of multiple sclerosis (MS) for which there are no treatments. Reduced brain -acetylaspartylglutamate (NAAG) levels are linked to impaired cognition in various neurological diseases, including MS. NAAG levels are regulated by glutamate carboxypeptidase II (GCPII), which hydrolyzes the neuropeptide to -acetyl-aspartate and glutamate.

Dendrimer-Triamcinolone Acetonide Reduces Neuroinflammation, Pathological Angiogenesis, and Neuroretinal Dysfunction in Ischemic Retinopathy.

Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Severe visual loss in DR is primarily due to proliferative diabetic retinopathy, characterized by pathologic preretinal angiogenesis driven by retinal ischemia. Microglia, the resident immune cells of the retina, have emerged as a potentially important regulator of pathologic retinal angiogenesis.

Systemic dendrimer nanotherapies for targeted suppression of choroidal inflammation and neovascularization in age-related macular degeneration.

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.

Burst Pressures in Eyes with Clear Corneal Incisions Treated with ReSure Glue.

Purpose: This study aims to measure burst pressures in 3 mm clear corneal incisions sealed with ReSure, a biodegradable hydrogel sealant, and to compare it to traditional 10-0 nylon sutures and unsealed controls.

Design: An ex vivo animal study.

Methods: 3 mm clear corneal incisions were performed in rabbit eyes (ex vivo).

Evolution of oxidative stress, inflammation and neovascularization in the choroid and retina in a subretinal lipid induced age-related macular degeneration model.

Oxidative stress, inflammation and neovascularization are the key pathological events that are implicated in human age-related macular degeneration (AMD). There are a limited number of animal models available for evaluating and developing new therapies. Most models represent late exudative or neovascular AMD (nAMD) but there is a relative paucity of models that mimic early events in AMD.

Thermosensitive and biodegradable hydrogel encapsulating targeted nanoparticles for the sustained co-delivery of gemcitabine and paclitaxel to pancreatic cancer cells.

Pancreatic cancer represents a life threatening disease with rising mortality. Although the synergistic combination of gemcitabine and albumin-bound paclitaxel has proven to enhance the median survival rates as compared to gemcitabine alone, their systemic and repeated co-administration has been associated with serious toxic side effects and poor patient compliance. For this purpose, we designed a thermosensitive and biodegradable hydrogel encapsulating targeted nanoparticles for the local and sustained delivery of gemcitabine (GEM) and paclitaxel (PTX) to pancreatic cancer.

A role for mast cells in geographic atrophy.

Mast cells (MCs) are the initial responders of innate immunity and their degranulation contribute to various etiologies. While the abundance of MCs in the choroid implies their fundamental importance in the eye, little is known about the significance of MCs and their degranulation in choroid. The cause of geographic atrophy (GA), a progressive dry form of age-related macular degeneration is elusive and there is currently no therapy for this blinding disorder.

Dendrimer mediated targeted delivery of sinomenine for the treatment of acute neuroinflammation in traumatic brain injury.

Traumatic brain injury (TBI) is a significant medical problem with limited treatment options and is one of the main causes of life-long disability. Neuroinflammation orchestrated by activated microglia/macrophages at the site of injury plays a critical role in the onset of many pathological events following TBI, leading to blood brain barrier (BBB) dysfunction, neuronal damage and long term neuronal and behavioral deficits. Current treatment involves intravenous administration of anti-inflammatory drugs which have limited clinical outcomes only when dosed within the early time window after injury.

Dense hydroxyl polyethylene glycol dendrimer targets activated glia in multiple CNS disorders.

Poor transport of neuropharmaceutics through central nervous system (CNS) barriers limits the development of effective treatments for CNS disorders. We present the facile synthesis of a novel neuroinflammation-targeting polyethylene glycol-based dendrimer (PEGOL-60) using an efficient click chemistry approach. PEGOL-60 reduces synthetic burden by achieving high hydroxyl surface density at low generation, which plays a key role in brain penetration and glia targeting of dendrimers in CNS disorders.

Scalable synthesis and validation of PAMAM dendrimer--acetyl cysteine conjugate for potential translation.

Dendrimer--acetyl cysteine (D-NAC) conjugate has shown significant promise in multiple preclinical models of brain injury and is undergoing clinical translation. D-NAC is a generation-4 hydroxyl-polyamidoamine dendrimer conjugate where -acetyl cysteine (NAC) is covalently bound through disulfide linkages on the surface of the dendrimer. It has shown remarkable potential to selectively target and deliver NAC to activated microglia and astrocytes at the site of brain injury in several animal models, producing remarkable improvements in neurological outcomes at a fraction of the free drug dose.

Subconjunctival dendrimer-drug therapy for the treatment of dry eye in a rabbit model of induced autoimmune dacryoadenitis.

Purpose: To investigate the efficacy of a single subconjunctival injection of dendrimer-dexamethasone conjugate in a rabbit model of induced autoimmune dacryoadenitis (AID).

Methods: Dendrimer biodistribution after subconjunctival injection in AID animals was evaluated using Cy5-labelled dendrimer (D-Cy5) and confocal microscopy. Diseased animals were treated with free dexamethasone (Free-Dex), dendrimer-dexamethasone (D-Dex), or saline via a single subconjunctival injection.

Pediatric oral formulation of dendrimer-N-acetyl-l-cysteine conjugates for the treatment of neuroinflammation.

N-Acetyl-l-cysteine (NAC) commonly used as an antidote in acetaminophen poisoning has shown promise in the treatment of neurological disorders such as cerebral palsy (CP). However, NAC suffers from drawbacks such as poor oral bioavailability and suboptimal blood-brain-barrier (BBB) permeability limiting its clinical success. It was previously demonstrated that intravenous administration of dendrimer-NAC (D-NAC) conjugates have shown significant promise in the targeted treatment of neuroinflammation, in multiple preclinical models.

Correction to: Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome.

After publication of the article [1], it has been brought to our attention that an author's name has been formatted incorrectly.

Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome.

Background: Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome.

Activated Microglia Targeting Dendrimer-Minocycline Conjugate as Therapeutics for Neuroinflammation.

Brain-related disorders have outmatched cancer and cardiovascular diseases worldwide as the leading cause of morbidity and mortality. The lack of effective therapies and the relatively dry central nervous system (CNS) drug pipeline pose formidable challenge. Superior, targeted delivery of current clinically approved drugs may offer significant potential.

Effect of anesthetics on microglial activation and nanoparticle uptake: Implications for drug delivery in traumatic brain injury.

Traumatic brain injury (TBI) is a serious public health problem, often with devastating consequences for patients and their families. Affordable and timely therapies can have a substantial impact on outcomes in severe TBI. Despite the common use of sedatives and anesthetics in the acute phase of TBI management, their effect on glial cells is not well understood.

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

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.

Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers.

Cerebral Palsy (CP) is a chronic childhood disorder with limited therapeutic options. Maternal intrauterine inflammation/infection is a major risk factor in the pathogenesis of CP. In pre-clinical models, dendrimer-based therapies are viable in postnatal period, attenuating inflammation and improving motor function in vivo.

Nanoscale effects in dendrimer-mediated targeting of neuroinflammation.

Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of many neurological disorders. Systemically-administered dendrimers target neuroinflammation and deliver drugs with significant efficacy, without the need for ligands. Elucidating the nanoscale aspects of targeting neuroinflammation will enable superior nanodevices for eventual translation.

Systemic and Intravitreal Delivery of Dendrimers to Activated Microglia/Macrophage in Ischemia/Reperfusion Mouse Retina.

Purpose: Microglial activation and associated neuroinflammation play a key role in the pathogenesis of many diseases of the retina, including viral infection, diabetes, and retinal degeneration. Strategies to target activated microglia and macrophages and attenuate inflammation may be valuable in treating these diseases. We seek to develop dendrimer-based formulations that target retinal microglia and macrophages in a pathology-dependent manner, and deliver drugs, either intravenously or intravitreally.

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

Triamcinolone acetonide (TA) is a potent, intermediate-acting, steroid that has anti-inflammatory and anti-angiogenic activity. Intravitreal administration of TA has been used for diabetic macular edema, proliferative diabetic retinopathy and exudative age-related macular degeneration (AMD). However, the hydrophobicity, lack of solubility, and the side effects limit its effectiveness in the treatment of retinal diseases.