Low generation polyamine dendrimers bearing flexible tetraethylene glycol as nanocarriers for plasmids and siRNA

Sharma, Rishi; Zhang, Issan; Shiao, Tze Chieh; Pavan, Giovanni M.; Maysinger, Dušica; Roy, René

doi:10.1039/c5nr06757j

Cited by 25 publications

(13 citation statements)

References 68 publications

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“…D-Ene was used in order to anchor the linear thiolated hyaluronic acid (HA-SH) to form 3-dimensional cross-linked gels. Thiol-ene click chemistry was utilized for this process because it is a highly efficient free radical-mediated photopolymerization reaction and it has rapid gelation time [51–53]. Upon UV exposure (350 nm UV-A), the photo initiator was excited to generate thiyl radicals.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…Dendrimers are structurally "monodisperse" with well-defined building blocks and surface functionality, and have garnered significant attention as promising scaffolds for various biomedical applications including drug/gene delivery, targeting, imaging and diagnosis due to their unique physico-chemical properties. [19][20][21][22][23][24][25] These multivalent nanostructures can be tuned conveniently to incorporate various molecules of interest.…”

Section: Introductionmentioning

confidence: 99%

Scalable synthesis and validation of PAMAM dendrimer‐N‐acetyl cysteine conjugate for potential translation

Sharma

Kambhampati

et al. 2018

Bioengineering & Transla Med

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Dendrimer‐N‐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 N‐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. Here we present a highly efficient, scalable, greener, well‐defined route to the synthesis of D‐NAC, and validate the structure, stability and activity to define the benchmarks for this compound. This newly developed synthetic route has significantly reduced the synthesis time from three weeks to one week, uses industry‐friendly solvents/reagents, and involves simple purification procedures, potentially enabling efficient scale up.

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“…Dendrimers 17,18 are hyperbranched, monodispersed macromolecules that have shown significant potential in gene delivery, 19,20 drug delivery, 20-22 imaging, 23 and numerous other applications related to nanomedicine. 24 Dendrimers offer unique physicochemical features such as (1) highly defined monodisperse structure, (2) nanometer size range, (3) multivalency, and (4) easy tuneability.…”

Section: Introductionmentioning

confidence: 99%

Activated Microglia Targeting Dendrimer–Minocycline Conjugate as Therapeutics for Neuroinflammation

et al. 2017

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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. Minocycline has shown promise for the treatment of neurological diseases owing to its ability to penetrate the blood–brain barrier (BBB) and potency. Despite its potential in the clinic and in preclinical models, the high doses needed to affect a positive therapeutic response have led to side effects. Targeted delivery of minocycline to the injured site and injured cells in the brain can be highly beneficial. Systemically administered hydroxyl poly(amidoamine) (PAMAM) generation-6 (G6) dendrimers have a longer blood circulation time and have been shown to cross the impaired BBB. We have successfully prepared and characterized the in vitro efficacy and in vivo targeting ability of hydroxyl-G6 PAMAM dendrimer–9-amino-minocycline conjugate (D-mino). Minocycline is a challenging drug to carry out chemical transformations due to its inherent instability. We used a combination of a highly efficient and mild copper catalyzed azide–alkyne click reaction (CuAAC) along with microwave energy to conjugate 9-amino-minocycline (mino) to the dendrimer surface via enzyme responsive linkages. D-mino was further evaluated for anti-inflammatory and antioxidant activity in lipopolysaccharides-activated murine microglial cells. D-mino conjugates enhanced the intracellular availability of the drug due to their rapid uptake, suppressed inflammatory cytokine tumor necrosis factor α (TNF-α) production, and reduced oxidative stress by suppressing nitric oxide production, all significantly better than the free drug. Fluorescently labeled dendrimer conjugate (Cy5–D-mino) was systematically administered (intravenous, 55 mg/kg) on postnatal day 1 to rabbit kits with a clinically relevant phenotype of cerebral palsy. The in vivo imaging study indicates that Cy5–D-mino crossed the impaired blood–brain barrier and co-localized with activated microglia at the periventricular white matter areas, including the corpus callosum and the angle of the lateral ventricle, with significant implications for positive therapeutic outcomes. The enhanced efficacy of D-mino, when combined with the inherent neuroinflammation-targeting capability of the PAMAM dendrimers, may provide new opportunities for targeted drug delivery to treat neurological disorders.

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Low generation polyamine dendrimers bearing flexible tetraethylene glycol as nanocarriers for plasmids and siRNA

Cited by 25 publications

References 68 publications

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

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

Scalable synthesis and validation of PAMAM dendrimer‐N‐acetyl cysteine conjugate for potential translation

Activated Microglia Targeting Dendrimer–Minocycline Conjugate as Therapeutics for Neuroinflammation

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