Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge

Hoang, Ky V.; Curry, Heather M.; Collier, Michael A.; Borteh, Hassan; Bachelder, Eric M.; Schlesinger, Larry S.; Ainslie, Kristy M.

doi:10.1128/aac.02228-15

Cited by 18 publications

(27 citation statements)

References 47 publications

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“…The effect of AR-12 as part of combination treatment regimens consisting of both virus-targeting and host-targeting drugs should be evaluated in future studies, as this treatment strategy may be associated with improved clinical outcomes for ZIKV and other RNA viral infections (Hung et al, 2017;Pires de Mello et al, 2017;Zumla et al, 2016). Further optimization of the delivery of AR-12, such as encapsulation of the drug into biodegradable polymeric nanoparticles to reduce cytotoxicity and increase drug concentration per cell may facilitate its use in these clinical settings Hoang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

et al. 2018

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A B S T R A C TZika virus (ZIKV) is a human-pathogenic flavivirus that has recently emerged as a global public health threat. ZIKV infection may be associated with congenital malformations in infected fetuses and severe neurological and systemic complications in infected adults. There are currently limited treatment options for ZIKV infection. AR-12 (OSU-03012) is a celecoxib derivative cellular kinase inhibitor that has broad-spectrum antiviral activities. In this study, we investigated the antiviral activity and mechanism of AR-12 against ZIKV. We evaluated the in vitro anti-ZIKV activity of AR-12, using cell protection and virus yield reduction assays, in multiple clinically relevant cell lines, and the in vivo treatment effects of AR-12 in a lethal mouse model using type I interferon receptordeficient A129 mice. AR-12 inhibited ZIKV strains belonging to both the African and Asian/American lineages in Huh-7 and/or neuronal cells. AR12's IC 50 against ZIKV was consistently < 2 μM in these cells. ZIKV-infected A129 mice treated with intraperitoneally or orally administered AR-12 had significantly higher survival rate (50.0%-83.3% vs 0%, P < 0.05), less body weight loss, and lower blood and tissue ZIKV RNA loads than untreated control A129 mice. These anti-ZIKV effects were likely the results of down-regulation of the PI3K/Akt pathway by AR-12. Clinical trials using the clinically available and broad-spectrum AR-12 as an empirical treatment should be considered especially for patients residing in or returning from areas endemic of ZIKV and other arboviral infections who present with an acute undifferentiated febrile illness.

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Section: Discussionmentioning

confidence: 99%

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

et al. 2018

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“…Unlike PLGA, degradation products of Ace‐DEX (dextran, acetone, and ethanol) are pH‐neutral, which prevents potential toxicities associated with acidification of the local microenvironment. Ace‐DEX is well tolerated in vivo, can be stored outside the cold chain, and has tunable degradation half‐lives based on dextran molecular weight and relative cyclic acetal coverage . Therefore, Ace‐DEX serves as a promising candidate for drug delivery to induce antigen‐specific tolerance for MS treatment.…”

Section: Introductionmentioning

confidence: 99%

Co‐Delivery of Disease Associated Peptide and Rapamycin via Acetalated Dextran Microparticles for Treatment of Multiple Sclerosis

et al. 2017

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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system. While 2.5 million people are affected by MS worldwide, there is no cure other than ameliorating the symptoms through broad immune suppression, which leads to side effects, including increased risks of infection and cancer development. Therefore, tolerance induction specific to disease-associated antigens serves as a promising alternative as it inhibits disease progression without sacrificing immune competence. In this study, the authors show the efficacy of acetalated dextran (Ace-DEX) microparticles (MPs) as a potential MS treatment. Ace-DEX MPs encapsulating ovalbumin (OVA) and the immunosuppressant rapamycin (Rapa) substantially inhibits the inflammation in OVA-induced delayed-type hypersensitivity reactions. When tested as a therapeutic treatment for experimental autoimmune encephalomyelitis, the

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“…AR-12 is a celecoxib-derivative that has been shown to have antimicrobial properties against microbes ranging from bacteria to parasites to fungi and even viruses. [90][91][92][93][94] Early mechanistic studies in cancer cells suggested AR-12 inhibited cellular phosphoinositide-dependent kinase-1 (Pdk1), however this does not appear to be the case in fungi. Recently, it was shown that AR-12 inhibits acetylCoA synthetase, an essential enzyme in fungi.…”

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confidence: 99%

Antifungal therapeutics for dimorphic fungal pathogens

Goughenour

Rappleye

2016

Virulence

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Dimorphic fungi cause several endemic mycoses which range from subclinical respiratory infections to life-threatening systemic disease. Pathogenic-phase cells of Histoplasma, Blastomyces, Paracoccidioides and Coccidioides escape elimination by the innate immune response with control ultimately requiring activation of cell-mediated immunity. Clinical management of disease relies primarily on antifungal compounds; however, dimorphic fungal pathogens create a number of challenges for antifungal drug therapy. In addition to the drug toxicity issues known for current antifungals, barriers to efficient drug treatment of dimorphic fungal infections include natural resistance to the echinocandins, residence of fungal cells within immune cells, the requirement for systemic delivery of drugs, prolonged treatment times, potential for latent infections, and lack of optimized standardized methodology for in vitro testing of drug susceptibilities. This review will highlight recent advances, current therapeutic options, and new compounds on the horizon for treating infections by dimorphic fungal pathogens.

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Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge

Cited by 18 publications

References 47 publications

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

Co‐Delivery of Disease Associated Peptide and Rapamycin via Acetalated Dextran Microparticles for Treatment of Multiple Sclerosis

Antifungal therapeutics for dimorphic fungal pathogens

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