Topical Application of GS-Nitroxide JP4-039 Emulsion Mitigates Ionizing Irradiation Induced Skin Burns

Epperly, Michael W.; Brand, Rhonda M.; Stottlemyer, J. Mark; Dixon, Tracy; Gao, Xiang; Li, S.; Huq, S.; Wipf, Peter; Falo, Louis D.; Greenberger, J.S.

doi:10.1016/j.ijrobp.2010.07.1478

Cited by 2 publications

(6 citation statements)

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“…3C) is a mitochondria targeted scavenger for reactive oxygen species [6–8]. It has been shown to have protective effects for mucosa [9], skin [10], and bone marrow stems cells against radiation-induced damage. It also ameliorates the irradiation-induced delay of wound healing of bone and improves the survival of mice exposed to large doses of ionizing radiation [11].…”

Section: Introductionmentioning

confidence: 99%

“…and i.v .) or topical such as skin [10] and esophageal [9] deliveries. However, JP4-039 slowly disassociated from the emulsion or liposome particles and started to crystalize.…”

Section: Introductionmentioning

confidence: 99%

“…6−8 It has been shown to have protective effects for mucosa, 9 skin, 10 and bone marrow stem cells 11 of wound healing of bone and improves the survival of mice exposed to large doses of ionizing radiation. 11 Poor water solubility prevented the assessment of the in vivo activity of JP4-039, and we have previously developed biocompatible emulsionand liposome-based formulations for this agent suitable for either systemic (ip and iv) or topical such as skin 10 and esophageal 9 deliveries. However, JP4-039 slowly disassociated from the emulsion or liposome particles and started to crystallize.…”

Section: Introductionmentioning

confidence: 99%

“…Our primary interest is to develop suitable nanoparticle carriers that solubilize JP4-039, a novel peptidomimetic nitroxide antioxidant that showed promising radiation mitigating activities in 32Dcl3 cells and in mouse models. − JP4-039 (Figure C) is a mitochondrion targeted scavenger for reactive oxygen species. − It has been shown to have protective effects for mucosa, skin, and bone marrow stem cells against radiation-induced damage. It also ameliorates the irradiation-induced delay of wound healing of bone and improves the survival of mice exposed to large doses of ionizing radiation .…”

Section: Introductionmentioning

confidence: 99%

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Nanoassembly of Surfactants with Interfacial Drug-Interactive Motifs as Tailor-Designed Drug Carriers

et al. 2012

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PEGylated lipopeptide surfactants carrying drug-interactive motifs specific for a peptide-nitroxide antioxidant, JP4-039, were designed and constructed to facilitate the solubilization of this drug candidate as micelles and emulsion nanoparticles. A simple screening process based on the ability that prevents the formation of crystals of JP4-039 in aqueous solution was used to identify agents that have potential drug-interactive activities. Several protected lysine derivatives possessing this activity were identified, of which α-Fmoc-ε-tBoc lysine is the most potent, followed by α-Cbz- and α-iso-butyloxycarbonyl-ε-tBoc-lysine. Using polymer-supported liquid-phase synthesis approach, a series of synthetic lipopeptide surfactants with PEG head group, varied numbers and geometries of α-Fmoc or α-Cbz-lysyl groups located at interfacial region as the drug-interactive domains, and oleoyl chains as the hydrophobic tails were synthesized. All α-Fmoc-lysyl-containing lipopeptide surfactants were able to solubilize JP4-039 as micelles, with enhanced solubilizing activity for surfactants with increased numbers of α-Fmoc groups. The PEGylated lipopeptide surfactants with α-Fmoc-lysyl groups alone tend to form filamentous or worm-like micelles. The presence of JP4-039 transformed α-Fmoc-containing filamentous micelles into dots and bar-like mixed micelles with substantially reduced sizes. Fluorescence quenching and NMR studies revealed that the drug and surfactant molecules were in a close proximity in the complex. JP4-039-loaded emulsion carrying α-Cbz-containing surfactants demonstrated enhanced stability over drug loaded emulsion without lipopeptide surfactants. JP4-039-emulsion showed significant mitigation effect on mice exposed to a lethal dose of radiation. PEGylated lipopeptides with an interfacially located drug-interactive domain are therefore tailor-designed formulation materials potentially useful for drug development.

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Section: Introductionmentioning

confidence: 99%

“…and i.v .) or topical such as skin [10] and esophageal [9] deliveries. However, JP4-039 slowly disassociated from the emulsion or liposome particles and started to crystalize.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nanoassembly of Surfactants with Interfacial Drug-Interactive Motifs as Tailor-Designed Drug Carriers

et al. 2012

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“…The principles developed in MnSOD–PL normal tissue radioprotection for clinical radiotherapy have helped guide targeted approaches for the protection and mitigation of normal tissue (Epperly et al, 1999c , 2000b , c , 2001b , 2002a , c , 2003a , b , c , d , 2004b , d , e , 2006a , b , 2007b , c , d , 2009 , 2010a , b , e ; Kanai et al, 2002 ; Niu et al, 2010 ). Measuring levels of normal tissue antioxidants and radiation protective physiologic responses has been a valuable concept.…”

Section: Discussionmentioning

confidence: 99%

Strategies for Discovery of Small Molecule Radiation Protectors and Radiation Mitigators

Greenberger¹,

Clump²,

Kagan³

et al. 2012

Front. Oncol.

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Mitochondrial targeted radiation damage protectors (delivered prior to irradiation) and mitigators (delivered after irradiation, but before the appearance of symptoms associated with radiation syndrome) have been a recent focus in drug discovery for (1) normal tissue radiation protection during fractionated radiotherapy, and (2) radiation terrorism counter measures. Several categories of such molecules have been discovered: nitroxide-linked hybrid molecules, including GS-nitroxide, GS-nitric oxide synthase inhibitors, p53/mdm2/mdm4 inhibitors, and pharmaceutical agents including inhibitors of the phosphoinositide-3-kinase pathway and the anti-seizure medicine, carbamazepine. Evaluation of potential new radiation dose modifying molecules to protect normal tissue includes: clonogenic radiation survival curves, assays for apoptosis and DNA repair, and irradiation-induced depletion of antioxidant stores. Studies of organ specific radioprotection and in total body irradiation-induced hematopoietic syndrome in the mouse model for protection/mitigation facilitate rational means by which to move candidate small molecule drugs along the drug discovery pipeline into clinical development.

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Topical Application of GS-Nitroxide JP4-039 Emulsion Mitigates Ionizing Irradiation Induced Skin Burns

Cited by 2 publications

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Nanoassembly of Surfactants with Interfacial Drug-Interactive Motifs as Tailor-Designed Drug Carriers

Nanoassembly of Surfactants with Interfacial Drug-Interactive Motifs as Tailor-Designed Drug Carriers

Strategies for Discovery of Small Molecule Radiation Protectors and Radiation Mitigators

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