Optimization of Liposomal Lipid Composition for a New, Reactive Sulfur Donor, and<i>In Vivo</i>Efficacy Studies on Mice to Antagonize Cyanide Intoxication

Petrikovics, Ilona; Jayanna, Prashanth K.; Childress, J.; Budai, Marianna; Martin, Sarah; Kuzmitcheva, G.; Rockwood, Gary A.

doi:10.1155/2011/928626

Cited by 9 publications

(7 citation statements)

References 25 publications

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“…NanoTLZ was synthesized using 1, 2-dipalmitoyl- sn -glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-3-tri methyl-ammonium-propane (chloride salt) (DOTAP), cholesterol, 1,2-distearoyl- sn -glycero-3 phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000 (DSPE-PEG 2000 , Avanti Polar Lipids), and Talazoparib. DOTAP was incorporated within the formulation because some literature suggests it can enhance the encapsulation of hydrophobic compounds 24, 25. It also imparts a slightly positive surface charge, which allows better cell uptake, as cells more readily take up positively charged particles.…”

Section: Methodsmentioning

confidence: 99%

A nano-liposome formulation of the PARP inhibitor Talazoparib enhances treatment efficacy and modulates immune cell populations in mammary tumors of BRCA-deficient mice

et al. 2019

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Two recently approved PARP inhibitors provide an important new therapeutic option for patients with BRCA-mutated metastatic breast cancer. PARP inhibitors significantly prolong progression-free survival in patients, but conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and off-target toxicities, thus compromising the therapeutic benefits and quality of life for patients. Here, we developed a new delivery system, in which the PARP inhibitor Talazoparib is encapsulated in the bilayer of a nano-liposome, to overcome these limitations.Methods: Nano-Talazoparib (NanoTLZ) was characterized both in vitro and in vivo. The therapeutic efficacy and toxicity of Nano-Talazoparib (NanoTLZ) were evaluated in BRCA-deficient mice. The regulation of NanoTLZ on gene transcription and immunomodulation were further investigated in spontaneous BRCA-deficient tumors.Results: NanoTLZ significantly (p<0.05) prolonged the overall survival of BRCA-deficient mice compared to all of the other experimental groups, including saline control, empty nanoparticles, and free Talazoparib groups (oral and i.v.). Moreover, NanoTLZ was better tolerated than treatment with free Talazoparib, with no significant weight lost or alopecia as was observed with the free drug. After 5 doses, NanoTLZ altered the expression of over 140 genes and induced DNA damage, cell cycle arrest and inhibition of cell proliferation in the tumor. In addition, NanoTLZ favorably modulated immune cell populations in vivo and significantly (p<0.05) decreased the percentage of myeloid derived suppressor cells in both the tumor and spleen compared to control groups.Conclusions: Our results demonstrate that delivering nanoformulated Talazoparib not only enhances treatment efficacy but also reduces off-target toxicities in BRCA-deficient mice; the same potential is predicted for patients with BRCA-deficient breast cancer.

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Section: Methodsmentioning

confidence: 99%

A nano-liposome formulation of the PARP inhibitor Talazoparib enhances treatment efficacy and modulates immune cell populations in mammary tumors of BRCA-deficient mice

et al. 2019

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“…The dual interactions lead to very high interaction which was indeed observed experimentally [49]. The toxic effects of cyanide exposure were rapidly reduced by treating 630 mice with rhodanese-loaded liposomes [53]. For further discussion, 631 the authors direct readers to a recent review article by Szilasi et al 632 which summarizes the development of liposomal carriers of enzymes 633 to treat organophosphate and cyanide toxicity [63].…”

mentioning

confidence: 95%

Parenteral emulsions and liposomes to treat drug overdose

Damitz

Chauhan

2015

Advanced Drug Delivery Reviews

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“…Nithiodote®, an FDA approved therapy for cyanide poisoning, contains sodium nitrite and sodium thiosulfate [3]. Sodium thiosulfate acts as a sulfur donor, converting cyanide to the less toxic, renally excreted compound thiocyante [4,5,6]. Thiosulfate relies on the sulfur transferase rhodanese, which is primarily found in the mitochondria of the liver and kidneys.…”

Section: Introductionmentioning

confidence: 99%

Intramuscular dimethyl trisulfide: efficacy in a large swine model of acute severe cyanide toxicity

Hendry‐Hofer

Witeof

Lippner³

et al. 2018

Clinical Toxicology

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Background-Cyanide is a deadly compound used as a terrorist agent. Current FDA approved antidotes require intravenous administration, limiting their utility in a mass casualty scenario. Dimethyl trisulfide (DMTS), a sulfur-based molecule, binds cyanide converting it to the less toxic by-product thiocyanate. Studies evaluating efficacy in rodents have been performed, but a large, clinically relevant animal model has not been reported. Objective-This study evaluates the efficacy of intramuscular DMTS on survival and clinical outcomes in a swine model of acute, severe cyanide toxicity. Methods-Anesthetized swine were instrumented for continuous monitoring of hemodynamics. Prior to potassium cyanide infusion animals were acclimated and breathing spontaneously. At 5minutes post apnea animals were treated with DMTS or saline. Vital signs, hemodynamics, and laboratory values were evaluated at various time points. Results-Baseline values and time to apnea were similar in both groups. Survival in the DMTS treated group was 83.3% and 0% in saline controls (p=0.005). The DMTS group returned to breathing at a mean time of 19.3+10 min after antidote, control animals did not return to breathing (CI difference 8.8, 29.8). At the end of the experiment or time of death, mean lactate was 9.41 mmol/L vs. 4.35 mmol/L (CI difference −10.94,0.82) in the saline and DMTS groups, respectively and pH was 7.20 vs. 7.37 (CI difference −0.04, 0.38). No adverse effects were observed at the injection site. Conclusion-Intramuscular administration of DMTS improves survival and clinical outcomes in our large animal swine model of acute cyanide toxicity.

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Optimization of Liposomal Lipid Composition for a New, Reactive Sulfur Donor, andIn VivoEfficacy Studies on Mice to Antagonize Cyanide Intoxication

Cited by 9 publications

References 25 publications

A nano-liposome formulation of the PARP inhibitor Talazoparib enhances treatment efficacy and modulates immune cell populations in mammary tumors of BRCA-deficient mice

A nano-liposome formulation of the PARP inhibitor Talazoparib enhances treatment efficacy and modulates immune cell populations in mammary tumors of BRCA-deficient mice

Parenteral emulsions and liposomes to treat drug overdose

Intramuscular dimethyl trisulfide: efficacy in a large swine model of acute severe cyanide toxicity

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