Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development

Background: Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed

Intraesophageal administratio (JP4-039) and p53/MDM2/MDM4 Inhibitor (BEB55) ameliorates radiation esophagitisn of GS-Nitroxide

Purpose/Objective(s): To evaluate the esophageal radiation dose modification properties of the GS-nitroxide (JP4-039) and the p53/MDM2/MDM4 inhibitor (BEB55). Materials/Methods: Esophagitis is a significant toxicity of radiation therapy of thoracic cancers. We evaluated radiation dose modification in the mouse esophagus by GS-nitroxide (JP4-039) and p53/MDM2/MDM4 inhibitor (BEB55). JP4-039 was administered to C57Bl/6Hnsd mice by tube-feed swallow of a novel F15 liposome formulation. The esophagus was excised and esophageal progenitors (SP) and differentiated (NSP) cells separated by cell sorting. The nitroxide uptake was quantified by electron paramagnetic resonance (EPR). C56BL/6Hnsd mice were treated with BEB55 or JP4-039 swallow immediately prior to 28 Gy upper body irradiation. Additional mice were administered 3LL cells intratracheally to induce orthotopic carinal lung tumors. JP4-039 uptake in liver, peripheral blood and lung orthotopic tumor at 10, 30 and 60 minutes after intraesophageal administration was quantified by EPR (n = 3 / time point). Mice with lung orthotopic tumors were treated with intraesophageal BEB55 or JP4-039 prior to receiving 20 Gy upper body irradiation. Results: JP4-039 nitroxide was detected in higher concentrations in SP cells (275 fmole / 1 x 105cells) compared to NSP cells (221 fmole / 3.3 x 106 cells). Mice that received BEB55 or JP4-039 prior to 28 Gy upper body irradiation showed increased survival compared to mice that received irradiation only (p = 0.033 and p = 0.0001, respectively). JP4-039 nitroxide content in excised esophagus, liver, peripheral blood and orthotopic lung tumor had a peak value 10 minutes after swallow (430.1 ± 21.5, 122.2 ± 49.6, 39.0 ± 9.7, 169.5 ± 67.0 pmol / mg protein, respectively). Lung orthotopic tumor bearing mice that received BEB55 or JP4-039 immediately prior to 20 Gy upper body irradiation demonstrated increased survival compared to mice that received irradiation alone (p = 0.044 and p = 0.023, respectively). While detected after swallow in tumor tissue, esophageal radioprotective JP4-039 nitroxide does not detectably decrease the radiation control of thoracic tumors. Conclusions: Swallowed JP4-039 and BEB55 in F15 liposome formulation ameliorates radiation-induced esophagitis without compromising radiation control of orthotopic tumors

A mitochondrial-targeted inhibitor of cytochrorme c peroxidase mitigates radiation-induced death

The risk of radionuclide release in terrorist acts or exposure of healthy tissue during radiotherapy demand potent radioprotectants/radiomitigators. Ionizing radiation induces cell death by initiating the selective peroxidation of cardiolipin in mitochondria by the peroxidase activity of its complex with cytochrome c leading to release of haemoprotein into the cytosol and commitment to the apoptotic program. Here we design and synthesize mitochondria-targeted triphenylphosphonium-conjugated imidazole-substituted oleic and stearic acids that blocked peroxidase activity of cytochrome c/cardiolipin complex by specifically binding to its haem-iron. We show that both compounds inhibit pro-apoptotic oxidative events, suppress cyt c release, prevent cell death, and protect mice against lethal doses of irradiation. Significant radioprotective/radiomitigative effects of imidazole-substituted oleic acid are observed after pretreatment of mice from 1 h before through 24 h after the irradiation