Septic shock continues to be a leading cause of morbidity and mortality worldwide. The increasing bacterialantibiotic resistance is forcing the search for new methods to improve prognosis. Traditional resuscitationtherapy is not designed to address the physiological mechanisms of septic shock that contribute tohypotension and organ failure. The inflammatory response is a limiting factor even with interventions such asrenal replacement therapy and extracorporeal membrane oxygenation. Vivacelle Bio has patented VBI-1, anovel anti-inflammatory suspension of phospholipid nanoparticles designed to modulate the bioavailability ofnitric oxide (NO) responsible for excessive vasodilatation, hypotension, or dangerous reperfusion injury thatleads to organ failure in septic shock. Preliminary data support the ability of VBI-1 to carry life-sustainingamounts of oxygen and to absorb reversibly and quickly NO. Because of this reversibility, VBI-1 representsa novel approach to the modulation of NO that reduces its bioavailability without stopping its production or itsautocrine or paracrine effects. Through its NO uptake and release, VBI-1 acts as a high-capacity NOmodulator. At the same time, VBI-1 can carry oxygen and enable oxygen transport during resuscitationtherapy. VBI-1 also inhibits the inflammatory response, reducing ischemia-reperfusion injury and organdysfunction. Also, the small nanoparticle size and high emulsifier content of VBI-1 guarantee longer stabilityand higher efficacy in raising blood pressure when compared to currently used resuscitation fluids. Finally,VBI-1 is based on non-allergic soybean-oil micelles and liposomes comprised of phospholipid bilayers whichmake the new formulation highly biocompatible. VBI-1 formulation has been successfully proven to treathemorrhagic shock with up to 55% replacement of blood volume without evidence of fat emboli, toxicity, orlung injury. In this SBIR grant, Vivacelle Bio will validate VBI-1 as a superior product for intravascular volumereplacement compared to current resuscitation fluids, such as albumin or saline, in treating septic shock. Toestablish the feasibility of this approach, we propose the following two specific aims: 1) demonstrate theefficacy of VBI-1 when used in vivo on a Cecal Ligation Puncture (CLP) rat model of severe septic shock and2) validate in vivo the NO modulatory effect by measuring NO biomarkers in the same CLP rat model. Thiswork will be preparatory for further studies in Phase II, aimed at optimizing the formulation of VBI-1 andobtaining an FDA licensure for its use as a fluid for reducing the intensity of the inflammatory process in theintravascular space.
Public Health Relevance Statement: PROJECT NARRATIVE
Given the high mortality of septic shock and the worsening of bacterial antibiotic resistance, there is an urgent
need for new antibiotic-independent methods to treat septic shock. Vivacelle Bio is developing a phospholipid
nanoparticle colloid to treat refractory septic shock by effectively raising blood pressure, modulating nitric
oxide (NO), and protecting against reperfusion injury. The proposed project will establish the feasibility of this
novel product in a preclinical animal model for sepsis by demonstrating its efficacy and validating its NO
modulatory effect, to drive future clinical validation.
Project Terms: Albumins ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Antibiotics ; Antibiotic Agents ; Antibiotic Drugs ; Miscellaneous Antibiotic ; bile salts ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Biophysics ; biophysical foundation ; biophysical principles ; biophysical sciences ; Blood ; Blood Reticuloendothelial System ; Blood Chemical Analysis ; Blood Chemical Analyses ; blood chemistry ; Blood Pressure ; Blood Volume ; Cardiovascular system ; Cardiovascular ; Cardiovascular Body System ; Cardiovascular Organ System ; Heart Vascular ; circulatory system ; Cause of Death ; Clinical Trials ; Colloids ; Dangerousness ; Cessation of life ; Death ; Embolism ; Embolus ; Therapeutic Embolization ; Embolization Therapy ; Embolotherapy ; embolization ; Emulsions ; Environment ; Extracorporeal Membrane Oxygenation ; Fatty acid glycerol esters ; Fats ; Future ; Grant ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Health ; Hemorrhage ; Bleeding ; blood loss ; Human ; Modern Man ; Hypotension ; Low Blood Pressure ; Vascular Hypotensive Disorder ; Licensure ; Liposomes ; Liposomal ; Metabolism ; Intermediary Metabolism ; Metabolic Processes ; Methemoglobin ; Ferrihemoglobin ; met-hemoglobins ; Methods ; Micelles ; Mitochondria ; mitochondrial ; Morbidity - disease rate ; Morbidity ; mortality ; Nitrates ; NO3- ; nitrate ; Nitric Oxide ; Endogenous Nitrate Vasodilator ; Endothelium-Derived Nitric Oxide ; Mononitrogen Monoxide ; Nitrogen Monoxide ; Nitrogen Protoxide ; endothelial cell derived relaxing factor ; Nitrites ; Oxygen ; O element ; O2 element ; Legal patent ; Patents ; Perfusion ; Drug Kinetics ; Pharmacokinetics ; Phospholipids ; Phosphatides ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Plasmapheresis ; Therapeutic Plasma Exchange ; Therapeutic Plasmapheresis ; Privatization ; Production ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Reperfusion Injury ; Ischemia-Reperfusion Injury ; Reperfusion Damage ; Respiration ; respiratory mechanism ; Rest ; Resuscitation ; Safety ; Saline ; Saline Solution ; Hemorrhagic Shock ; Septic Shock ; Soybean Oil ; Soy Bean Oil ; Soya Oil ; Spectrophotometry ; spectrophotometer ; Mass Spectrum Analysis ; Mass Photometry/Spectrum Analysis ; Mass Spectrometry ; Mass Spectroscopy ; Mass Spectrum ; Mass Spectrum Analyses ; Survival Rate ; Suspensions ; Suspension substance ; Time ; Tissues ; Body Tissues ; vasoconstriction ; vascular constriction ; Vasoconstrictor Agents ; Vasoactive Agonists ; Vasoconstrictor Drugs ; Vasoconstrictors ; Vasopressor Agents ; vasopressor ; Vasodilation ; Vasodilatation ; Vasorelaxation ; Work ; Lactated Ringer's Solution ; Hartmann's solution ; Ringer's lactate ; Measures ; Treatment outcome ; Antibiotic Resistance ; Resistance to antibiotics ; Resistant to antibiotics ; antibiotic drug resistance ; antibiotic resistant ; Treatment Cost ; Sodium Cholate ; Sodium Choleate ; Injury to Kidney ; kidney injury ; renal injury ; base ; Organ ; improved ; Area ; Clinical ; Refractory ; Phase ; Physiological ; Physiologic ; Renal Replacement Therapy ; Kidney Replacement Therapy ; Ensure ; Failure ; Licensing ; uptake ; lung injury ; Lung damage ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Intellectual Property ; Therapeutic ; fluid ; liquid ; Liquid substance ; Inflammatory ; Life ; Exhaling ; Respiratory Expiration ; Exhalation ; Hypovolemia ; Infusion ; Infusion procedures ; Autocrine Systems ; autocrine ; biocompatibility ; biomaterial compatibility ; blood filtration ; oxygen transport ; paracrine ; particle ; Hydrophobicity ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; aqueous ; Toxicities ; Toxic effect ; novel ; Modeling ; Property ; Intervention Strategies ; interventional strategy ; Intervention ; health organization ; Organ failure ; antibiotic resistant bacteria ; bacterial antibiotic resistant ; bacterial resistance to antibiotic ; Bacterial Antibiotic Resistance ; Inflammatory Response ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Diameter ; Caliber ; Address ; Data ; Detection ; International ; in vivo ; Nitric Oxide Synthetase Inhibitor ; nitric oxide synthase inhibitor ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Validation ; Pathologic ; Immunologics ; Immunochemical Immunologic ; Immunologic ; Immunological ; Immunologically ; Monitor ; Characteristics ; Process ; Development ; developmental ; Allergic Reaction ; nano ; Pathway interactions ; pathway ; pre-clinical ; preclinical ; design ; designing ; Sepsis ; blood infection ; bloodstream infection ; novel strategies ; new approaches ; novel approaches ; novel strategy ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Outcome ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; Formulation ; improved outcome ; experimental study ; experiment ; experimental research ; efficacy study ; cecal ligation puncture ; CLP model ; CLP mouse model ; Cecal ligation perforation ; pre-clinical assessment ; preclinical assessment ; sheep model ; ovine animal model ; ovine model ; Prognosis ;
