Acute kidney injury (AKI) is a common clinical condition associated with increased morbidity and mortality. AKIaccounts for approximately 2% of hospital admissions in the US, and the annual costs for hospital-acquired AKIare approximately $10 billion. Therapeutic interventions for all forms of AKI remain inadequate, in part due tolow drug specificity and poor pharmacokinetic profiles. We have developed a novel nanoscale drug deliveryplatform that selectively targets the proximal tubular epithelium in rodents (Williams, Nano Letters, 2015;Williams, Hypertension, 2018). This strategy localizes drugs up to 26-fold more efficiently in mouse kidneys thanany other organ. The particles release their drug cargo within the proximal and distal tubules while exhibiting notoxic effects on the kidneys or other organs. We and our collaborators have successfully treated murine modelsof both cisplatin-induced AKI (CI-AKI) and ischemia-reperfusion-induced AKI (IR-AKI). Specifically, weadministered mesoscale nanoparticles loaded with the reactive oxygen species (ROS) scavenger edaravone,resulting in striking efficacy against a murine CI-AKI model using a dose of edaravone that was approximately154 times lower than that previously shown to treat AKI systemically in a rodent model (Williams, bioRxiv, 2020).Further, the platform demonstrated effective treatment against IR-AKI in mice via delivery of either animmunomodulatory oligonucleotide (Han, Kidney International, 2020) or a peptide modulator of NF-κB (Han, JCIInsight, 2020). The data presented in our published studies along with preliminary data in this proposaldemonstrate that this mesoscale nanoparticle (MNP) platform exhibits exceptional clinical potential. The overallgoal of our company is to address the unmet need for treatment strategies for renal diseases by targeting bothapproved and experimental therapeutic payloads to the kidneys. The objective of this proposal is to evaluate thepharmacokinetic, biodistribution and efficacy of edaravone-encapsulated MNPs in a pig model of cisplatin-induced AKI. We will pursue the following specific aims: Aim 1: Assess Pharmacokinetics and Biodistribution ofEdaravone-Loaded MNPs in a Porcine AKI Model. We will evaluate the pharmacokinetics and biodistribution ofedaravone-loaded mesoscale nanoparticles in a pig model of AKI. Aim 2: Assess Efficacy and Safety ofEdaravone-Loaded MNPs in a Porcine AKI Model. We will determine efficacy and safety of edaravone-MNPsand compare with soluble edaravone in a cisplatin-induced pig AKI model. The outcomes of this Phase I SBIRinclude an assessment of the biodistribution, pharmacokinetics and efficacy of edaravone-MNPs in pigs as thebest characterized large-animal model to approximate human renal physiology. This work will substantially de-risk this technology. It will also allow the company to initiate CMC and IND-enabling studies and will set the stagefor planning appropriate clinical trials in AKI patients.
Public Health Relevance Statement: PROJECT NARRATIVE
Acute kidney injury (AKI) represents a serious public health problem in the United States for which there is no
effective clinical treatment. We are developing a new drug delivery strategy, mesoscale nanoparticles, to target
therapies directly to the proximal tubular epithelium, where all AKI originates. This project will investigate the
biodistribution, pharmacokinetics and efficacy of mesoscale nanoparticles in a porcine model of cisplatin-induced
AKI as a crucial next step toward advancing this new therapeutic strategy into clinical studies in patients with
AKI.
Project Terms: Affect ; Animals ; Cisplatin ; CDDP ; Cis-diammine-dichloroplatinum ; Cis-diamminedichloridoplatinum ; Cis-diamminedichloro Platinum (II) ; Cis-dichloroammine Platinum (II) ; Cis-platinous Diamine Dichloride ; Cis-platinum II ; Cis-platinum II Diamine Dichloride ; Cisplatina ; Cisplatinum ; Cysplatyna ; Dichlorodiammineplatinum ; Peyrone's Chloride ; Peyrone's Salt ; Platinum Diamminodichloride ; cis dichlorodiammineplatinum ; cis platinum compound ; cis-Diaminedichloroplatinum ; cis-Diamminedichloroplatinum ; cis-Diamminedichloroplatinum(II) ; cis-Dichlorodiammineplatinum(II) ; cis-Platinum ; Clinical Research ; Clinical Study ; Clinical Trials ; Complete Blood Count ; Creatinine ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Dyes ; Coloring Agents ; Exhibits ; Patient Care ; Patient Care Delivery ; Goals ; Histology ; Hospitalization ; Hospital Admission ; Human ; Modern Man ; Hypertension ; Vascular Hypertensive Disease ; Vascular Hypertensive Disorder ; high blood pressure ; hyperpiesia ; hyperpiesis ; hypertensive disease ; Immunohistochemistry ; Immunohistochemistry Cell/Tissue ; Immunohistochemistry Staining Method ; Ischemia ; Kidney ; Kidney Urinary System ; renal ; Kidney Diseases ; Nephropathy ; Renal Disease ; kidney disorder ; renal disorder ; Laboratories ; Length of Stay ; Number of Days in Hospital ; hospital days ; hospital length of stay ; hospital stay ; Morbidity - disease rate ; Morbidity ; mortality ; Multiple Trauma ; Multiple Injuries ; polytrauma ; Mus ; Mice ; Mice Mammals ; Murine ; Nephrons ; Uriniferous Tube ; Oligonucleotides ; Oligo ; oligos ; Patients ; Peptides ; Drug Kinetics ; Pharmacokinetics ; Physiology ; Public Health ; Publishing ; Reperfusion Therapy ; reperfusion ; Risk ; Rodent ; Rodentia ; Rodents Mammals ; Safety ; Specificity ; Mass Spectrum Analysis ; Mass Photometry/Spectrum Analysis ; Mass Spectrometry ; Mass Spectroscopy ; Mass Spectrum ; Mass Spectrum Analyses ; Family suidae ; Pigs ; Suidae ; Swine ; porcine ; suid ; Technology ; Testing ; Time ; Tissues ; Body Tissues ; Translating ; United States ; Urinalysis ; Work ; phenylmethylpyrazolone ; edarabone ; edaravone ; norantipyrine ; norphenazone ; Measures ; Drug Delivery Systems ; Drug Delivery ; lung small cell carcinoma ; Oat cell carcinoma ; Small Cell Lung Cancer ; lung oat cell carcinoma ; lung small cell neuroendocrine carcinoma ; oat cell cancer ; small cell undifferentiated carcinoma ; Injury to Kidney ; kidney injury ; renal injury ; Reactive Oxygen Species ; Active Oxygen ; Oxygen Radicals ; Pro-Oxidants ; Injury ; injuries ; Organ ; improved ; Distal ; Site ; Clinical ; Encapsulated ; Phase ; Medical ; Renal Replacement Therapy ; Kidney Replacement Therapy ; Hospital Costs ; Hospitalization cost ; Epithelial ; Serum ; Blood Serum ; insight ; residence ; residential building ; residential site ; Measurement ; Letters ; Therapeutic ; Metabolic ; Attenuated ; Tubular ; Tubular formation ; Hour ; Complex ; Tumor Tissue ; Heterograft ; Heterologous Transplantation ; Xenograft ; Xenotransplantation ; xeno-transplant ; xeno-transplantation ; Xenograft procedure ; acute kidney injury ; Acute Renal Failure with Renal Papillary Necrosis ; particle ; animal data ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Blood Urea ; Blood Urea Nitrogen ; Toxicities ; Toxic effect ; Immunomodulation ; immune modulation ; immune regulation ; immunologic reactivity control ; immunomodulatory ; immunoregulatory ; immunoregulation ; novel ; economic impact ; intervention therapy ; Therapeutic Intervention ; Modeling ; Experimental Therapies ; Investigational Treatments ; experimental therapeutic agents ; experimental therapeutics ; Investigational Therapies ; Causality ; causation ; disease causation ; Etiology ; small molecule ; Address ; Dose ; Control Animal ; Data ; Clinical Drug Testing/Development ; Clinical Drug Development ; International ; Clinical Treatment ; trial regimen ; trial treatment ; Pharmacological Treatment ; Rodent Model ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Development ; developmental ; nano ; nanoscale ; nano meter scale ; nano meter sized ; nano scale ; nanometer scale ; nanometer sized ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Biodistribution ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Outcome ; targeted delivery ; site targeted delivery ; human disease ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; clinical care ; FDA approved ; standard measure ; treatment strategy ; effective therapy ; effective treatment ; clinical decision-making ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; LCN2 gene ; LCN2 ; Lipocalin 2 ; NGAL ; Neutrophil Gelatinase-Associated Lipocalin ; Oncogenic Lipocalin 24P3 ; Uterocalin ; systemic toxicity ; clinical translation ; porcine model ; pig model ; piglet model ; swine model ;
