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Principal Investigator: WILLIAM E. CARSON
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2020
Award: $506,986
Funding agency: National Cancer Institute
PROJECT SUMMARY
RNA nanotechnology has progressed rapidly during the past several years. This nanotechnology includes
the integration of multiple functional modules into one nanoparticle, of which the scaffolds, ligands,
therapeutics, and regulators can be composed mainly or exclusively of RNA. We have constructed RNA
nanoparticles of diverse size, shape, and stoichiometry displaying high chemical and thermodynamic stability
and demonstrated their ability to harbor different functional groups, such as siRNA, miRNA, ribozyme, drug,
and cancer targeting RNA aptamer. All functional modules retain their authentic folding and independent
functionalities for specific cell binding, gene silencing, and cancer targeting in vivo. Upon systemic injection in
tumor bearing mice, RNA nanoparticles bind to xenograft and metastatic tumors specifically and strongly with
little to no accumulation in healthy vital organs and tissues 3-4 hours post-administration. The RNA
nanoparticles are non-toxic and display favorable biodistribution and pharmacokinetic profiles.
Our long-term goal is to promote RNA nanoparticles as a new generation of drug for the treatment of
cancers in the clinic. The short-term goal of this project is to characterize the behavior of RNA nanoparticles in
vitro and in vivo, with an aim to improve the efficiency for specific cell targeting, internalization and intracellular
trafficking, favorable biodistribution without entrapment in liver, endosome escape, and tumor regression.
These studies are based on three central hypotheses: (1) intracellular trafficking pathways and endosome
escape are critical for effective cancer therapy; (2) biodistribution and pharmacological profiles of RNA
nanoparticles are shape and size dependent; and, (3) immune responses elicited by RNA nanoparticles are
highly dependent on RNA sequence, chemical modifications, size, shape, and stoichiometry. To address our
goals, we will (1) systemically dissect the intracellular pathways taken by RNA nanoparticles and enhance
their endosome escape capabilities; (2) inspect the pharmacokinetics (PK); pharmacodynamics (PD); and
biodistribution of RNA nanoparticles with the goal of enhancing cancer targeting with minimal accumulation in
healthy organs; and, (3) evaluate the immune responses of RNA nanoparticles to minimize non-specific side
effects, as well as develop methods to stimulate the immune system by incorporating immuno-stimulatory
modules to RNA nanoparticles for cancer immunotherapy. Upon completion of these pre-clinical studies, we
will have identified several RNA nanoparticles with optimized shape, size, and stoichiometry displaying
favorable safety profiles and high therapeutic efficacy to comply with FDA Investigational New Drug guidelines
for initiating clinical trials.
Terms: <Address><Animals><Antibodies><Attributes of Chemicals><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Behavior><Binding><Biodistribution><Biologic Sciences><Biological Sciences><Bioscience><Biotech><Biotechnology><Body Tissues><Cancer Treatment><Cancers><Catalytic RNA><Caveolin Proteins><Caveolins><Cell Body><Cell Membrane Lipid Rafts><Cells><Chemicals><Clathrin><Clinic><Clinical Trials><Data><Dendritic Cells><Drug Kinetics><Drug Therapy><Drugs><Endocytosis><Endosomes><Excretory function><Exhibits><Gene Inactivation><Gene Silencing><Generations><Goals><Guidelines><Hepatic Neoplasms><Heterograft><Heterologous Transplantation><Hour><IFN><IMiD><Immune><Immune mediated therapy><Immune modulatory therapeutic><Immune reaction><Immune response><Immune system><Immunes><Immunological response><Immunologically Directed Therapy><Immunomodulators><Immunotherapy><In Vitro><Injections><Interferons><Intermediary Metabolism><Investigational Drugs><Investigational New Drug Application><Investigational New Drugs><Lead><Life Sciences><Ligands><Liver><Liver neoplasms><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Membrane Microdomains><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modification><Molecular><Molecular Interaction><Murine><Mus><Nano platform><Nano-technological platform><Nano-technology platform><Nanoplatform><Nanotechnological platform><Nanotechnology><Nature><Neoplasm Metastasis><Non-Polyadenylated RNA><Nucleic Acids><Organ><PK/PD><Pathway interactions><Pb element><Phagocytosis><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Pharmacology><Pharmacotherapy><Pinocytosis><RNA><RNA Gene Products><RNA Sequences><Receptosomes><Reporting><Research><Ribonucleic Acid><Ribozymes><Safety><Secondary Neoplasm><Secondary Tumor><Shapes><Short interfering RNA><Small Interfering RNA><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><T-Cells><T-Lymphocyte><Therapeutic><Thermodynamic><Thermodynamics><Tissues><Toxic effect><Toxicities><Treatment Efficacy><Validation><Veiled Cells><Xenograft><Xenograft procedure><Xenotransplantation><absorption><allergic/immunologic body system><allergic/immunologic organ system><anti-cancer immunotherapy><anti-cancer therapy><anticancer immunotherapy><anticancer therapy><aptamer><base><cancer immunotherapy><cancer metastasis><cancer therapy><clinical relevance><clinical translation><clinically relevant><cytokine><drug treatment><drug/agent><excretion><functional group><heavy metal Pb><heavy metal lead><hepatic body system><hepatic neoplasia><hepatic neoplasm><hepatic organ system><hepatic tumor><host response><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulators><immune modulatory agents><immune modulatory drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunomodulating agents><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoreaction><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><intervention efficacy><large scale production><lead candidate><lipid raft><liver tumor><macrophage><malignancy><miRNA><miRNAs><mouse model><murine model><nano><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanosized particle><nanotech><nanotechnological><nanotechnology platform><neoplasm/cancer><pathway><pharmacokinetics and pharmacodynamics><pre-clinical><pre-clinical safety><pre-clinical study><preclinical><preclinical safety><preclinical study><scaffold><scaffolding><self assembly><siRNA><side effect><stoichiometry><subcutaneous><therapeutic efficacy><therapeutically effective><therapy efficacy><thymus derived lymphocyte><trafficking><transcriptional silencing><tumor><tumor cell metastasis><uptake><xeno-transplant><xeno-transplantation>