Document text
Principal Investigator: Dmitri Simberg
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2019
Award: $343,881
Funding agency: National Institute of Biomedical Imaging and Bioengineering
DESCRIPTION (provided by applicant): While having tremendous potential as a therapeutic tool, clinical use of engineered nanoparticles has also been associated with serious safety concerns. Following systemic injection, nanoparticles interact with blood proteins causing life-threating hypersensitivity. The uptake of nanoformulations loaded with anticancer toxins by immune cells causes' severe immunosuppression and dose-limiting toxicity. Activation of complement cascade is responsible for many side effects and immune uptake of engineered nanomaterials. In the preliminary data, we demonstrate that activation of complement via the alternative pathway is responsible for the majority of uptake of iron oxide nanoparticles by neutrophils, monocytes, lymphocytes, and platelets. Despite the fact that the alternative pathway has been shown to be essential for complement activation in many types of nanoformulations, the strategies to mitigate the alternative pathway activation on nanoparticles are virtually non-existent. The novel contribution of this proposal is to develop nanosurface-conjugated complement inhibitors based on natural inhibitor proteins. These proteins have been used in the therapeutics of complement-related disorders but have never been evaluated for protecting nanosurfaces against complement. Our preliminary data strongly support the hypothesis that conjugation of the natural alternative pathway inhibitors will significantly improv hemocompatibility of nanoparticles. We established the following Specific Aims: 1) Design alternative pathway inhibitors in silico for subsequent conjugation to nanosurfaces. We will perform 3-D computer modeling of the complement factors and the inhibitor proteins on nanoparticle surface to identify candidate inhibitors and conjugation strategies; 2) determine the complement inhibition efficiency of surface conjugated inhibitors. We will overexpress the inhibitor proteins, or chemically synthesize smaller polypeptides. The inhibitors will be conjugated to various types of nanoparticles via an engineered cysteine group. We will determine the efficiency of the conjugated inhibitors as a function of the inhibitor density, linke type, nanoparticle size, and surface chemistry (charge, presence of targeting antibody and fluorescent dye). These experiments will determine the most efficient inhibitors and conjugation strategies; 3) determine the efficiency of the inhibitors in improving hemocompatibility of drug delivery nanoplatforms. We will prepare nanoplatforms loaded with chemotherapy drugs. The nanoparticles will be modified with inhibitors and tested for complement activation and immune cell uptake using blood from healthy individuals and cancer patients. The results will be highly beneficial in guiding future preclinical and clinical development of inhibitor-decorated nanoplatforms.
Terms: <14-Hydroxydaunomycin><3-D><3-Dimensional><3D><Adriamycine><Allelism Test><Allergy><Alternative Complement Pathway><Antibodies><Artificial nano particles><Artificial nanoparticles><Blood><Blood Eosinophil><Blood Neutrophil><Blood Platelets><Blood Polymorphonuclear Neutrophil><Blood Proteins><Blood Reticuloendothelial System><Blood Serum><Blood leukocyte><Blood monocyte><C3 a><C3a><C3b><C5 a><C5a><Cancer Patient><Cell Body><Cell membrane><Cell surface><Cells><Charge><Chemicals><Chemistry><Clinical><Collaborations><Complement><Complement 3a><Complement 3b><Complement 5a><Complement Activation><Complement C3a><Complement C3b><Complement C5a><Complement Factor H><Complement Inactivators><Complement Inhibitors><Complement Proteins><Complementation Test><Computational Biology><Computer Models><Computer Simulation><Computer based Simulation><Computerized Models><Core Facility><Cysteine><Cytoplasmic Membrane><Data><Deposit><Deposition><Development><Disease><Disorder><Dose-Limiting><Doxorubicin><Doxorubicina><Drug Delivery><Drug Delivery Systems><Drug Targeting><Drug usage><Drugs><Engineering><Eosinophilic Granulocyte><Eosinophilic Leukocyte><Event><Factor H><Fe oxide><Fluorescence Agents><Fluorescent Agents><Fluorescent Dyes><Future><Genetic Complementation Test><Goals><Half-Cystine><Human><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Hypersensitivity><ImProv><Image><Immune><Immunes><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Individual><Inflammatory><Injections><L-Cysteine><Lectin><Leukocytes><Leukocytes Reticuloendothelial System><Life><Lipids><Liposomal><Liposomes><Lymphocyte><Lymphocytic><Marrow Eosinophil><Marrow Neutrophil><Marrow leukocyte><Marrow monocyte><Marrow platelet><Mathematical Model Simulation><Mathematical Models and Simulations><Mediating><Medication><Modeling><Modern Man><Nano platform><Nano-technological platform><Nano-technology platform><Nanoplatform><Nanotechnological platform><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Organism><Pathway interactions><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Plasma Membrane><Platelets><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Properdin Pathway><Proteins><Reaction><Recombinant C5a><Role><Safety><Serum><Serum Proteins><Surface><Taxotere><Testing><Therapeutic><Thrombocytes><Toxic effect><Toxicities><Toxin><Trans Test><White Blood Cells><White Cell><Work><anti-cancer><anticancer><base><chemical conjugate><chemotherapy><clinical development><colcothar><complement pathway regulation><complement system><computational chemistry><computational modeling><computational models><computational simulation><computer based models><computer biology><computerized modeling><computerized simulation><density><design><designing><developmental><docetaxel><docetaxol><drug use><drug/agent><engineered nano particle><engineered nanoparticle><eosinophil><experiment><experimental research><experimental study><ferric oxide><fluorescent dye/probe><hemocompatibility><imaging><immune suppression><improved><in silico><individual patient><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><iron oxide><iron oxide nano particle><iron oxide nanoparticle><lipid nanoparticle><living system><lymph cell><monocyte><nano formulation><nano materials><nano particle><nano-sized particle><nanoformulation><nanomaterials><nanoparticle><nanosized particle><nanotechnology platform><neutrophil><novel><overexpress><overexpression><pathway><plasmalemma><polypeptide><pre-clinical development><preclinical development><prevent><preventing><public health relevance><red iron oxide><side effect><social role><superparamagnetic><superparamagnetism><tool><translational pipeline><translational spectrum><uptake><virtual><virtual simulation><white blood cell><white blood corpuscle>