B IOE N 640 6405/P HC E U 72 7230 Summary Notes for Exam I Fall Semester 2017
Introduction / Nanofabrication / Instrumentation •
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Definition of a nanoparticle Examples of nanomaterials/their composition and classification Definitions of nanobiotechnology and nanomedicine Potential routes of exposure of nanoparticles and ramifications Composition and function of a specific nanoenabled system for use in medicine Define and distinguish top down and bottom up approaches Three basic steps of top down planar fabrication process
Inorganic Nanoparticles •
Physicochemical characterization of nanoparticles: parameters (e.g., size), and methods (e.g. DLS)
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Inorganic nanoparticle classification:
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Core composition
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Surface composition
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Shape
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Structural organization
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Inorganic nanoparticle synthesis and characterization:
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Core formation
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Surface modification
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Characterization methods
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Importance of surfaces of nanomaterials
Inorganic Nanoparticles Cont’d •
Reaction parameters to control synthesis
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Microemulsions: definitions and preparation
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Examples of how to control shape/aspect ratio: e.g., gold, zinc, silica Preparation of mesoporous structures Principles of particle size and size distribution methods Zeta potential measurements and surface charge
Polymeric Materials •
Interactions between polymers –
intermolecular forces, MW, packing
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Arrangement of monomers and polymer chains
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Methods of polymer synthesis –
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Key polymerization methods –
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Chain vs step growth: advantages / disadvantages
Bulk, solution, suspension, emulsion
Key characterization methods
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MW, TGA, DSC, thermomechanical •
Reaction of polymers –
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Side reactions, neighboring group effect, local concentration effect
Natural polymers and their examples
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Advances in fabrication and synthetic techniques
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Key conjugation strategies
Nanotoxicology & Cellular Uptake •
Modes of exposure and definitions
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Impact of structural features on biocompatibility
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Key characterization techniques
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Cytotoxicity assays
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Factors to consider in cytotoxicity assays
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Immunotoxicity
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Blood contact
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Key modes of cellular uptake
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In vitro vs in vivo toxicological evaluation
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Interactions at the biological interface
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Influence of protein adsorption
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Cell-type dependence of uptake/toxicity
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Pathways of cellular uptake and trafficking
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Size and shape dependence of internalization Phagocytosis, Autophagy
Drug Release from Polymeric Nanoparticles: Summary A. Diffusion-controlled systems: 1. Monolithic (matrix) devices2. Reservoir devices
B. Solvent-controlled systems: 1. Osmotically controlled devices 2. Swelling-controlled devices
C. Chemically-controlled systems: 1. Drug covalently attached to the polymer backbone 2. Drug in a core surrounded by a bioerodible ratecontrolling membrane. 3. Drug homogeneously dispersed in a bioerodible polymer
Liposome vs. Typical Detergent
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In the aqueous media molecules of PC align themselves in planar bilayer sheets in order to minimize the unfavorable interactions between the bulk aqueous phase and the long hydrocarbon fatty acid chains. These interactions are completely eliminated when the sheets fold on themselves and form closed sealed vesicles. The double fatty acid chain is
Interaction of Liposomes with Cells 1. Adsorption onto cell surface: Nonspecific vs specific. Solid vesicles tend to strongly adsorb onto cell surfaces. 2. Fusion of cell with vesicle: A less likely mechanism. More likely with fluid vesicles. 3. Endocytosis: ”Professional" phagocytes such as the macrophages, internalize vesicles by an active energy dependent phagocytic process. Nonphagocytic cells endocytose liposomes to a lesser extent. Implication in targeting of cancer cells: malignant cells have a higher endocytic indice than other cells types such as muscle cells. 4. Lipid exchange: transfer of lipid molecules between the outer monolayer of liposome and cell without direct association of the two entities. For most vesicle compositions and most cell types, adsorption and
Mechanisms of Drug Delivery by Liposomes 1. The –
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monocyte phagocyte system (MPS) directed delivery:
Useful for the treatment of intracellular infections Liposomes are readily taken up by RES cells, therefore site-specific drug delivery e.g., treatment of systemic fungal infections with liposomal amphotericin B.
Controlled delivery of encapsulated substance:
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Extended release reduces toxic side effects Two main approaches to increase the circulation time/decrease uptake by RES »
a) Blockade of phagocytic uptake by predosing with high doses of liposomes •
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limited value since it is not feasible to close down the defense system of the host.
b) Surface modification of liposomes with PEG (Stealth concept)
Targeted delivery of encapsulated substance:
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Modification of membrane with targeting moieties
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Example: binding antibodies to liposome surface to target cancer cells.
Hemocompatibility of nanomaterials •
Definitions: –
Coagulation, hemostasis, thrombosis, contact activation
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Understand Dr. Grainger’s slides on what happens when a foreign surface contacts the blood… –
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Understand what happens to platelets » Contact activations » Platelet receptors for thrombin and fibrin Understand what happens to proteins » opsonization
Complement activation pathways How long does it take for nanoparticles to be cleared from the blood? (what about long circulating nanoparticles?)
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R ead and unders tand reading materi als provi ded by Dr. Grainger
Nanotoxicogenomics •
Toxicology terms: –
Toxicity
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Dose
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Toxicogenomics
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Dose response curve, exposure, hazard
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Fundamental rules: –
Route
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Frequency
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Duration
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Microarrays and gene expression profiles
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Omics
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Integration of exposure and response
