4 results on '"Kauffman, Kevin"'
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2. Optimization of Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with Fractional Factorial and Definitive Screening Designs.
- Author
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Kauffman KJ, Dorkin JR, Yang JH, Heartlein MW, DeRosa F, Mir FF, Fenton OS, and Anderson DG
- Subjects
- Cell Line, Tumor, Humans, Lipids administration & dosage, Liposomes administration & dosage, Liposomes chemistry, Liver drug effects, Nanoparticles administration & dosage, Phosphatidylethanolamines administration & dosage, Phosphatidylethanolamines chemistry, Polyethylene Glycols chemistry, RNA, Messenger chemistry, Transfection, Gene Transfer Techniques, Lipids chemistry, Nanoparticles chemistry, RNA, Messenger administration & dosage
- Abstract
Intracellular delivery of messenger RNA (mRNA) has the potential to induce protein production for many therapeutic applications. Although lipid nanoparticles have shown considerable promise for the delivery of small interfering RNAs (siRNA), their utility as agents for mRNA delivery has only recently been investigated. The most common siRNA formulations contain four components: an amine-containing lipid or lipid-like material, phospholipid, cholesterol, and lipid-anchored polyethylene glycol, the relative ratios of which can have profound effects on the formulation potency. Here, we develop a generalized strategy to optimize lipid nanoparticle formulations for mRNA delivery to the liver in vivo using Design of Experiment (DOE) methodologies including Definitive Screening and Fractional Factorial Designs. By simultaneously varying lipid ratios and structures, we developed an optimized formulation which increased the potency of erythropoietin-mRNA-loaded C12-200 lipid nanoparticles 7-fold relative to formulations previously used for siRNA delivery. Key features of this optimized formulation were the incorporation of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and increased ionizable lipid:mRNA weight ratios. Interestingly, the optimized lipid nanoparticle formulation did not improve siRNA delivery, indicating differences in optimized formulation parameter design spaces for siRNA and mRNA. We believe the general method described here can accelerate in vivo screening and optimization of nanoparticle formulations with large multidimensional design spaces.
- Published
- 2015
- Full Text
- View/download PDF
3. Synthesis and characterization of acetalated dextran polymer and microparticles with ethanol as a degradation product.
- Author
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Kauffman KJ, Do C, Sharma S, Gallovic MD, Bachelder EM, and Ainslie KM
- Subjects
- Animals, Cell Line, Cell Survival, Humans, Hydrogen-Ion Concentration, Immune System, Kinetics, Magnetic Resonance Spectroscopy methods, Mice, Microspheres, Models, Chemical, Particle Size, Tetrazolium Salts chemistry, Thiazoles chemistry, Vaccines chemistry, Dextrans chemistry, Ethanol chemistry, Polymers chemistry, Tissue Engineering instrumentation, Tissue Engineering methods, Tissue Scaffolds chemistry
- Abstract
In the field of drug delivery, pH-sensitive polymeric microparticles can be used to release therapeutic payloads slowly in extracellular conditions (pH 7.4) and faster in more acidic areas in vivo, such as sites of inflammation, tumors, or intracellular conditions. Our group currently uses and is further developing the pH-sensitive polymer acetalated dextran (Ac-DEX), which is a biodegradable polymer with highly tunable degradation kinetics. Ac-DEX has displayed enhanced delivery of vaccine and drug components to immune and other cells, making it an extremely desirable polymer for immune applications. Currently, one of the degradation products of Ac-DEX is methanol, which may cause toxicity issues if applied at high concentrations with repeated doses. Therefore, in this manuscript we report the first synthesis and characterization of an Ac-DEX analog which, instead of a methanol degradation product, has a much safer ethanol degradation product. We abbreviate this ethoxy acetal derivatized acetalated dextran polymer as Ace-DEX, with the 'e' to indicate an ethanol degradation product. Like Ac-DEX, Ace-DEX microparticles have tunable degradation rates at pH 5 (intracellular). These rates range from hours to several days and are controlled simply by reaction time. Ace-DEX microparticles also show minimal cytotoxicity compared to commonly used poly(lactic-co-glycolic acid) (PLGA) microparticles when incubated with macrophages. This study aims to enhance the biocompatibility of acetalated dextran-type polymers to allow their use in high volume clinical applications such as multiple dosing and tissue engineering.
- Published
- 2012
- Full Text
- View/download PDF
4. Synthesis, optimization, and characterization of camptothecin-loaded acetalated dextran porous microparticles for pulmonary delivery.
- Author
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Meenach SA, Kim YJ, Kauffman KJ, Kanthamneni N, Bachelder EM, and Ainslie KM
- Subjects
- Acetals chemistry, Administration, Inhalation, Antineoplastic Agents, Phytogenic chemistry, Camptothecin chemistry, Cell Line, Tumor, Delayed-Action Preparations administration & dosage, Dose-Response Relationship, Drug, Humans, Hydrogen-Ion Concentration, Lactic Acid chemistry, Macrophages, Alveolar metabolism, Microspheres, Molecular Weight, Particle Size, Polyglycolic Acid chemistry, Polylactic Acid-Polyglycolic Acid Copolymer, Porosity, Antineoplastic Agents, Phytogenic administration & dosage, Camptothecin administration & dosage, Delayed-Action Preparations chemistry, Dextrans chemistry, Lung, Macrophages, Alveolar drug effects
- Abstract
We propose the use of a new biopolymer, acetalated dextran (Ac-DEX), to synthesize porous microparticles for pulmonary drug delivery. Ac-DEX is derived from the polysaccharide dextran and, unlike polyesters, has tunable degradation from days to months and pH neutral degradation products. Ac-DEX microparticles fabricated through emulsion techniques were optimized using a variety of postprocessing techniques to enhance the respirable fraction for pulmonary delivery. Tangential flow filtration resulted in a maximum 37% respirable fraction for Ac-DEX porous microparticles, compared to a 10% respirable fraction for poly(lactic-co-glycolic acid) (PLGA) porous microparticles. Ac-DEX microparticles were of an optimum diameter to minimize macrophage clearance but had a low enough theoretical density for deep lung penetration. Transepithelial electrical resistance (TEER) measurements showed that the particles did not impinge on a monolayer of lung epithelial cells in either air or liquid conditions. Also, the release of the chemotherapeutic camptothecin was shown to be tunable depending on Ac-DEX degradation time and molecular weight, and drug release was shown to be bioactive over a range of concentrations. Our results indicate that both release kinetics and fraction of burst release of drug from Ac-DEX porous microparticles can be tuned by simply changing the Ac-DEX polymer properties, affording a large range of formulation options for drug delivery to the pulmonary cavity. Overall, Ac-DEX porous microparticles show promise as an emerging carrier for pulmonary delivery of drugs to the alveolar region of the lung, particularly for the treatment of lung diseases.
- Published
- 2012
- Full Text
- View/download PDF
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