6 results on '"Kauffman, Kevin"'
Search Results
2. Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics.
- Author
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Yiping Xing, Shaw, Taylor E., Dahlman, James E., Langer, Robert, Anderson, Daniel G., Mir, Faryal F., Dlott, Chloe C., Kauffman, Kevin J., and Wang, Eric T.
- Subjects
NANOPARTICLES ,THERAPEUTIC nanotechnology ,DRUG delivery systems ,NUCLEIC acids ,GENE therapy ,THERAPEUTICS - Abstract
Nucleic acid therapeutics are limited by inefficient delivery to target tissues and cells and by an incomplete understanding of how nanoparticle structure affects biodistribution to off-target organs. Although thousands of nanoparticle formulations have been designed to deliver nucleic acids, most nanoparticles have been tested in cell culture contexts that do not recapitulate systemic in vivo delivery. To increase the number of nanoparticles that could be tested in vivo, we developed a method to simultaneously measure the biodistribution of many chemically distinct nanoparticles. We formulated nanoparticles to carry specific nucleic acid barcodes, administered the pool of particles, and quantified particle biodistribution by deep sequencing the barcodes. This method distinguished previously characterized lung- and liver-targeting nanoparticles and accurately reported relative quantities of nucleic acid delivered to tissues. Barcode sequences did not affect delivery, and no evidence of particle mixing was observed for tested particles. By measuring the biodistribution of 30 nanoparticles to eight tissues simultaneously, we identified chemical properties promoting delivery to some tissues relative to others. Finally, particles that distributed to the liver also silenced gene expression in hepatocytes when formulated with siRNA. This system can facilitate discovery of nanoparticles targeting specific tissues and cells and accelerate the study of relationships between chemical structure and delivery in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
3. Materials for non-viral intracellular delivery of messenger RNA therapeutics.
- Author
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Kauffman, Kevin J., Webber, Matthew J., and Anderson, Daniel G.
- Subjects
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MESSENGER RNA , *CANCER immunotherapy , *GENE transfection , *BIOCHEMICAL mechanism of action , *DRUG administration , *GENE delivery techniques - Abstract
Though therapeutics based on messenger RNA (mRNA) have broad potential in applications such as protein replacement therapy, cancer immunotherapy, and genomic engineering, their effective intracellular delivery remains a challenge. A chemically diverse suite of delivery materials with origins as materials for cellular transfection of DNA and small interfering RNAs (siRNAs) has recently been reported to have promise as non-viral delivery agents for mRNA. These materials include covalent conjugates, protamine complexes, nanoparticles based on lipids or polymers, and hybrid formulations. This review will highlight the use of delivery materials for mRNA, with a specific focus on their mechanisms of action, routes of administration, and dosages. Additionally, strategies in which these materials can be adapted and optimized to address challenges specific to mRNA delivery are also discussed. The technologies included have shown varying promise for therapeutic use, specifically having been used to deliver mRNA in vivo or exhibiting characteristics that could make in vivo use a possibility. In so doing, it is the intention of this review to provide a comprehensive look at the progress and possibilities in applying nucleic acid delivery technology specifically toward the emerging area of mRNA therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
4. Polymer-Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs.
- Author
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Kaczmarek, James C., Patel, Asha K., Kauffman, Kevin J., Fenton, Owen S., Webber, Matthew J., Heartlein, Michael W., DeRosa, Frank, and Anderson, Daniel G.
- Subjects
MESSENGER RNA ,DRUG delivery systems ,NUCLEIC acids ,POLYETHYLENE glycol ,LUNG disease treatment - Abstract
Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors for safe and effective delivery. Synthetic nanoparticle vectors composed of poly(β-amino esters) (PBAEs) and nucleic acids have previously demonstrated potential utility for local delivery applications. To expand this potential utility to include systemic delivery of mRNA, hybrid polymer-lipid nanoformulations for systemic delivery to the lungs were developed. Through coformulation of PBAEs with lipid-polyethylene glycol (PEG), mRNA formulations were developed with increased serum stability and increased in vitro potency. The formulations were capable of functional delivery of mRNA to the lungs after intravenous administration in mice. To our knowledge, this is the first report of the systemic administration of mRNA for delivery to the lungs using degradable polymer-lipid nanoparticles. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
5. Chapter Three: Nanotechnology for In vivo Targeted siRNA Delivery.
- Author
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Dahlman, James E., Kauffman, Kevin J., Langer, Robert, and Anderson, Daniel G.
- Abstract
Small interfering RNAs (siRNAs) can specifically inhibit gene expression. As a result, they have tremendous scientific and clinical potential. However, the use of these molecules in patients and animal models has been limited by challenges with delivery. Intracellular RNA delivery is difficult; it requires a system that protects the siRNA from degradative nucleases in the bloodstream, minimizes clearance by the reticuloendothelial system, maximizes delivery to the target tissue, and promotes entry into, and out of, an endocytic vesicle. Despite these barriers, recent data suggest that RNA may be targeted to cells of interest in vivo. Herein we outline strategies for targeted siRNA delivery, and describe how these strategies may be improved. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
6. Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent In Vivo mRNA Delivery
- Author
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Mark W. Tibbitt, Rebecca L. McClellan, J. Robert Dorkin, Robert Langer, Frank Derosa, Owen S. Fenton, Eric A. Appel, Kevin J. Kauffman, Daniel G. Anderson, Michael W. Heartlein, Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Koch Institute for Integrative Cancer Research at MIT, Fenton, Owen S., Kauffman, Kevin John, McClellan, Rebecca L, Appel, Eric, Dorkin, Joseph Robert, Tibbitt, Mark W, Langer, Robert S, and Anderson, Daniel Griffith
- Subjects
0301 basic medicine ,Biological inspiration ,Materials science ,Alcohol ,02 engineering and technology ,Alkenes ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Biomimetic Materials ,In vivo ,Humans ,General Materials Science ,RNA, Messenger ,Erythropoietin ,Drug Carriers ,Messenger RNA ,Mechanical Engineering ,RNA ,021001 nanoscience & nanotechnology ,Amino Alcohols ,Lipids ,030104 developmental biology ,Biochemistry ,chemistry ,Mechanics of Materials ,Drug delivery ,Nucleic acid ,Nanoparticles ,0210 nano-technology ,Drug carrier - Abstract
Thousands of human diseases could be treated by selectively controlling the expression of specific proteins in vivo. A new series of alkenyl amino alcohol (AAA) ionizable lipid nanoparticles (LNPs) capable of delivering human mRNA with unprecedented levels of in vivo efficacy is demonstrated. This study highlights the importance of utilizing synthesis tools in tandem with biological inspiration to understand and improve nucleic acid delivery in vivo., National Science Foundation (U.S.). Graduate Research Fellowship Program, Shire Pharmaceuticals, Wellcome Trust-MIT Postdoctoral Fellowship
- Published
- 2016
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