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3 results on '"J. Robert Dorkin"'

1. Poly(glycoamidoamine) Brushes Formulated Nanomaterials for Systemic siRNA and mRNA Delivery in Vivo

Author

J. Robert Dorkin, Frank Derosa, Daniel G. Anderson, Michael W. Heartlein, Philip H. Chang, Dganit Danino, Yizhou Dong, Benjamin C. Tang, Weiheng Wang, Matthew J. Webber, Junghoon Yang, Robert Langer, and Inbal Abutbul-Ionita

Subjects
0301 basic medicine, Materials science, medicine.medical_treatment, Bioengineering, 02 engineering and technology, Pharmacology, Polymer brush, Article, Nanomaterials, Mice, 03 medical and health sciences, In vivo, Liver enzyme, medicine, Animals, Humans, General Materials Science, RNA, Messenger, RNA, Small Interfering, Erythropoietin, Messenger RNA, Mechanical Engineering, Gene Transfer Techniques, Genetic Therapy, General Chemistry, Factor VII, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Effective dose (pharmacology), Molecular biology, 030104 developmental biology, Cytokine, Nanoparticles, 0210 nano-technology, medicine.drug
Abstract

Safe and effective delivery is required for siRNA and mRNA-based therapeutics to reach their potential. Here, we report on the development of poly(glycoamidoamine) brush nanoparticles as delivery vehicles for siRNA and mRNA. These polymers were capable of significant delivery of siRNA against FVII and mRNA-encoding erythropoietin (EPO) in mice. Importantly, these nanoparticles were well-tolerated at their effective dose based on analysis of tissue histology, systemic cytokine levels, and liver enzyme chemistry. The polymer brush nanoparticles reported here are promising for therapeutic applications.

Published
2016

2. Optimization of Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with Fractional Factorial and Definitive Screening Designs

Author

Jung H. Yang, Owen S. Fenton, J. Robert Dorkin, Kevin J. Kauffman, Michael W. Heartlein, Frank Derosa, Faryal F. Mir, and Daniel G. Anderson

Subjects
Materials science, Phospholipid, Bioengineering, Polyethylene glycol, Transfection, Polyethylene Glycols, chemistry.chemical_compound, In vivo, Cell Line, Tumor, Protein biosynthesis, Potency, Humans, General Materials Science, RNA, Messenger, Messenger RNA, Cholesterol, Mechanical Engineering, Phosphatidylethanolamines, Gene Transfer Techniques, Fractional factorial design, General Chemistry, Condensed Matter Physics, Lipids, chemistry, Biochemistry, Liver, Liposomes, Nanoparticles, lipids (amino acids, peptides, and proteins)
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

3. Optimization of Lipid Nanoparticle Formulations formRNA Delivery in Vivo with Fractional Factorial and Definitive ScreeningDesigns.

Author

Kevin J. Kauffman, J. Robert Dorkin, Jung H. Yang, Michael W. Heartlein, Frank DeRosa, Faryal F. Mir, Owen S. Fenton, and Daniel G. Anderson

Subjects
*NANOPARTICLES, *LIPIDS, *MESSENGER RNA, *DRUG delivery systems, *MATHEMATICAL optimization, *SMALL interfering RNA, *POLYETHYLENE glycol
Abstract

Intracellulardelivery of messenger RNA (mRNA) has the potential to induce proteinproduction for many therapeutic applications. Although lipid nanoparticleshave shown considerable promise for the delivery of small interferingRNAs (siRNA), their utility as agents for mRNA delivery has only recentlybeen investigated. The most common siRNA formulations contain fourcomponents: an amine-containing lipid or lipid-like material, phospholipid,cholesterol, and lipid-anchored polyethylene glycol, the relativeratios of which can have profound effects on the formulation potency.Here, we develop a generalized strategy to optimize lipid nanoparticleformulations for mRNA delivery to the liver in vivo using Design ofExperiment (DOE) methodologies including Definitive Screening andFractional Factorial Designs. By simultaneously varying lipid ratiosand structures, we developed an optimized formulation which increasedthe potency of erythropoietin-mRNA-loaded C12-200 lipid nanoparticles7-fold relative to formulations previously used for siRNA delivery.Key features of this optimized formulation were the incorporationof 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine(DOPE) and increased ionizable lipid:mRNA weight ratios. Interestingly,the optimized lipid nanoparticle formulation did not improve siRNAdelivery, indicating differences in optimized formulation parameterdesign spaces for siRNA and mRNA. We believe the general method describedhere can accelerate in vivo screening and optimization of nanoparticleformulations with large multidimensional design spaces. [ABSTRACT FROM AUTHOR]

Published
2015
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