1. In vitro-in vivo translation of lipid nanoparticles for hepatocellular siRNA delivery
- Author
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Daniel G. Anderson, Kathryn A. Whitehead, J. Robert Dorkin, Philip H. Chang, Farnaz Niroui, Mariano Severgnini, Jonathan Matthews, 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 Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Whitehead, Kathryn Ann, Matthews, Jonathan, Chang, Philip H., Niroui, Farnaz, Dorkin, Joseph Robert, and Anderson, Daniel Griffith
- Subjects
Carcinoma, Hepatocellular ,Surface Properties ,Cell ,General Physics and Astronomy ,Transfection ,Article ,HeLa ,Mice ,Nanocapsules ,In vivo ,Cell Line, Tumor ,medicine ,Gene silencing ,Animals ,Humans ,General Materials Science ,Gene Silencing ,Particle Size ,RNA, Small Interfering ,Liposome ,biology ,General Engineering ,biology.organism_classification ,Molecular biology ,Lipids ,In vitro ,Cell biology ,medicine.anatomical_structure ,Cell culture ,HeLa Cells - Abstract
A significant challenge in the development of clinically viable siRNA delivery systems is a lack of in vitro–in vivo translatability: many delivery vehicles that are initially promising in cell culture do not retain efficacy in animals. Despite its importance, little information exists on the predictive nature of in vitro methodologies, most likely due to the cost and time associated with generating in vitro–in vivo data sets. Recently, high-throughput techniques have been developed that have allowed the examination of hundreds of lipid nanoparticle formulations for transfection efficiency in multiple experimental systems. The large resulting data set has allowed the development of correlations between in vitro and characterization data and in vivo efficacy for hepatocellular delivery vehicles. Consistency of formulation technique and the type of cell used for in vitro experiments was found to significantly affect correlations, with primary hepatocytes and HeLa cells yielding the most predictive data. Interestingly, in vitro data acquired using HeLa cells were more predictive of in vivo performance than mouse hepatoma Hepa1-6 cells. Of the characterization parameters, only siRNA entrapment efficiency was partially predictive of in vivo silencing potential, while zeta-potential and, surprisingly, nanoparticle size (when, Alnylam Pharmaceuticals (Firm), National Institutes of Health (U.S.) (Fellowship Award F32EB009623)
- Published
- 2012