Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates
siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2014
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| Online Access: | http://hdl.handle.net/1721.1/91468 https://orcid.org/0000-0002-2100-1171 https://orcid.org/0000-0002-4680-3832 https://orcid.org/0000-0001-5786-0659 https://orcid.org/0000-0001-5629-4798 https://orcid.org/0000-0001-6898-3793 https://orcid.org/0000-0003-3298-6022 https://orcid.org/0000-0001-9522-8208 https://orcid.org/0000-0003-4255-0492 |
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| author | Dong, Yizhou Love, Kevin T. Dorkin, Joseph Robert Sirirungruang, Sasilada Zhang, Yunlong Chen, Delai Bogorad, Roman Yin, Hao Chen, Yi Vegas, Arturo Alabi, Christopher A. Sahay, Gaurav Olejnik, Karsten Wang, Weiheng Schroeder, Avi Lytton-Jean, Abigail K. R. Siegwart, Daniel J. Akinc, Akin Barnes, Carmen Barros, Scott A. Carioto, Mary Fitzgerald, Kevin Hettinger, Julia Kumar, Varun Novobrantseva, Tatiana I. Qin, June Querbes, William Kotelianski, Victor E. Langer, Robert Anderson, Daniel Griffith |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Dong, Yizhou Love, Kevin T. Dorkin, Joseph Robert Sirirungruang, Sasilada Zhang, Yunlong Chen, Delai Bogorad, Roman Yin, Hao Chen, Yi Vegas, Arturo Alabi, Christopher A. Sahay, Gaurav Olejnik, Karsten Wang, Weiheng Schroeder, Avi Lytton-Jean, Abigail K. R. Siegwart, Daniel J. Akinc, Akin Barnes, Carmen Barros, Scott A. Carioto, Mary Fitzgerald, Kevin Hettinger, Julia Kumar, Varun Novobrantseva, Tatiana I. Qin, June Querbes, William Kotelianski, Victor E. Langer, Robert Anderson, Daniel Griffith |
| author_sort | Dong, Yizhou |
| collection | MIT |
| description | siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. cKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date. |
| first_indexed | 2024-09-23T10:50:37Z |
| format | Article |
| id | mit-1721.1/91468 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:50:37Z |
| publishDate | 2014 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/914682022-09-27T15:23:49Z Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates Dong, Yizhou Love, Kevin T. Dorkin, Joseph Robert Sirirungruang, Sasilada Zhang, Yunlong Chen, Delai Bogorad, Roman Yin, Hao Chen, Yi Vegas, Arturo Alabi, Christopher A. Sahay, Gaurav Olejnik, Karsten Wang, Weiheng Schroeder, Avi Lytton-Jean, Abigail K. R. Siegwart, Daniel J. Akinc, Akin Barnes, Carmen Barros, Scott A. Carioto, Mary Fitzgerald, Kevin Hettinger, Julia Kumar, Varun Novobrantseva, Tatiana I. Qin, June Querbes, William Kotelianski, Victor E. Langer, Robert Anderson, Daniel Griffith Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Dong, Yizhou Love, Kevin T. Dorkin, Joseph Robert Sirirungruang, Sasilada Zhang, Yunlong Chen, Delai Bogorad, Roman Yin, Hao Chen, Yi Vegas, Arturo Alabi, Christopher A. Sahay, Gaurav Olejnik, Karsten Wang, Weiheng Schroeder, Avi Lytton-Jean, Abigail K. R. Siegwart, Daniel J. Langer, Robert Anderson, Daniel Griffith siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. cKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date. Alnylam Pharmaceuticals (Firm) National Institutes of Health (U.S.) (NIH Grant R01-EB000244-27) National Institutes of Health (U.S.) (NIH Grant 5-R01-CA132091-04) National Institutes of Health (U.S.) (Postdoctoral Fellowship) 2014-11-05T20:15:35Z 2014-11-05T20:15:35Z 2014-02 2013-12 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/91468 Dong, Y., K. T. Love, J. R. Dorkin, S. Sirirungruang, Y. Zhang, D. Chen, R. L. Bogorad, et al. “Lipopeptide Nanoparticles for Potent and Selective siRNA Delivery in Rodents and Nonhuman Primates.” Proceedings of the National Academy of Sciences 111, no. 11 (February 10, 2014): 3955–3960. https://orcid.org/0000-0002-2100-1171 https://orcid.org/0000-0002-4680-3832 https://orcid.org/0000-0001-5786-0659 https://orcid.org/0000-0001-5629-4798 https://orcid.org/0000-0001-6898-3793 https://orcid.org/0000-0003-3298-6022 https://orcid.org/0000-0001-9522-8208 https://orcid.org/0000-0003-4255-0492 en_US http://dx.doi.org/10.1073/pnas.1322937111 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Dong, Yizhou Love, Kevin T. Dorkin, Joseph Robert Sirirungruang, Sasilada Zhang, Yunlong Chen, Delai Bogorad, Roman Yin, Hao Chen, Yi Vegas, Arturo Alabi, Christopher A. Sahay, Gaurav Olejnik, Karsten Wang, Weiheng Schroeder, Avi Lytton-Jean, Abigail K. R. Siegwart, Daniel J. Akinc, Akin Barnes, Carmen Barros, Scott A. Carioto, Mary Fitzgerald, Kevin Hettinger, Julia Kumar, Varun Novobrantseva, Tatiana I. Qin, June Querbes, William Kotelianski, Victor E. Langer, Robert Anderson, Daniel Griffith Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates |
| title | Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates |
| title_full | Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates |
| title_fullStr | Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates |
| title_full_unstemmed | Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates |
| title_short | Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates |
| title_sort | lipopeptide nanoparticles for potent and selective sirna delivery in rodents and nonhuman primates |
| url | http://hdl.handle.net/1721.1/91468 https://orcid.org/0000-0002-2100-1171 https://orcid.org/0000-0002-4680-3832 https://orcid.org/0000-0001-5786-0659 https://orcid.org/0000-0001-5629-4798 https://orcid.org/0000-0001-6898-3793 https://orcid.org/0000-0003-3298-6022 https://orcid.org/0000-0001-9522-8208 https://orcid.org/0000-0003-4255-0492 |
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