Niemann-Pick C1 Affects the Gene Delivery Efficacy of Degradable Polymeric Nanoparticles
Despite intensive research effort, the rational design of improved nanoparticulate drug carriers remains challenging, in part due to a limited understanding of the determinants of nanoparticle entry and transport in target cells. Recent studies have shown that Niemann-Pick C1 (NPC1), the lysosome me...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2016
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| Online Access: | http://hdl.handle.net/1721.1/101134 https://orcid.org/0000-0002-2100-1171 https://orcid.org/0000-0001-5629-4798 |
| _version_ | 1811073171139330048 |
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| author | Eltoukhy, Ahmed A. Sahay, Gaurav Cunningham, James M. Anderson, Daniel Griffith |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Eltoukhy, Ahmed A. Sahay, Gaurav Cunningham, James M. Anderson, Daniel Griffith |
| author_sort | Eltoukhy, Ahmed A. |
| collection | MIT |
| description | Despite intensive research effort, the rational design of improved nanoparticulate drug carriers remains challenging, in part due to a limited understanding of the determinants of nanoparticle entry and transport in target cells. Recent studies have shown that Niemann-Pick C1 (NPC1), the lysosome membrane protein that mediates trafficking of cholesterol in cells, is involved in the endosomal escape and subsequent infection caused by filoviruses, and that its absence promotes the retention and efficacy of lipid nanoparticles encapsulating siRNA. Here, we report that NPC1 deficiency results in dramatic reduction in internalization and transfection efficiency mediated by degradable cationic gene delivery polymers, poly(β-amino ester)s (PBAEs). PBAEs utilized cholesterol and dynamin-dependent endocytosis pathways, and these were found to be heavily compromised in NPC1-deficient cells. In contrast, the absence of NPC1 had minor effects on DNA uptake mediated by polyethylenimine or Lipofectamine 2000. Strikingly, stable overexpression of human NPC1 in chinese hamster ovary cells was associated with enhanced gene uptake (3-fold) and transfection (10-fold) by PBAEs. These findings reveal a role of NPC1 in the regulation of endocytic mechanisms affecting nanoparticle trafficking. We hypothesize that in-depth understanding sites of entry and endosomal escape may lead to highly efficient nanotechnologies for drug delivery. |
| first_indexed | 2024-09-23T09:29:30Z |
| format | Article |
| id | mit-1721.1/101134 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:29:30Z |
| publishDate | 2016 |
| publisher | American Chemical Society (ACS) |
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| spelling | mit-1721.1/1011342022-09-30T14:47:24Z Niemann-Pick C1 Affects the Gene Delivery Efficacy of Degradable Polymeric Nanoparticles Eltoukhy, Ahmed A. Sahay, Gaurav Cunningham, James M. Anderson, Daniel Griffith Massachusetts Institute of Technology. Institute for Medical Engineering & Science Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Eltoukhy, Ahmed A. Sahay, Gaurav Anderson, Daniel Griffith Despite intensive research effort, the rational design of improved nanoparticulate drug carriers remains challenging, in part due to a limited understanding of the determinants of nanoparticle entry and transport in target cells. Recent studies have shown that Niemann-Pick C1 (NPC1), the lysosome membrane protein that mediates trafficking of cholesterol in cells, is involved in the endosomal escape and subsequent infection caused by filoviruses, and that its absence promotes the retention and efficacy of lipid nanoparticles encapsulating siRNA. Here, we report that NPC1 deficiency results in dramatic reduction in internalization and transfection efficiency mediated by degradable cationic gene delivery polymers, poly(β-amino ester)s (PBAEs). PBAEs utilized cholesterol and dynamin-dependent endocytosis pathways, and these were found to be heavily compromised in NPC1-deficient cells. In contrast, the absence of NPC1 had minor effects on DNA uptake mediated by polyethylenimine or Lipofectamine 2000. Strikingly, stable overexpression of human NPC1 in chinese hamster ovary cells was associated with enhanced gene uptake (3-fold) and transfection (10-fold) by PBAEs. These findings reveal a role of NPC1 in the regulation of endocytic mechanisms affecting nanoparticle trafficking. We hypothesize that in-depth understanding sites of entry and endosomal escape may lead to highly efficient nanotechnologies for drug delivery. National Cancer Institute (U.S.) (Grant U54CA151884) National Cancer Institute (U.S.) (Grant 5R01HL107550-03) National Heart, Lung, and Blood Institute (Program of Excellence in Nanotechnology (PEN) Award Contract HHSN268201000045C) Skolkovo Foundation 2016-02-09T16:19:38Z 2016-02-09T16:19:38Z 2014-07 2014-03 Article http://purl.org/eprint/type/JournalArticle 1936-0851 1936-086X http://hdl.handle.net/1721.1/101134 Eltoukhy, Ahmed A., Gaurav Sahay, James M. Cunningham, and Daniel G. Anderson. “Niemann-Pick C1 Affects the Gene Delivery Efficacy of Degradable Polymeric Nanoparticles.” ACS Nano 8, no. 8 (August 26, 2014): 7905–13. © 2014 American Chemical Society https://orcid.org/0000-0002-2100-1171 https://orcid.org/0000-0001-5629-4798 en_US http://dx.doi.org/10.1021/nn501630h ACS Nano 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 American Chemical Society (ACS) ACS |
| spellingShingle | Eltoukhy, Ahmed A. Sahay, Gaurav Cunningham, James M. Anderson, Daniel Griffith Niemann-Pick C1 Affects the Gene Delivery Efficacy of Degradable Polymeric Nanoparticles |
| title | Niemann-Pick C1 Affects the Gene Delivery Efficacy of Degradable Polymeric Nanoparticles |
| title_full | Niemann-Pick C1 Affects the Gene Delivery Efficacy of Degradable Polymeric Nanoparticles |
| title_fullStr | Niemann-Pick C1 Affects the Gene Delivery Efficacy of Degradable Polymeric Nanoparticles |
| title_full_unstemmed | Niemann-Pick C1 Affects the Gene Delivery Efficacy of Degradable Polymeric Nanoparticles |
| title_short | Niemann-Pick C1 Affects the Gene Delivery Efficacy of Degradable Polymeric Nanoparticles |
| title_sort | niemann pick c1 affects the gene delivery efficacy of degradable polymeric nanoparticles |
| url | http://hdl.handle.net/1721.1/101134 https://orcid.org/0000-0002-2100-1171 https://orcid.org/0000-0001-5629-4798 |
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