Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles
We sought to develop a nanoparticle vehicle that could efficiently deliver small molecule drugs to target lymphocyte populations. The synthesized amphiphilic organic ligand-protected gold nanoparticles (amph-NPs) were capable of sequestering large payloads of small molecule drugs within hydrophobic...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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Royal Society of Chemistry
2019
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| Online Access: | http://hdl.handle.net/1721.1/120167 https://orcid.org/0000-0003-0787-298X https://orcid.org/0000-0002-1090-6071 |
| _version_ | 1826216523981651968 |
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| author | Bekdemir, Ahmet Watson, Nicki Ingram, Jessica Stellacci, Francesco R. Yang, Yu-Sang Sabrina Moynihan, Kelly Dare Dichwalkar, Tanmay M Noh, Michelle M. Melo, Mariane Bandeira Suh, Heikyung Ploegh, Hidde Irvine, Darrell J |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Bekdemir, Ahmet Watson, Nicki Ingram, Jessica Stellacci, Francesco R. Yang, Yu-Sang Sabrina Moynihan, Kelly Dare Dichwalkar, Tanmay M Noh, Michelle M. Melo, Mariane Bandeira Suh, Heikyung Ploegh, Hidde Irvine, Darrell J |
| author_sort | Bekdemir, Ahmet |
| collection | MIT |
| description | We sought to develop a nanoparticle vehicle that could efficiently deliver small molecule drugs to target lymphocyte populations. The synthesized amphiphilic organic ligand-protected gold nanoparticles (amph-NPs) were capable of sequestering large payloads of small molecule drugs within hydrophobic pockets of their ligand shells. These particles exhibit membrane-penetrating activity in mammalian cells, and thus enhanced uptake of a small molecule TGF-β inhibitor in T cells in cell culture. By conjugating amph-NPs with targeting antibodies or camelid-derived nanobodies, the particles' cell-penetrating properties could be temporarily suppressed, allowing targeted uptake in specific lymphocyte subpopulations. Degradation of the protein targeting moieties following particle endocytosis allowed the NPs to recover their cell-penetrating activity in situ to enter the cytoplasm of T cells. In vivo, targeted amph-NPs showed 40-fold enhanced uptake in CD8+ T cells relative to untargeted particles, and delivery of TGF-β inhibitor-loaded particles to T cells enhanced their cytokine polyfunctionality in a cancer vaccine model. Thus, this system provides a facile approach to concentrate small molecule compounds in target lymphocyte populations of interest for immunotherapy in cancer and other diseases. |
| first_indexed | 2024-09-23T16:49:04Z |
| format | Article |
| id | mit-1721.1/120167 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T16:49:04Z |
| publishDate | 2019 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | mit-1721.1/1201672022-10-03T08:31:03Z Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles Bekdemir, Ahmet Watson, Nicki Ingram, Jessica Stellacci, Francesco R. Yang, Yu-Sang Sabrina Moynihan, Kelly Dare Dichwalkar, Tanmay M Noh, Michelle M. Melo, Mariane Bandeira Suh, Heikyung Ploegh, Hidde Irvine, Darrell J Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Materials Science and Engineering Koch Institute for Integrative Cancer Research at MIT Yang, Yu-Sang Sabrina Moynihan, Kelly Dare Dichwalkar, Tanmay M Noh, Michelle M. Melo, Mariane Bandeira Suh, Heikyung Ploegh, Hidde Irvine, Darrell J We sought to develop a nanoparticle vehicle that could efficiently deliver small molecule drugs to target lymphocyte populations. The synthesized amphiphilic organic ligand-protected gold nanoparticles (amph-NPs) were capable of sequestering large payloads of small molecule drugs within hydrophobic pockets of their ligand shells. These particles exhibit membrane-penetrating activity in mammalian cells, and thus enhanced uptake of a small molecule TGF-β inhibitor in T cells in cell culture. By conjugating amph-NPs with targeting antibodies or camelid-derived nanobodies, the particles' cell-penetrating properties could be temporarily suppressed, allowing targeted uptake in specific lymphocyte subpopulations. Degradation of the protein targeting moieties following particle endocytosis allowed the NPs to recover their cell-penetrating activity in situ to enter the cytoplasm of T cells. In vivo, targeted amph-NPs showed 40-fold enhanced uptake in CD8+ T cells relative to untargeted particles, and delivery of TGF-β inhibitor-loaded particles to T cells enhanced their cytokine polyfunctionality in a cancer vaccine model. Thus, this system provides a facile approach to concentrate small molecule compounds in target lymphocyte populations of interest for immunotherapy in cancer and other diseases. Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Contract W911NF-13-D-0001) Melanoma Research Alliance National Cancer Institute (U.S.) (David H. Koch Institute for Integrative Cancer Research at MIT. (Support (Core) Grant P30-CA14051) National Institutes of Health (U.S.) (Grant CA174795) National Institutes of Health (U.S.) (Grant CA172164) Horizon 2020 Framework Programme (European Commission). FutureNanoNeeds Project 2019-02-04T15:43:27Z 2019-02-04T15:43:27Z 2018-11 2018-10 2019-01-17T13:49:03Z Article http://purl.org/eprint/type/JournalArticle 2047-4830 2047-4849 http://hdl.handle.net/1721.1/120167 Yang, Yu-Sang Sabrina, Kelly D. Moynihan, Ahmet Bekdemir, Tanmay M. Dichwalkar, Michelle M. Noh, Nicki Watson, Mariane Melo, et al. “Targeting Small Molecule Drugs to T Cells with Antibody-Directed Cell-Penetrating Gold Nanoparticles.” Biomaterials Science 7, no. 1 (2019): 113–124. © The Royal Society of Chemistry https://orcid.org/0000-0003-0787-298X https://orcid.org/0000-0002-1090-6071 http://dx.doi.org/10.1039/c8bm01208c Biomaterials Science Creative Commons Attribution Noncommercial 3.0 unported license https://creativecommons.org/licenses/by-nc/3.0/ application/pdf Royal Society of Chemistry Royal Society of Chemistry (RSC) |
| spellingShingle | Bekdemir, Ahmet Watson, Nicki Ingram, Jessica Stellacci, Francesco R. Yang, Yu-Sang Sabrina Moynihan, Kelly Dare Dichwalkar, Tanmay M Noh, Michelle M. Melo, Mariane Bandeira Suh, Heikyung Ploegh, Hidde Irvine, Darrell J Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles |
| title | Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles |
| title_full | Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles |
| title_fullStr | Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles |
| title_full_unstemmed | Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles |
| title_short | Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles |
| title_sort | targeting small molecule drugs to t cells with antibody directed cell penetrating gold nanoparticles |
| url | http://hdl.handle.net/1721.1/120167 https://orcid.org/0000-0003-0787-298X https://orcid.org/0000-0002-1090-6071 |
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