Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles
Author(s)
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; ... Show more Show less
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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.
Date issued
2018-11Department
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 MITJournal
Biomaterials Science
Publisher
Royal Society of Chemistry
Citation
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
Version: Final published version
ISSN
2047-4830
2047-4849