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Author Notes:

Krishnendu Roy, PhD, Robert A. Milton Chair Professor, Director, Center for ImmunoEngineering, Director, NSF Engineering Research Center (ERC) for Cell Manufacturing Technologies, Director, Marcus Center for Therapeutic Cell Characterization and Manufacturing, The Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, The Parker H. Petit Institute for Bioengineering and Biosciences

K.R., J.L. and R.T. conceived the idea. J.L., R.T., and P.P. designed the chemistry and in vitro and in vivo biological experiments. C.V., J.W, Z.L and J.L. designed, conducted and analyzed the TEM, STEM-EDS images of Janus and non-Janus nanoparticles. C.V., and J.J.K designed, conducted and analyzed the data of the modification level quantification study. J.L., R.T., and P.P. carried out the mouse experiments with the assistance of S.D., A.A., and S.K.G.. J.L. analyzed the results and discussed the results with K.R., R.T., and P.P.. C.V. and N.J.W designed the rat experiments and C.V. and E.J.D. conducted the rat experiments. J.C.G., Z.Z., and K.M.K. designed and conducted molecular dynamic simulations and analyzed the simulation results. J.L., C.V., K.P.K. and S.Y.E. designed the photoacoustic imaging experiments and J.L., C.V., K.P.K. performed the experiments and analyzed the results. J.L., D.H., and Y.X designed the ICP-MS biodistribution study and J.L., D.H. performed the experiments and analyzed the data. J.L. composed the manuscript. K.R., R.T., and C.V. edited the manuscript and all other authors commented on the manuscript.

The authors acknowledge financial support from the Georgia Tech Foundation through the Robert A. Milton Chaired Professorship to Krishnendu.Roy., start-up funds from the Georgia Institute of Technology, funds from the Children and Athletes Regenerative Medicine Foundation (12456J4), and Giglio Breast Cancer Innovation Fund (1255d06).

For TEM imaging, the authors acknowledge the Institute for Electronics and Nanotechnology at the Georgia Tech, a member of the National Nanotechnology Coordinated Infrastructure (NNCI), which is supported by the National Science Foundation (ECCS-2025462) and the Center for Nanoscale Materials, an Office of Science user facility supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. For molecular dynamic simulations, the authors acknowledge support from the National Institutes of Health (R01-GM123169). Computational resources were provided through the Extreme Science and Engineering Discovery Environment (XSEDE; allocation TG-MCB130173), which is supported by the National Science Foundation.

The authors declare no competing interests.

Subjects:

Keywords:

  • Science & Technology
  • Physical Sciences
  • Technology
  • Chemistry, Multidisciplinary
  • Chemistry, Physical
  • Nanoscience & Nanotechnology
  • Materials Science, Multidisciplinary
  • Physics, Applied
  • Physics, Condensed Matter
  • Chemistry
  • Science & Technology - Other Topics
  • Materials Science
  • Physics
  • monoclonal antibody
  • Janus nanoparticle
  • myeloid-derived suppressor cell
  • antibody-dependent cellular responses
  • immunotherapy
  • SUPPRESSOR-CELLS
  • S100 PROTEINS
  • PHAGE DISPLAY
  • FC-RECEPTOR
  • ENHANCE
  • ACCUMULATION
  • ACTIVATION
  • TRACKING
  • THERAPY
  • PEPTIDE

Bifunctional Janus Particles as Multivalent Synthetic Nanoparticle Antibodies (SNAbs) for Selective Depletion of Target Cells

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Tools:

Journal Title:

NANO LETTERS

Volume:

Volume 21, Number 1

Publisher:

, Pages 875-886

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Monoclonal antibodies (mAb) have had a transformative impact on treating cancers and immune disorders. However, their use is limited by high development time and monetary cost, manufacturing complexities, suboptimal pharmacokinetics, and availability of disease-specific targets. To address some of these challenges, we developed an entirely synthetic, multivalent, Janus nanotherapeutic platform, called Synthetic Nanoparticle Antibodies (SNAbs). SNAbs, with phage-display-identified cell-targeting ligands on one "face"and Fc-mimicking ligands on the opposite "face", were synthesized using a custom, multistep, solid-phase chemistry method. SNAbs efficiently targeted and depleted myeloid-derived immune-suppressor cells (MDSCs) from mouse-tumor and rat-trauma models, ex vivo. Systemic injection of MDSC-targeting SNAbs efficiently depleted circulating MDSCs in a mouse triple-negative breast cancer model, enabling enhanced T cell and Natural Killer cell infiltration into tumors. Our results demonstrate that SNAbs are a versatile and effective functional alternative to mAbs, with advantages of a plug-and-play, cell-free manufacturing process, and high-throughput screening (HTS)-enabled library of potential targeting ligands.
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