Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles

Biomaterials. 2012 Aug;33(23):5776-87. doi: 10.1016/j.biomaterials.2012.04.029. Epub 2012 May 15.

Abstract

Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T-cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T-cell/APC contact zone during antigen recognition. To translate these findings into a therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T-cell receptor activation in the synapse, in the context of adoptive T cell therapy of cancer. Conjugating NSC-87877-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer promoted a much greater T-cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. In summary, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well as the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Drug Delivery Systems / methods*
  • Immunologic Factors / administration & dosage*
  • Immunologic Factors / therapeutic use
  • Immunological Synapses / metabolism*
  • Immunotherapy
  • Male
  • Maleimides / chemistry
  • Mass Spectrometry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nanoparticles / chemistry*
  • Prostate / pathology
  • Prostatic Neoplasms / therapy
  • Sulfhydryl Compounds / chemistry
  • T-Lymphocytes / cytology*

Substances

  • Immunologic Factors
  • Maleimides
  • Sulfhydryl Compounds
  • maleimide