Antigen recognition-triggered drug delivery mediated by nanocapsule-functionalized cytotoxic T-cells

R Brad Jones; Stephanie Mueller; Sudha Kumari; Vlad Vrbanac; Shy Genel; Andrew M Tager; Todd M Allen; Bruce D Walker; Darrell J Irvine

doi:10.1016/j.biomaterials.2016.11.048

Antigen recognition-triggered drug delivery mediated by nanocapsule-functionalized cytotoxic T-cells

Biomaterials. 2017 Feb:117:44-53. doi: 10.1016/j.biomaterials.2016.11.048. Epub 2016 Nov 25.

Authors

R Brad Jones¹, Stephanie Mueller², Sudha Kumari², Vlad Vrbanac³, Shy Genel⁴, Andrew M Tager⁵, Todd M Allen⁵, Bruce D Walker⁶, Darrell J Irvine⁷

Affiliations

¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Dept of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington DC, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
² Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
³ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, MGH, Boston, MA, USA.
⁴ Astronomy Dept., Columbia University, New York, NY, USA.
⁵ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁶ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Dept. of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA; Dept. of Biological Engineering, MIT, Cambridge, MA, USA; Dept. of Materials Science & Engineering, MIT, Cambridge, MA, USA.
⁷ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Dept. of Biological Engineering, MIT, Cambridge, MA, USA; Dept. of Materials Science & Engineering, MIT, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address: [email protected].

Abstract

Cytotoxic T-Lymphocytes (CTLs) kill pathogen-infected or transformed cells following interaction of their T-cell receptors (TCRs) with foreign (e.g. virus-derived) peptides bound to MHC-I molecules on the target cell. TCR binding triggers CTLs to secrete perforin, which forms pores in the target cell membrane, promoting target death. Here, we show that by conjugating drug-loaded lipid nanoparticles to the surface of CTLs, their lytic machinery can be co-opted to lyse the cell-bound drug carrier, providing triggered release of drug cargo upon target cell recognition. Protein encapsulated in T-cell-bound nanoparticles was released following culture of CTLs with target cells in an antigen dose- and perforin-dependent manner and coincided with target cell lysis. Using this approach, we demonstrate the capacity of HIV-specific CTLs to deliver an immunotherapeutic agent to an anatomical site of viral replication. This strategy provides a novel means to couple drug delivery to the action of therapeutic cells in vivo.

Keywords: Cytotoxic T lymphocytes; Drug delivery; Immunotherapy; Lipid nanocapsules; T-pharmacyte.

Publication types

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

MeSH terms

Animals
Anti-HIV Agents / administration & dosage*
Autoantigens / immunology*
Delayed-Action Preparations / administration & dosage
HIV Infections / immunology*
HIV Infections / therapy*
Mice
Nanocapsules / administration & dosage*
T-Lymphocytes, Cytotoxic / immunology*
T-Lymphocytes, Cytotoxic / transplantation*

Substances

Anti-HIV Agents
Autoantigens
Delayed-Action Preparations
Nanocapsules

Abstract

Publication types

MeSH terms

Substances

Grants and funding