Versatile activatable vSIRPα-probe for cancer-targeted imaging and macrophage-mediated phagocytosis of cancer cells

Young Ji Ko, Jong Won Lee, Hyosuk Kim, Eun Ji Cho, Yoosoo Yang, In San Kim, Sun Hwa Kim, Ick Chan Kwon

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Signal-regulatory protein alpha (SIRPα) engaged by CD47, that is overexpressed in a wide range of human solid tumors, serves as a ‘Don't eat me’ signal for phagocytic cells such as macrophages and dendritic cells. The SIRPα-CD47 interactions have recently attracted increasing attention in both cancer diagnosis and cancer immunotherapy. Herein, we designed and suggested a lysosomal enzyme-activatable vSIRPα-probe (vSIRPα-probe) capable of facilitating CD47-targeted cancer imaging and eliciting anti-cancer immune responses depending on phagocytosis as a versatile platform for potential cancer theranostic applications. For more efficient and precise cancer targeting, a recombinant SIRPα variant (vSIRPα) having a 50,000-fold higher binding affinity to CD47 than wild-type SIRPα was used to fabricate the vSIRPα-probe by conjugating to a dark-quenched fluorogenic peptide that is a substrate of lysosomal endopeptidases. The vSIRPα-probe could specifically bind to CD47 in different types of cancer cells and be activated by dequenching after cellular internalization. By interrupting the SIRPα-CD47 interaction between macrophages and cancer cells, the vSIRPα-probe promoted the destruction of cancer cells by macrophage-mediated phagocytosis, which was highly comparable to the un-modified vSIRPα recombinant protein. In the mouse tumor-xenografts treated with intravenous injection of the vSIRPα-probe, its enhanced in vivo tumor-targeting and imaging abilities drastically diminished after blocking the SIRPα-CD47 interaction via intratumoral administration of anti-CD47 antibodies. This study demonstrates that our vSIRPα-probe provides a promising tumor-targeted immunotheranostic probe for a novel cancer diagnostic and therapeutic strategy.

Original languageEnglish
Pages (from-to)376-386
Number of pages11
JournalJournal of Controlled Release
Volume323
DOIs
Publication statusPublished - 2020 Jul 10

Keywords

  • Activatable probe
  • CD47-mediated endocytosis
  • Macrophage-mediated phagocytosis of tumor cells
  • Signal-regulatory protein alpha (SIRPα)
  • Tumor-targeted imaging

ASJC Scopus subject areas

  • Pharmaceutical Science

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