Targeted Elimination of Tumorigenic Human Pluripotent Stem Cells Using Suicide-Inducing Virus-like Particles

ACS Chem Biol. 2018 Aug 17;13(8):2329-2338. doi: 10.1021/acschembio.8b00490. Epub 2018 Jul 19.

Abstract

Sensitization to prodrugs via transgenic expression of suicide genes is a leading strategy for the selective elimination of potentially tumorigenic human pluripotent stem cells (hPSCs) in regenerative medicine, but transgenic modification poses safety risks such as deleterious mutagenesis. We describe here an alternative method of delivering suicide-inducing molecules explicitly to hPSCs using virus-like particles (VLPs) and demonstrate its use in eliminating undifferentiated hPSCs in vitro. VLPs were engineered from Qβ bacteriophage capsids to contain enhanced green fluorescent protein (EGFP) or cytosine deaminase (CD) and to simultaneously display multiple IgG-binding ZZ domains. After labeling with antibodies against the hPSC-specific surface glycan SSEA-5, EGFP-containing particles were shown to specifically bind undifferentiated cells in culture, and CD-containing particles were able to eliminate undifferentiated hPSCs with virtually no cytotoxicity to differentiated cells upon treatment with the prodrug 5-fluorocytosine.

Publication types

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

MeSH terms

  • Antimetabolites / administration & dosage*
  • Antimetabolites / pharmacology
  • Capsid Proteins / chemistry*
  • Carcinogenesis / drug effects
  • Cell Differentiation / drug effects*
  • Cell Line
  • Coliphages / chemistry
  • Drug Carriers / chemistry
  • Drug Delivery Systems*
  • Flucytosine / administration & dosage*
  • Flucytosine / pharmacology
  • Green Fluorescent Proteins / administration & dosage
  • Humans
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / drug effects
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / drug effects
  • Prodrugs / administration & dosage*
  • Prodrugs / pharmacology
  • Virion / chemistry*

Substances

  • Antimetabolites
  • Capsid Proteins
  • Drug Carriers
  • Prodrugs
  • coat protein, Bacteriophage Qbeta
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Flucytosine