title: Photochemical internalization of CD133-targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity.
abstract: BACKGROUND
  The normal stem cell marker CD133 is also a putative marker of cancer stem cells (CSCs) in different types of cancers. Hence, a major challenge when targeting CD133-expressing CSCs is to prevent depletion of the normal stem cell pool. We hypothesized that the site-specific and light-controlled drug delivery method photochemical internalization (PCI) may have the potential to enhance selectivity and endosomal escape of CD133-targeting immunotoxins in stem-like sarcoma cells.
  
  
  METHODS
  We have used a sarcoma model, SW872 cells isolated from xenografts harboring CSCs within a ~2% CD133(high) subpopulation to investigate the potential of PCI of CD133-targeting toxin as a novel strategy to kill CSCs. Model immunotoxins were generated by binding the ribosome-inactivating protein toxin saporin to each of the monoclonal antibodies CD133/1 (AC133) or CD133/2 (293C), specific for individual CD133-epitopes. Cellular targeting, intracellular co-localization with the PCI photosensitizer, disulfonated meso-tetraphenylchlorin (TPCS2a), and cytotoxic efficacy of PCI of the CD133-targeting toxins were evaluated.
  
  
  RESULTS
  PCI of CD133-saporin efficiently targets CD133-expressing SW872 and HT1080 sarcoma cells and results in loss of cell viability. Following sub-toxic treatment, surviving SW872 cells, depleted of the CD133-expressing population, display reduced proliferative capacity and attenuated CSC properties, such as reduced colony-forming ability and tumorigenicity.
  
  
  CONCLUSIONS
  Here we present a proof-of-concept study, where PCI enables light-triggered delivery of CD133-targeting antibody-drug conjugates, resulting in decreased sarcoma tumor-initiating capacity.
  
  
  CONCLUSIONS
  PCI of CD133-targeting toxins may be used as a minimal invasive strategy in the treatment of sarcomas, and potentially as a therapeutic for other solid tumors expressing CD133.
authors: Department of Tumor Biology, Oslo University Hospital, Oslo, Norway.
authors: Eva Wessel
authors: EW
authors: Stratford
authors: Monica
authors: M
authors: Bostad
authors: Russell
authors: R
authors: Castro
authors: Ellen
authors: E
authors: Skarpen
authors: Kristian
authors: K
authors: Berg
authors: Anders
authors: A
authors: Høgset
authors: Ola
authors: O
authors: Myklebost
authors: Pål Kristian
authors: PK
authors: Selbo
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000008:administration & dosage*; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D000922:Immunotoxins; C000606023:PROM1 protein, human; D010455:Peptides; D017319:Photosensitizing Agents; C000606024:Prom1 protein, mouse