Photochemical internalization of CD133-targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity |
| |
Authors: | Eva Wessel Stratford,Monica Bostad,Russell Castro,Ellen Skarpen,Kristian Berg,Anders Hø gset,Ola Myklebost,På l Kristian Selbo |
| |
Affiliation: | 1. Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway;2. Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway;3. Cancer Stem Cell Innovation Centre (SFI-CAST), Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway;4. Confocal Microscopy Core Facility, Department of Biochemistry, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway;5. PCI Biotech AS, Lysaker, Norway;6. Department of Molecular Bioscience, University of Oslo, Norway |
| |
Abstract: | BackgroundThe 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.MethodsWe have used a sarcoma model, SW872 cells isolated from xenografts harboring CSCs within a ~ 2% CD133high 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.ResultsPCI 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.ConclusionHere 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.General significancePCI 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. |
| |
Keywords: | CD133 Cancer stem cell Photochemical internalization Endosomal escape Drug delivery Sarcoma |
本文献已被 ScienceDirect 等数据库收录! |
|