Photochemical internalization (PCI) of immunotoxins targeting CD133 is specific and highly potent at femtomolar levels in cells with cancer stem cell properties

CD133 is a putative cancer stem cell (CSC) marker for a number of different cancers and is suggested to be a therapeutic target. Since also normal stem cells express CD133 it is of paramount importance that targeting strategies provide a specific and efficient delivery of cytotoxic drugs in only CD1...

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Bibliographic Details
Published in:Journal of controlled release 2013-06, Vol.168 (3), p.317-326
Main Authors: Bostad, Monica, Berg, Kristian, Høgset, Anders, Skarpen, Ellen, Stenmark, Harald, Selbo, Pål K.
Format: Article
Language:English
Subjects:
AC133 Antigen
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal - chemistry
Antigens, CD - immunology
Cancer stem cells
CD133
Cell Line, Tumor
colon
Colorectal cancer
cytosol
cytotoxicity
Drug Delivery Systems
drugs
endosomes
flow cytometry
fluorescence microscopy
Glycoproteins - immunology
Humans
Immunotoxin
lysosomes
mice
neoplasm cells
neoplasms
Neoplastic Stem Cells - immunology
pancreas
Peptides - immunology
Photochemical internalization
Photochemical Processes
Photochemotherapy
Photodynamic therapy
Photosensitizing Agents - administration & dosage
Porphyrins - administration & dosage
Ribosome Inactivating Proteins, Type 1 - administration & dosage
Ribosome Inactivating Proteins, Type 1 - chemistry
ribosomes
stem cells
therapeutics
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Summary:CD133 is a putative cancer stem cell (CSC) marker for a number of different cancers and is suggested to be a therapeutic target. Since also normal stem cells express CD133 it is of paramount importance that targeting strategies provide a specific and efficient delivery of cytotoxic drugs in only CD133-positive CSCs. In this study, we have employed photochemical internalization (PCI), a minimally invasive method for light-controlled, specific delivery of membrane-impermeable macromolecules from endocytic vesicles to the cytosol, to specifically target CD133-positive cancer cells. We demonstrate that PCI increases the cytotoxic effect of an immunotoxin (IT) targeting CD133-expressing cancer cells of colon (WiDr and HCT116) and pancreas (BxPC-3) origin. The IT consisted of the mAb CD133/1 (AC133) bound to the ribosome inactivating plant toxin saporin (anti-CD133/1-sap). We show that TPCS2a-PCI of anti-CD133/1-sap is specific, and highly cytotoxic at femto-molar concentrations. Specific binding and uptake of CD133/1, was shown by fluorescence microscopy and co-localization with TPCS2a in endosomes/lysosomes was determined by confocal microscopy. CD133high WiDr cells, isolated by fluorescence activated cell sorting, had a 7-fold higher capacity to initiate spheroids than CD133low cells (P
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2013.03.023