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Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin
Epidermal growth factor receptor (EGFR) targeting has become a major field in both cancer research and therapy. In the present study an EGF–saporin affinity toxin has been established and evaluated in two EGFR overexpressing cancer cell lines. The binding of saporin to EGF did not influence the ribo...
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Published in: | Journal of controlled release 2006-03, Vol.111 (1), p.165-173 |
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description | Epidermal growth factor receptor (EGFR) targeting has become a major field in both cancer research and therapy. In the present study an EGF–saporin affinity toxin has been established and evaluated in two EGFR overexpressing cancer cell lines. The binding of saporin to EGF did not influence the ribosome-inactivating activity of saporin as measured by a luminescence based reticulocyte lysate assay. Control experiments, using untargeted saporin, EGFR-negative cell lines and competition with EGF and anti-EGFR antibody were used to document selective uptake of the affinity toxin. One limitation in administration of macromolecular-drugs is lysosomal degradation. Photochemical internalization (PCI) is a modality for cytosolic release of macromolecules based on photochemical rupture of endocytic membranes and subsequent drug release. It was shown that PCI increases the toxicity of EGF–saporin significantly in EGFR-positive cells. EGF binding to saporin enhanced the PCI-induced cytotoxicity in NuTu-19 cells about 1000-fold when the photochemical treatment alone killed 50% of the cells. In conclusion, PCI of EGF–saporin is a promising method for increasing the efficiency of protein toxin-based cancer therapies. PCI of targeting toxins also exert a triple tumour-selectivity; utilization of an affinity toxin, preferential accumulation of the photosensitizer in neoplastic lesions, and site-directed light activation. |
doi_str_mv | 10.1016/j.jconrel.2005.12.002 |
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In the present study an EGF–saporin affinity toxin has been established and evaluated in two EGFR overexpressing cancer cell lines. The binding of saporin to EGF did not influence the ribosome-inactivating activity of saporin as measured by a luminescence based reticulocyte lysate assay. Control experiments, using untargeted saporin, EGFR-negative cell lines and competition with EGF and anti-EGFR antibody were used to document selective uptake of the affinity toxin. One limitation in administration of macromolecular-drugs is lysosomal degradation. Photochemical internalization (PCI) is a modality for cytosolic release of macromolecules based on photochemical rupture of endocytic membranes and subsequent drug release. It was shown that PCI increases the toxicity of EGF–saporin significantly in EGFR-positive cells. EGF binding to saporin enhanced the PCI-induced cytotoxicity in NuTu-19 cells about 1000-fold when the photochemical treatment alone killed 50% of the cells. In conclusion, PCI of EGF–saporin is a promising method for increasing the efficiency of protein toxin-based cancer therapies. 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In the present study an EGF–saporin affinity toxin has been established and evaluated in two EGFR overexpressing cancer cell lines. The binding of saporin to EGF did not influence the ribosome-inactivating activity of saporin as measured by a luminescence based reticulocyte lysate assay. Control experiments, using untargeted saporin, EGFR-negative cell lines and competition with EGF and anti-EGFR antibody were used to document selective uptake of the affinity toxin. One limitation in administration of macromolecular-drugs is lysosomal degradation. Photochemical internalization (PCI) is a modality for cytosolic release of macromolecules based on photochemical rupture of endocytic membranes and subsequent drug release. It was shown that PCI increases the toxicity of EGF–saporin significantly in EGFR-positive cells. EGF binding to saporin enhanced the PCI-induced cytotoxicity in NuTu-19 cells about 1000-fold when the photochemical treatment alone killed 50% of the cells. In conclusion, PCI of EGF–saporin is a promising method for increasing the efficiency of protein toxin-based cancer therapies. PCI of targeting toxins also exert a triple tumour-selectivity; utilization of an affinity toxin, preferential accumulation of the photosensitizer in neoplastic lesions, and site-directed light activation.</description><subject>Affinity toxin</subject><subject>Animals</subject><subject>Biotin - chemistry</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - radiation effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Synergism</subject><subject>Drug targeting</subject><subject>EGFR</subject><subject>Epidermal Growth Factor - chemistry</subject><subject>Epidermal Growth Factor - pharmacology</subject><subject>Humans</subject><subject>Immunotoxins - chemistry</subject><subject>Immunotoxins - pharmacology</subject><subject>Microscopy, Fluorescence</subject><subject>Photochemistry</subject><subject>Photodynamic</subject><subject>Protein Synthesis Inhibitors - chemistry</subject><subject>Protein Synthesis Inhibitors - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>Ribosomes - drug effects</subject><subject>Ribosomes - metabolism</subject><subject>Streptavidin - chemistry</subject><subject>Time Factors</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><recordid>eNqFkMtu1DAUhi0EotOWRwB5xS7BlzhxVghVvSBVggVdW57jY8ajJB5spyI73qFvyJM01YzEktXRkb7__DofIe85qznj7ad9vYc4JRxqwZiquagZE6_IhutOVk3fq9dks3K6kq3qz8h5znu2grLp3pIz3jZtq4XcEPd9F0uEHY4B7DAsNJcwzoMt6KhL80_qcAiPmBYaJkhoM2ZadkhhKWvud4BQFmonR_MBIfjjHj29vr35--cp20NMYbokb7wdMr47zQvycHP94-quuv92-_Xqy30FinWl4nrLtn3fadWITtlGC6Z9LxuvFSp00MoGhAWputZzAJTMe9tvpVQMOuWVvCAfj3cPKf6aMRczhgw4DHbCOGfD-0YoptsVVEcQUsw5oTeHFEabFsOZedFr9uak17zoNVyYVe-a-3AqmLcjun-pk88V-HwEcH3zMWAyGQJOgC4khGJcDP-peAZFiZE-</recordid><startdate>20060310</startdate><enddate>20060310</enddate><creator>Weyergang, Anette</creator><creator>Selbo, Pål Kristian</creator><creator>Berg, Kristian</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20060310</creationdate><title>Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin</title><author>Weyergang, Anette ; 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In conclusion, PCI of EGF–saporin is a promising method for increasing the efficiency of protein toxin-based cancer therapies. PCI of targeting toxins also exert a triple tumour-selectivity; utilization of an affinity toxin, preferential accumulation of the photosensitizer in neoplastic lesions, and site-directed light activation.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>16466823</pmid><doi>10.1016/j.jconrel.2005.12.002</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Affinity toxin Animals Biotin - chemistry Cell Line, Tumor Cell Survival - drug effects Cell Survival - radiation effects Dose-Response Relationship, Drug Drug Synergism Drug targeting EGFR Epidermal Growth Factor - chemistry Epidermal Growth Factor - pharmacology Humans Immunotoxins - chemistry Immunotoxins - pharmacology Microscopy, Fluorescence Photochemistry Photodynamic Protein Synthesis Inhibitors - chemistry Protein Synthesis Inhibitors - pharmacology Receptor, Epidermal Growth Factor - metabolism Ribosomes - drug effects Ribosomes - metabolism Streptavidin - chemistry Time Factors |
title | Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin |
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