LEAPT: lectin-directed enzyme-activated prodrug therapy.
Targeted drug delivery to selected sites allows reduced toxicity, enhanced efficiency and interchangeable target potential [Langer, R. (2001) Science 293, 58-59 and Molema, G. and Meijer, D. K. F., eds. (2001) Drug Targeting (Wiley-VCH, Weinheim, Germany)]. We describe a bipartite drug-delivery syst...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Sprog: | English |
| Udgivet: |
2004
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| _version_ | 1826277346075738112 |
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| author | Robinson, M Charlton, S Garnier, P Wang, X Davis, S Perkins, A Frier, M Duncan, R Savage, T Wyatt, D Watson, SA Davis, B |
| author_facet | Robinson, M Charlton, S Garnier, P Wang, X Davis, S Perkins, A Frier, M Duncan, R Savage, T Wyatt, D Watson, SA Davis, B |
| author_sort | Robinson, M |
| collection | OXFORD |
| description | Targeted drug delivery to selected sites allows reduced toxicity, enhanced efficiency and interchangeable target potential [Langer, R. (2001) Science 293, 58-59 and Molema, G. and Meijer, D. K. F., eds. (2001) Drug Targeting (Wiley-VCH, Weinheim, Germany)]. We describe a bipartite drug-delivery system that exploits (I) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (II) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an alpha-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of alpha-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzyme-activated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model. |
| first_indexed | 2024-03-06T23:27:31Z |
| format | Journal article |
| id | oxford-uuid:6ae4a3cb-5767-4483-ba4e-dc4f373c4f8f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:27:31Z |
| publishDate | 2004 |
| record_format | dspace |
| spelling | oxford-uuid:6ae4a3cb-5767-4483-ba4e-dc4f373c4f8f2022-03-26T19:00:43ZLEAPT: lectin-directed enzyme-activated prodrug therapy.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6ae4a3cb-5767-4483-ba4e-dc4f373c4f8fEnglishSymplectic Elements at Oxford2004Robinson, MCharlton, SGarnier, PWang, XDavis, SPerkins, AFrier, MDuncan, RSavage, TWyatt, DWatson, SADavis, BTargeted drug delivery to selected sites allows reduced toxicity, enhanced efficiency and interchangeable target potential [Langer, R. (2001) Science 293, 58-59 and Molema, G. and Meijer, D. K. F., eds. (2001) Drug Targeting (Wiley-VCH, Weinheim, Germany)]. We describe a bipartite drug-delivery system that exploits (I) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (II) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an alpha-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of alpha-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzyme-activated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model. |
| spellingShingle | Robinson, M Charlton, S Garnier, P Wang, X Davis, S Perkins, A Frier, M Duncan, R Savage, T Wyatt, D Watson, SA Davis, B LEAPT: lectin-directed enzyme-activated prodrug therapy. |
| title | LEAPT: lectin-directed enzyme-activated prodrug therapy. |
| title_full | LEAPT: lectin-directed enzyme-activated prodrug therapy. |
| title_fullStr | LEAPT: lectin-directed enzyme-activated prodrug therapy. |
| title_full_unstemmed | LEAPT: lectin-directed enzyme-activated prodrug therapy. |
| title_short | LEAPT: lectin-directed enzyme-activated prodrug therapy. |
| title_sort | leapt lectin directed enzyme activated prodrug therapy |
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