Die Anämie bei malignen Tumorerkrankungen

Aulbert, E.

doi:10.1055/s-0038-1629491

Cited by 3 publications

(1 citation statement)

References 17 publications

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“…25 Expected advantages of these protein conjugates are preferable tissue distribution, prolonged half-life of the drug in the plasma, and controlled Among naturally occurring proteins, transferrin is a potential carrier due to a suitable molecular size for passive tumor targeting (EPR phenomenon) as well as the large number of transferrin receptors on the surface of tumor cells. 26 For this reason we have coupled the anticancer drug doxorubicin to this serum protein. Preferably, these transferrin conjugates should be preparable in sufficient purity, they should exhibit a high in vivo stability under physiological conditions (pH ≈7.4) and should retain the anticancer activity of the parent drug.…”

Section: Discussionmentioning

confidence: 99%

Transferrin Conjugates of Doxorubicin: Synthesis, Characterization, Cellular Uptake, and in Vitro Efficacy||

Kratz¹,

Beyer²,

Roth³

et al. 1998

Journal of Pharmaceutical Sciences

148

123

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One strategy for improving the antitumor selectivity and toxicity profile of antitumor agents is to design drug carrier systems employing suitable carrier proteins. Thus, thiolated human serum transferrin was conjugated with four maleimide derivatives of doxorubicin that differed in the stability of the chemical link between drug and spacer. Of the maleimide derivatives, 3-maleimidobenzoic or 4-maleimidophenylacetic acid was bound to the 3'-amino position of doxorubicin through a benzoyl or phenylacetyl amide bond, and 3-maleimidobenzoic acid hydrazide or 4-maleimidophenylacetic acid hydrazide was bound to the 13-keto position through a benzoyl hydrazone or phenylacetyl hydrazone bond. The acid-sensitive transferrin conjugates prepared with the carboxylic hydrazone doxorubicin derivatives exhibited an inhibitory efficacy in the MDA-MB-468 breast cancer cell line and U937 leukemia cell line comparable to that of the free drug (employing the BrdU (5-bromo-2'-deoxyuridine) incorporation assay and tritiated thymidine incorporation assay, respectively, IC50 approximately 0.1-1 mM), whereas conjugates with the amide derivatives showed no activity. Furthermore, antiproliferative activity of the most active transferrin conjugate (i.e. the conjugate containing a benzoyl hydrazone link) was demonstrated in the LXFL 529 lung carcinoma cell line employing a sulforhodamine B assay. In contrast to in vitro studies in tumor cells, cell culture experiments performed with human endothelial cells (HUVEC) showed that the acid-sensitive transferrin conjugates of doxorubicin were significantly less active than free doxorubicin (IC50 values approximately 10-40 higher by the BrdU incorporation assay), indicating selectivity of the doxorubicin-transferrin conjugates for tumor cells. Fluorescence microscopy studies in the MDA-MB-468 breast cancer cell showed that free doxorubicin accumulates in the cell nucleus, whereas doxorubicin of the transferrin conjugates is found localized primarily in the cytoplasm. The differences in the intracellular distribution between transferrin-doxorubicin conjugates and doxorubicin were confirmed by laser scanning confocal microscopy in LXFL 529 cells after a 24 h incubation that revealed an uptake and mode of action other than intercalation with DNA. The relationship between stability, cellular uptake, and cytotoxicity of the conjugates is discussed.

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Section: Discussionmentioning

confidence: 99%