Synthesis of new maleimide derivatives of daunorubicin and biological activity of acid labile transferrin conjugates

Kratz, Felix; Beyer, Ulrich; Schumacher, Peter; Krüger, Michael; Zahn, Heike; Roth, Thomas; Fiebig, Heinz H.; Unger, Clemens

doi:10.1016/s0960-894x(97)00069-3

Cited by 43 publications

(33 citation statements)

References 10 publications

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“…Our time-dependent stability studies with the active acid-sensitive conjugates Tf-Hyd 1 and Tf-Hyd 2 in 10% FCS and "cell-conditioned" cell culture medium rule out the possibility that their antiproliferative activity is due to a rapid hydrolysis of the hydrazone bond realized in the conjugates as only very small amounts of doxorubicin are released under these conditions during 24 h. The importance of the acidsensitivity of the linker between doxorubicin and the carrier protein for anticancer activity has been noted by Greenfield et al 32 and by our group for acid-sensitive daunorubicin and chlorambucil conjugates. 33, 34 Faulk has prepared transferrin conjugates in which doxorubicin is bound to transferrin through glutaraldehyde coupling, 15 the chemical link between transferrin and the amino sugar position of doxorubicin presumably being realized by an imine bond. From a chemical point of view this bond exhibits acid-sensitivity.…”

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

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149

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%

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

Kratz¹,

Beyer²,

Roth³

et al. 1998

Journal of Pharmaceutical Sciences

Self Cite

149

123

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show abstract

“…Preparation of a thioether linked doxorubicin-antibody conjugate [111]. has prepared conjugates of doxo-and daunorubicin with human serum transferrin [117,118] and albumin [119]. The targeting mechanism for albumin relies on the enhanced permeability of the tumour vasculature for high molecular weight species such as human serum albumin (MW 66500) and the enhanced retention of these species in tumour tissue (enhance permeability and retention or EPR effect [14]).…”

Section: -Hydrazone Linkagesmentioning

confidence: 99%

Reversible Covalent Chemistry in Drug Delivery

West

Otto

2005

CDDT

150

109

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The targeting of drugs specifically to their sites of action is an important strategy for increasing drug efficacy. Chemists have come up with many elegant schemes that aim to convert drugs into magic bullets. This review focuses on the chemistry that underlies these schemes, with particular emphasis on two types of cleavable covalent bonds that are frequently used to link drugs to their various carriers: disulfide bonds and hydrazone bonds. These linkages have been used to release drugs under specific conditions; in the case of disulfides, cleavage is triggered by the mildly reducing environment found in intracellular fluids, and in the case of hydrazones, the acidic conditions that prevail in endosomes cause release of the drug. The applications of these chemistries in drug delivery are reviewed.

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“…The acid-sensitive acylhydrazone function has shown successful applications in drug delivery (Mueller et al 1990;Kaneko et al 1991;Kratz et al 1997;Rodrigues et al 1999) and has recently been applied to lipoplexmediated gene delivery. The synthesis, characterization and transfection efficiency of a series of four cationic lipids incorporating an acylhydrazone linker between a guanidinium-based headgroup and a steroid hydrophobic moiety was reported (Aissaoui et al 2004).…”

Section: Release Of Dna In Cytoplasm By Intracellular Disulfide Reducmentioning

confidence: 99%

Nature as a source of inspiration for cationic lipid synthesis

Labas

Beilvert

Barteau³

et al. 2009

Genetica

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Synthetic gene delivery systems represent an attractive alternative to viral vectors for DNA transfection. Cationic lipids are one of the most widely used non-viral vectors for the delivery of DNA into cultured cells and are easily synthesized, leading to a large variety of well-characterized molecules. This review discusses strategies for the design of efficient cationic lipids that overcome the critical barriers of in vitro transfection. A particular focus is placed on natural hydrophilic headgroups and lipophilic tails that have been used to synthesize biocompatible and non-toxic cationic lipids. We also present chemical features that have been investigated to enhance the transfection efficiency of cationic lipids by promoting the escape of lipoplexes from the endosomal compartment and DNA release from DNA-liposome complexes. Transfection efficiency studies using these strategies are likely to improve the understanding of the mechanism of cationic lipid-mediated gene delivery and to help the rational design of novel cationic lipids.

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Synthesis of new maleimide derivatives of daunorubicin and biological activity of acid labile transferrin conjugates

Cited by 43 publications

References 10 publications

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

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

Reversible Covalent Chemistry in Drug Delivery

Nature as a source of inspiration for cationic lipid synthesis

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