Lipoamino Acid Conjugates of Methotrexate with Antitumor Activity

Pignatello, Rosario; Jansen, Gerrit; Kathmann, Ietje; Puglisi, Giovanni; Tóth, István

doi:10.1021/js970194p

Cited by 26 publications

(18 citation statements)

References 19 publications

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“…As extensively reported, an increase in the overall lipophilicity of MTX can be achieved by a substitution at one or both the carboxyl groups present in its glutamate moiety [Piper et al, 1982;Antonjuk et al, 1984Antonjuk et al, , 1989Rosowsky et al, 1986;Pignatello et al, 1996Pignatello et al, , 1998Pignatello et al, , 1999Rahman and Cchabra, 1988]. LAA conjugation of anticancer drugs was shown to maintain or even increase the activity against different cell lines in vitro [Wood et al, 1992;Pignatello et al, 1998Pignatello et al, , 2000.…”

Section: Introductionmentioning

confidence: 91%

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Lipophilic methotrexate conjugates with glucose‐lipoamino acid moieties: Synthesis and in vitro antitumor activity

Pignatello

Vicari

Sorrenti

et al. 2001

Drug Development Research

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To obtain methotrexate (MTX) derivatives with a balanced hydrolipophilic character, we synthesized a series of conjugates in which the drug was linked to lipoamino acid (LAA)-glucose residues (LAAG-MTX). These conjugates displayed increased solubility in polar media compared with the corresponding LAA-MTX conjugates previously described. In vitro biological testing of LAAG-MTX indicated that the introduction of the sugar moiety decreased the biological activity of these MTX conjugates. The tetradecyl derivative 6b, however, was effective in inhibiting the dihydrofolate reductase activity in vitro and showed an inhibitory effect on human lymphoblastoid cell growth. Drug Dev. Res. 52:454-461, 2001.

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Section: Introductionmentioning

confidence: 91%

“…LAA conjugation of anticancer drugs was shown to maintain or even increase the activity against different cell lines in vitro [Wood et al, 1992;Pignatello et al, 1998Pignatello et al, , 2000. For instance, some of the described mono-or disubstituted MTX-LAA conjugates showed a higher activity than MTX against CEM/ MTX cells.…”

Section: Introductionmentioning

confidence: 99%

Lipophilic methotrexate conjugates with glucose‐lipoamino acid moieties: Synthesis and in vitro antitumor activity

Pignatello

Vicari

Sorrenti

et al. 2001

Drug Development Research

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“…LAAs combine the physico-chemical properties of both lipids and amino acids due to their amphipathic structure; LAAs linkage to drugs, apart from enhancing their lipophilicity, can also facilitate their interaction with cell membranes and penetration across absorption and biological barriers (8). Conjugation of drug molecules to lipoamino acids (LAA) has shown to increase biological uptake and intracellular concentration of drugs (8)(9)(10). The LAAs are also used to develop lipid core peptide systems useful for delivery of genes, drugs, and vaccines (11).…”

Section: Introductionmentioning

confidence: 99%

Development of Indinavir Submicron Lipid Emulsions Loaded with Lipoamino Acids—In Vivo Pharmacokinetics and Brain-Specific Delivery

et al. 2011

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Abstract. The aim of our present work was to develop indinavir O/W submicron lipid emulsions (SLEs) loaded with lipoamino acids for specific delivery to brain. Tetradecyl aspartic acid (A) and decyl glutamic acid (G) loaded stable SLEs of indinavir having a mean size range of 210-220 nm and average zeta potential of −23.54±1.2 mV were developed using homogenization and ultrasonication. The cumulative % drug release from different SLEs varied in between 26% and 85%. The formulations, SLE, SLE-A3, and SLE-G3 were stable to the centrifugal stress, dilution stress, and storage at RT. The total drug content and entrapment efficiency were determined by HPLC method. During pharmacokinetic studies in male Wistar rats there was no significant difference in the serum levels of indinavir for SLE, SLE-A3 and SLE-G3 formulations at all time points. In tissue distribution studies, the therapeutic availability (TA) of indinavir in brain and kidneys for SLE-A3 were 4.27-and 2.66-fold whereas for SLE-G3 were 2.94 and 2.12 times, respectively, higher than that of indinavir solution. But when compared with that of SLE, in brain tissue the levels of indinavir from SLE-G3 and SLE-A3 varied in between 2.5-and 3.38-fold. While in case of the kidney, it was between 1.23-and 1.54-fold only. However, the TA is not significantly different in tissues like the heart, liver, and spleen. Thus, brainspecific delivery of indinavir was improved by including tetradecyl aspartic acid and decyl glutamic acid in submicron lipid emulsions.

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“…Linked to alkylating agents like chlorambucil, LAAs increased selectivity toward tumor cells [Wood et al, 1992]. Methotrexate-LAA conjugates showed an enhanced ability in penetrating resistant tumor cells by means of a passive internalization through the cell membrane [Pignatello et al, 1998[Pignatello et al, , 2000[Pignatello et al, , 2001[Pignatello et al, , 2004. Paclitaxel-LAA prodrugs have been shown to modify the onset of activity of the drug in vitro against a human ATC cell line (Aro cells), as well as to improve its passive uptake by these tumor cells [Pignatello et al, 2009].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro cytotoxic activity on human anaplastic thyroid cancer cells of lipoamino acid conjugates of gemcitabine

Pignatello

Vicari²,

Pistarà

et al. 2010

Drug Development Research

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Lipophilic derivatives of the antitumor drug gemcitabine (GEM) with the potential for improving drug loading in lipid-based colloidal carriers, like liposomes or lipid nanoparticles, are described. GEM free base was conjugated to lipoamino acids bearing an alkyl side chain of different length, by either a carbodiimide-assisted or an ethylchloroformiate-assisted coupling reaction, to obtain N 4 -acyl GEM derivatives. These compounds retained the same in vitro cell growth inhibitory activity of the parent drug against two lines of human anaplastic thyroid cancer cells. Stability studies suggested that the observed activity was due mainly to intact derivatives and not to released GEM. Accordingly, these amphiphilic derivatives can be proposed in a further step for the encapsulation in liposomes or lipid nanocarriers, to achieve as a final goal an improvement of the pharmacokinetics and therapeutic activity of GEM. Drug Dev Res 71: 294-302, 2010.

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Lipoamino Acid Conjugates of Methotrexate with Antitumor Activity

Cited by 26 publications

References 19 publications

Lipophilic methotrexate conjugates with glucose‐lipoamino acid moieties: Synthesis and in vitro antitumor activity

Lipophilic methotrexate conjugates with glucose‐lipoamino acid moieties: Synthesis and in vitro antitumor activity

Development of Indinavir Submicron Lipid Emulsions Loaded with Lipoamino Acids—In Vivo Pharmacokinetics and Brain-Specific Delivery

Synthesis and in vitro cytotoxic activity on human anaplastic thyroid cancer cells of lipoamino acid conjugates of gemcitabine

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