Lipophilic methotrexate conjugates with antitumor activity

Pignatello, Rosario; Spampinato, Giorgia; Sorrenti, Valeria; Giacomo, Claudia Di; Vicari, Luisa; McGuire, John J.; Russell, Cynthia A.; Puglisi, Giovanni; Tóth, István

doi:10.1016/s0928-0987(00)00062-2

Cited by 43 publications

(26 citation statements)

References 18 publications

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“…The biological activity of lipophilic derivatives of methotrexate can be either the result of a direct effect on cell enzymes, or being mediated by intracellular release of free drug, that will ultimately be responsible for the activity. 35 The 75-fold greater uptake of LDE-ddMTX than methotrexate by HL60 cells was matched by 100-fold greater cytotoxicity, whereas the 90-fold greater uptake by K562 cells was linked with 10-fold greater cytotoxicity to these cells. Our results suggest that uptake of methotrexate is an important limitation for cytotoxicity, and when cell internalization of the drug increases, the pharmacological action of the compound can be optimized.…”

Section: Dovepressmentioning

confidence: 93%

Novel formulation of a methotrexate derivative with a lipid nanoemulsion

Moura¹,

Valduga²,

Tavares³

et al. 2011

IJN

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Background Lipid nanoemulsions that bind to low-density lipoprotein receptors can concentrate chemotherapeutic agents in tissues with low-density lipoprotein receptor overexpression and decrease the toxicity of the treatment. The aim of this study was to develop a new formulation using a lipophilic derivative of methotrexate, ie, didodecyl methotrexate (ddMTX), associated with a lipid nanoemulsion (ddMTX-LDE). Methods ddMTX was synthesized by an esterification reaction between methotrexate and dodecyl bromide. The lipid nanoemulsion was prepared by four hours of ultrasonication of a mixture of phosphatidylcholine, triolein, and cholesteryloleate. Association of ddMTX with the lipid nanoemulsion was performed by additional cosonication of ddMTX with the previously prepared lipid nanoemulsion. Formulation stability was evaluated, and cell uptake, cytotoxicity, and acute animal toxicity studies were performed. Results The yield of ddMTX incorporation was 98% and the particle size of LDE-ddMTX was 60 nm. After 48 hours of incubation with plasma, approximately 28% ddMTX was released from the lipid nanoemulsion. The formulation remained stable for at least 45 days at 4°C. Cytotoxicity of LDE-ddMTX against K562 and HL60 neoplastic cells was higher than for methotrexate (50% inhibitory concentration [IC 50 ] 1.6 versus 18.2 mM and 0.2 versus 26 mM, respectively), and cellular uptake of LDE-ddMTX was 90-fold higher than that of methotrexate in K562 cells and 75-fold in HL60 cells. Toxicity of LDE-ddMTX, administered at escalating doses, was higher than for methotrexate (LD 50 115 mg/kg versus 470 mg/kg; maximum tolerated dose 47 mg/kg versus 94 mg/kg) in mice. However, the hematological toxicity of LDE-ddMTX was lower than for methotrexate. Conclusion LDE-ddMTX was stable, and uptake of the formulation by neoplastic cells was remarkably greater than of methotrexate, which resulted in markedly greater cytotoxicity. LDE-ddMTX is thus a promising formulation to be tested in future animal models of cancer or rheumatic disease, wherein methotrexate is widely used.

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Section: Dovepressmentioning

confidence: 93%

Novel formulation of a methotrexate derivative with a lipid nanoemulsion

Moura¹,

Valduga²,

Tavares³

et al. 2011

IJN

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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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“…We previously reported on the synthesis and preliminary biological evaluation of methotrexate (4-amino-4-deoxy-N 10 -methylpteroyl-l-glutamic acid, MTX) conjugates with lipoamino acids (LAA) [Pignatello et al, , 2000. The membrane-like character of the LAA conjugates of drugs always increased their passive uptake [Toth, 1994].…”

Section: Introductionmentioning

confidence: 99%

“…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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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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Lipophilic methotrexate conjugates with antitumor activity

Cited by 43 publications

References 18 publications

Novel formulation of a methotrexate derivative with a lipid nanoemulsion

Novel formulation of a methotrexate derivative with a lipid nanoemulsion

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

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

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