Liposomes containing alkylated methotrexate analogues for phospholipase A2 mediated tumor targeted drug delivery

Kaasgaard, Thomas; Andresen, Thomas Lars; Jensen, Simon Skøde; Holte, Rene Oehlenschlæger; Jensen, L.T.; Jørgensen, Kent

doi:10.1016/j.chemphyslip.2008.11.005

Cited by 38 publications

(18 citation statements)

References 35 publications

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“…However, addition of benzyl group at a-carboxyl group rendered the compound to be nontoxic. It was concluded that alkylated MTX analogs were available only for cancer cell uptake, independent of liposome hydrolysis and resulting in a tumor-specific release of MTX derivative [88].…”

Section: High Affinity Toward Breast and Prostate Cancer Cellmentioning

confidence: 99%

Methotrexate: a detailed review on drug delivery and clinical aspects

Khan

Tripathi

Mishra³

2012

Expert Opinion on Drug Delivery

213

133

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Therapeutic drug monitoring of MTX is crucial to attain a good efficacy. In spite of the advantages of multiparticulate, prodrug and drug conjugates, clinical applications of such formulations of MTX are still under infancy. These drug delivery systems require the special attention of medical experts for its wider clinical usage, and pharmaceutical experts for its scale-up. The combination of MTX with other antineoplastic and immunosuppressants should also be subjected to clinical trials, such as the combination of misoprostol with MTX in abortion.

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Section: High Affinity Toward Breast and Prostate Cancer Cellmentioning

confidence: 99%

Methotrexate: a detailed review on drug delivery and clinical aspects

Khan

Tripathi

Mishra³

2012

Expert Opinion on Drug Delivery

213

133

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“…In conclusion, comparing LDE-ddMTX with other methotrexate delivery systems described in the literature, such as gelatin/methotrexate conjugates, 37 polymers, 7,8 liposomes, 4,5 dendrimers, 6 solid lipid nanoparticles, 11,12 and chylomicronmimicking carrier emulsions, 10 this novel formulation for intravenous use, in which the association of ddMTX with the vehicle is virtually complete and stable, showed equivalent or superior cytotoxicity. These findings warrant further preclinical investigation.…”

Section: Resultsmentioning

confidence: 99%

“…In this regard, the γ-carbonyl position is preferentially targeted to attach lipophilic groups to the methotrexate molecule, and in fact modification at the γ and, to a lesser extent, the α-carbonyl position did not decrease the drug cytotoxicity. 4 Drug delivery systems have also been used to improve cytotoxicity and reduce toxicity, such as loading of methotrexate into liposomes, 4,5 dendrimers, 6 micelles, 7 chitosan polymers, 8 and tuftsin-like peptide carriers, 9 as well as attachment to polymeric chains. Other formulations have been described, such as chylomicronlike emulsions, for oral use.…”

Section: Introductionmentioning

confidence: 99%

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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“…For instance, grafting peptides sensitive to extracellular matrix metalloproteinases, which are abundant in tumor environments, has been used to trigger drug-release from NPs [62 ]. Similarly, hyaluronic acid and certain lipids have been used to induce the controlled release of therapeutic cargoes from NPs in tumor environments enriched in their respective degrading enzymes: hyaluronidases [63] and secretory phospholipase A2 [64]. Worth mentioning, triggered release does not rely exclusively on catalytic processes.…”

Section: Biomolecules As Triggers Of Drug Releasementioning

confidence: 98%