In vitro cytotoxicity of the LDE: daunorubicin complex in acute myelogenous leukemia blast cells

Dorlhíac-Llacer, Pedro Enrique; Marquezini, Mônica V.; Toffoletto, Odaly; Carneiro, R C G; Maranhão, Raul C.; Chamone, Dalton F.

doi:10.1590/s0100-879x2001001000004

Cited by 19 publications

(15 citation statements)

References 16 publications

(14 reference statements)

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“…In addition to the studies conducted with AML, we demonstrated that other neoplastic diseases that are also responsive to DNR treatments, such as Hodgkin's and non‐Hodgkin's lymphomas and breast carcinomas, can also be targeted by LDE used as drug carrier [12–14]. Indeed, in an initial study, we showed that the incorporation of DNR to LDE resulted in a greater cytotoxic effect on leukaemia blast cells and effective protection to non‐tumoral cells from the toxic effects of the free DNR [15]. However, the yield of the association to LDE of free DNR, which is a hydrophilic compound, is poor (<1%).…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14] Indeed, in an initial study, we showed that the incorporation of DNR to LDE resulted in a greater cytotoxic effect on leukaemia blast cells and effective protection to non-tumoral cells from the toxic effects of the free DNR. [15] However, the yield of the association to LDE of free DNR, which is a hydrophilic compound, is poor (<1%). This would preclude the use of LDE-free DNR in the clinical practice, but subsequently we attained a high-yield (>90%) and stable preparation by associating the DNR lipophilic derivative N-oleyl daunorubicin (oDNR) with LDE.…”

Section: Introductionmentioning

confidence: 99%

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Association of daunorubicin to a lipid nanoemulsion that binds to low-density lipoprotein receptors enhances the antitumour action and decreases the toxicity of the drug in melanoma-bearing mice

Contente

Kretzer

Filippin-Monteiro

et al. 2014

Journal of Pharmacy and Pharmacology

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of daunorubicin to a lipid nanoemulsion that binds to low-density lipoprotein receptors enhances the antitumour action and decreases the toxicity of the drug in melanoma-bearing mice

Contente

Kretzer

Filippin-Monteiro

et al. 2014

Journal of Pharmacy and Pharmacology

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“…[13][14][15] To increase the yield of association with LDEs of those compounds and the stability of the preparations, an oleyl group was added to the molecular structure of the drugs, resulting in more lipophilic derivatives. [16][17][18][19] A prominent aspect of the LDEchemotherapeutic agent formulations is a remarkable reduction in drug toxicity.…”

Section: Introductionmentioning

confidence: 99%

Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

Kretzer¹,

Maria²,

Guido³

et al. 2016

IJN

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Purpose Lipid nanoemulsions (LDEs) that bind to low-density lipoprotein (LDL) receptors used as carriers of paclitaxel (PTX) can decrease toxicity and increase PTX antitumoral action. The administration of simvastatin (Simva), which lowers LDL-cholesterol, was tested as an adjuvant to commercial PTX and to PTX associated with LDE (LDE-PTX). Materials and methods B16F10 melanoma-bearing mice were treated with saline solution or LDE (controls), Simva, PTX, PTX and Simva, LDE-PTX, and LDE-PTX and Simva: PTX dose 17.5 μmol/kg (three intraperitoneal injections, 3 alternate days): Simva 50 mg/kg/day by gavage, 9 consecutive days. Results Compared with saline controls, 95% tumor-growth inhibition was achieved by LDE-PTX and Simva, 61% by LDE-PTX, 44% by PTX and Simva, and 43% by PTX. Simva alone had no effect. Metastasis developed in only 37% of the LDE-PTX and Simva, 60% in LDE-PTX, and 90% in PTX and Simva groups. Survival rates were higher in LDE-PTX and Simva and in LDE-PTX groups. The LDE-PTX and Simva group presented tumors with reduced cellular density and increased collagen fibers I and III. Tumors from all groups showed reduction in immunohistochemical expression of ICAM, MCP-1, and MMP-9; LDE-PTX and Simva presented the lowest MMP-9 expression. Expression of p21 was increased in the Simva, LDE-PTX, and LDE-PTX and Simva groups. In the Simva and LDE-PTX and Simva groups, expression of cyclin D1, a proliferation and survival promoter of tumor cells, was decreased. Therapy with LDE-PTX and Simva showed negligible toxicity compared with PTX and Simva, which resulted in weight loss and myelosuppression. Conclusion Simva increased the antitumor activity of PTX carried in LDE but not of PTX commercial presentation, possibly because statins increase the expression of LDL receptors that internalize LDE-PTX.

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“…A liposomal formulation of daunorubicin reportedly diminishes the toxicity of the drug (Alberts et al 2004), but the association with LDE would be interesting since this system has established drug-targeting properties (Maranhão et al 1993(Maranhão et al , 1994Azevedo et al 2005;Pinheiro et al 2005). However, daunorubicin associates poorly with LDE (Dorlhiac-Llacer et al 2001) and chemical modification is therefore required to improve the association and stability of the drug in the nanoemulsion (Masquelier et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Delivery of daunorubicin to cancer cells with decreased toxicity by association with a lipidic nanoemulsion that binds to LDL receptors

et al. 2008

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A lipidic nanoemulsion termed LDE concentrates in neoplastic cells after injection into the bloodstream and thus can be used as a drug carrier to tumour sites. The chemotherapeutic agent daunorubicin associates poorly with LDE; the aim of this study was to clarify whether the derivatization of daunorubicin by the attachment of an oleyl group increases the association with LDE, and to test the cytotoxicity and animal toxicity of the new preparation. The association of oleyl-daunorubicin (oDNR) to LDE showed high yield (93 +/- 2% and 84 +/- 4% at 1:10 and 1:5 drug:lipid mass, respectively) and was stable for at least 20 days. Association with oDNR increased the LDE particle diameter from 42 +/- 4 nm to 75 +/- 6 nm. Cytotoxicity of LDE-oDNR was reduced two-fold in HL-60 and K-562 cell lines, fourteen-fold in B16 cells and nine-fold in L1210 cells when compared with commercial daunorubicin. When tested in mice, LDE-oDNR showed remarkable reduced toxicity (maximum tolerated dose > 253 micromol kg(-1), compared with <3 micromol kg(-1) for commercial daunorubicin). At high doses, the cardiac tissue of LDE-oDNR-treated animals had much smaller structural lesions than with commercial daunorubicin. LDE-oDNR is therefore a promising new preparation that may offer superior tolerability compared with commercial daunorubicin.

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In vitro cytotoxicity of the LDE: daunorubicin complex in acute myelogenous leukemia blast cells

Cited by 19 publications

References 16 publications

Association of daunorubicin to a lipid nanoemulsion that binds to low-density lipoprotein receptors enhances the antitumour action and decreases the toxicity of the drug in melanoma-bearing mice

Association of daunorubicin to a lipid nanoemulsion that binds to low-density lipoprotein receptors enhances the antitumour action and decreases the toxicity of the drug in melanoma-bearing mice

Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

Delivery of daunorubicin to cancer cells with decreased toxicity by association with a lipidic nanoemulsion that binds to LDL receptors

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