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. 2014 Mar 25:9:1583-91.
doi: 10.2147/IJN.S56506. eCollection 2014.

Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line

Virginia C Yurgel  1 , Catiuscia P Oliveira  2 , Karine R Begnini  1 , Eduarda Schultze  1 , Helena S Thurow  1 , Priscila M M Leon  1 , Odir A Dellagostin  1 , Vinicius F Campos  1 , Ruy C R Beck  2 , Silvia S Guterres  2 , Tiago Collares  1 , Adriana R Pohlmann  3 , Fabiana K Seixas  1
Affiliations

Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line

Virginia C Yurgel et al. Int J Nanomedicine. .

Abstract

Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX) is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt)2]) and MTX(OEt)2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt)2 solution and MTX(OEt)2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231 cells, MTX(OEt)2-loaded lipid-core nanocapsules were significantly more efficient in inducing apoptosis than the solution of the free drug. S-phase cell cycle arrest was induced only by MTX(OEt)2 solution. The drug nanoencapsulation improved apoptosis induction for the cell line that presents MTX resistance by lack of transport receptors.

Keywords: MTX derivative; apoptotic cell death; cell cycle arrest; drug delivery; drug targeting; nanocarriers; resistance.

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Figures

Figure 1
Figure 1
Granulometric profiles obtained by PCS: (A1) LNC (intensity); (A2) LNC (volume); (A3) LNC (number); (B1) MTX(OEt)2-LNC (intensity); (B2) MTX(OEt)2-LNC (volume); and (B3) MTX(OEt)2-LNC (number). Abbreviations: LNC, lipid-core nanocapsule; MTX(OEt)2, methotrexate diethyl ester; MTX(OEt)2-LNC, MTX(OEt)2-loaded nanocapsule; PCS, photon correlation spectroscopy.
Figure 2
Figure 2
Granulometric profiles obtained by NTA: (A) LNC; (B) MTX(OEt)2-LNC. The drug content and the encapsulation efficiency were 0.50±0.06 mg mL−1 and 99%±1%, respectively. Abbreviations: LNC, lipid-core nanocapsule; MTX(OEt)2, methotrexate diethyl ester; MTX(OEt)2-LNC, MTX(OEt)2-loaded nanocapsule; NTA, nanoparticle tracking analysis.
Figure 3
Figure 3
Early apoptosis and late apoptosis or dead cell percentages of MCF-7 and MDA-MB-231 human breast adenocarcinoma cells after 48 hours treatment with MTX(OEt)2 solution, MTX(OEt)2-LNC, and unloaded nanocapsules (LNC). Notes: Data are expressed as mean ± standard error of the mean from three independent experiments. A–C indicate significant differences between treatment groups. *Significant differences considering treatment and concentration. Differences were considered significant at P<0.05. Abbreviations: LNC, lipid-core nanocapsule; MTX(OEt)2, methotrexate diethyl ester; MTX(OEt)2-LNC, MTX(OEt)2-loaded nanocapsule.
Figure 4
Figure 4
Late apoptosis percentages of MCF-7 and MDA-MB-231 human breast adenocarcinoma cells after 48 hours treatment with MTX(OEt)2 solution, MTX(OEt)2-LNC, and unloaded nanocapsules (LNC). Notes: Data are expressed as mean ± standard error of the mean from three independent experiments. A–E indicate significant differences considering treatment and concentration. Differences were considered significant at P<0.05. Abbreviations: LNC, lipid-core nanocapsule; MTX(OEt)2, methotrexate diethyl ester; MTX(OEt)2-LNC, MTX(OEt)2-loaded nanocapsules.
Figure 5
Figure 5
Number of MCF-7 and MDA-MB-231 human breast adenocarcinoma cells in each phase of the cell cycle (G1, S, G2/M) after 48 hours treatment with MTX(OEt)2 solution, MTX(OEt)2-LNC, and unloaded nanocapsules (LNC). Notes: Data are expressed as mean ± standard error of the mean from two independent experiments. *Significant differences between treatment groups within the phase. Differences were considered significant at P<0.05. Abbreviations: LNC, lipid-core nanocapsule; MTX(OEt)2, methotrexate diethyl ester; MTX(OEt)2-LNC, MTX(OEt)2-loaded nanocapsule.
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