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Anticancer drug-incorporated layered double hydroxide nanohybrids and their enhanced anticancer therapeutic efficacy in combination cancer treatment.

Kim TH, Lee GJ, Kang JH, Kim HJ, Kim TI, Oh JM - Biomed Res Int (2014)

Bottom Line: Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth.All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction.It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Medical Chemistry, College of Science & Technology, Yonsei University, Wonju, Gangwon-do 220-710, Republic of Korea.

ABSTRACT

Objective: Layered double hydroxide (LDH) nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles.

Method: Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy.

Conclusion: All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy.

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Hydrodynamic size distribution of nanohybrids (a) ML, (b) FL, and (c) MFL, dispersed into deionized water (solid line), DMEM (dashed line), and DMEM with 10% FBS (dashed dot line).
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fig5: Hydrodynamic size distribution of nanohybrids (a) ML, (b) FL, and (c) MFL, dispersed into deionized water (solid line), DMEM (dashed line), and DMEM with 10% FBS (dashed dot line).

Mentions: The hydrodynamic size distributions of nanohybrids in various suspending media are displayed in Figure 5. All the nanohybrids in deionized water and DMEM media showed agglomeration with average hydrodynamic size values of ~980, ~1010, and ~1021 nm in deionized water and ~1070, ~1050, and ~1070 nm in DMEM for ML, FL, and MFL, respectively. And the size distribution lies in the region of 600–2000, 700–2000, and 600–2000 nm in both deionized water and DMEM. The organic/LDH nanohybrids usually showed formation of agglomerate due to the strong interparticle interaction [59, 60]. However, it did not mean that the primary particles of nanohybrids with ~200 nm lateral size strongly aggregated in the aqueous media, as they can be easily stabilized into small assembly of particles under appropriate treatment of stabilizing agents. Nanomaterials produced in powder which form agglomerates can be separated into single particles in the presence of stabilizer such as surfactants or proteins [61]. In this study, we also observed that the degree of agglomeration strongly reduced with the addition of FBS containing albumin protein. The average hydrodynamic sizes of ML, FL, and MFL in DMEM with 10% FBS were determined to be ~43, ~337, and ~474 nm, respectively, showing agglomerate consisting of only a few (less than 3) particles. This result corroborated that the particles of nanohybrids can be separated into a smaller assembly in the physiological conditions containing proteins and that the formation of large agglomerates may not affect nanoparticulate properties of nanohybrids negatively, for their cellular uptake. Furthermore, we have verified, in the previous study, that the LDH or drug/LDH nanohybrid was taken up by cells in a small assembly even though they seemed to form agglomerate through TEM study [62]. It was considered that the biological system could sense single particles or small agglomerates of nanoparticles. Comparing with FL and MFL nanohybrids, ML showed much more reduction in hydrodynamic size (Figure 5(a)). It can be explained by the surface interaction between nanohybrids and proteins in the media. The surface of ML and FL nanohybrids was thought to be covered with MTX and 5-FU, respectively, which had different affinity toward proteins; MTX was reported to exhibit strong interaction with albumin [63], while 5-FU had low affinity for albumin [64]. The drug molecules attached on the surface of nanohybrids affected attraction to albumin, resulting in the difference in agglomeration degree. The relatively small hydrodynamic size ~43 nm of ML compared with the lateral particle size ~337 and 474 nm in the SEM (Figure 1(c)) was attributed to the bending of thin particles in the aqueous condition.


Anticancer drug-incorporated layered double hydroxide nanohybrids and their enhanced anticancer therapeutic efficacy in combination cancer treatment.

Kim TH, Lee GJ, Kang JH, Kim HJ, Kim TI, Oh JM - Biomed Res Int (2014)

Hydrodynamic size distribution of nanohybrids (a) ML, (b) FL, and (c) MFL, dispersed into deionized water (solid line), DMEM (dashed line), and DMEM with 10% FBS (dashed dot line).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016841&req=5

fig5: Hydrodynamic size distribution of nanohybrids (a) ML, (b) FL, and (c) MFL, dispersed into deionized water (solid line), DMEM (dashed line), and DMEM with 10% FBS (dashed dot line).
Mentions: The hydrodynamic size distributions of nanohybrids in various suspending media are displayed in Figure 5. All the nanohybrids in deionized water and DMEM media showed agglomeration with average hydrodynamic size values of ~980, ~1010, and ~1021 nm in deionized water and ~1070, ~1050, and ~1070 nm in DMEM for ML, FL, and MFL, respectively. And the size distribution lies in the region of 600–2000, 700–2000, and 600–2000 nm in both deionized water and DMEM. The organic/LDH nanohybrids usually showed formation of agglomerate due to the strong interparticle interaction [59, 60]. However, it did not mean that the primary particles of nanohybrids with ~200 nm lateral size strongly aggregated in the aqueous media, as they can be easily stabilized into small assembly of particles under appropriate treatment of stabilizing agents. Nanomaterials produced in powder which form agglomerates can be separated into single particles in the presence of stabilizer such as surfactants or proteins [61]. In this study, we also observed that the degree of agglomeration strongly reduced with the addition of FBS containing albumin protein. The average hydrodynamic sizes of ML, FL, and MFL in DMEM with 10% FBS were determined to be ~43, ~337, and ~474 nm, respectively, showing agglomerate consisting of only a few (less than 3) particles. This result corroborated that the particles of nanohybrids can be separated into a smaller assembly in the physiological conditions containing proteins and that the formation of large agglomerates may not affect nanoparticulate properties of nanohybrids negatively, for their cellular uptake. Furthermore, we have verified, in the previous study, that the LDH or drug/LDH nanohybrid was taken up by cells in a small assembly even though they seemed to form agglomerate through TEM study [62]. It was considered that the biological system could sense single particles or small agglomerates of nanoparticles. Comparing with FL and MFL nanohybrids, ML showed much more reduction in hydrodynamic size (Figure 5(a)). It can be explained by the surface interaction between nanohybrids and proteins in the media. The surface of ML and FL nanohybrids was thought to be covered with MTX and 5-FU, respectively, which had different affinity toward proteins; MTX was reported to exhibit strong interaction with albumin [63], while 5-FU had low affinity for albumin [64]. The drug molecules attached on the surface of nanohybrids affected attraction to albumin, resulting in the difference in agglomeration degree. The relatively small hydrodynamic size ~43 nm of ML compared with the lateral particle size ~337 and 474 nm in the SEM (Figure 1(c)) was attributed to the bending of thin particles in the aqueous condition.

Bottom Line: Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth.All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction.It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Medical Chemistry, College of Science & Technology, Yonsei University, Wonju, Gangwon-do 220-710, Republic of Korea.

ABSTRACT

Objective: Layered double hydroxide (LDH) nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles.

Method: Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy.

Conclusion: All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy.

Show MeSH
Related in: MedlinePlus