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. 2015 Jul 21;20(7):13226-39.
doi: 10.3390/molecules200713226.

The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells

Zoltán Ujhelyi  1 , Azin Kalantari  2 , Miklós Vecsernyés  3 , Eszter Róka  4 , Ferenc Fenyvesi  5 , Róbert Póka  6 , Bence Kozma  7 , Ildikó Bácskay  8
Affiliations

The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells

Zoltán Ujhelyi et al. Molecules. .

Abstract

The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations.

Keywords: HeLa; SMEDDS; bleomycin; cisplatin; ifosfamide.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pseudoternary phase diagrams of compositions 1–6, (Shaded areas represented microemulsions).
Figure 2
Figure 2
Evaluated droplet size of SMEDDS in water via DLS measurement. Evaluated average droplet sizes: composition 1: 137.81 ± 1.25 nm, composition 2: 68.44 ± 1.05 nm, composition 3: 73.28 ± 0.95 nm, composition 4: 129.31 ± 1.95 nm, composition 5: 149.35 ± 1.00 nm, composition 6: 76.90 ± 1.00 nm. Values are expressed as means ± SD, n = 5.
Figure 3
Figure 3
Cytotoxic effects of applied SMEDDS components (surfactant and co-surfactants) on HeLa cells determined by MTT-test. Cell viability was expressed as the percentage of untreated control in the function of surfactant concentration. Positive control: Triton X 100 (10% w/v). Values are expressed as means ± SD, n = 5.
Figure 4
Figure 4
Inhibitory effect of different SMEDDS compositions containing antitumor agent (bleomycin sulfate, Ifosfamide and cisplatin) evaluated by MTT test. Cell viability was expressed as the percentage of untreated control (HBSS). Values are expressed as means ± SD, n = 5.
Figure 5
Figure 5
Inhibitory effect of different SMEDDS compositions containing antitumor agent (bleomycin sulfate, ifosfamide and cisplatin) in the presence of inflammatory mediators evaluated by MTT test. Cell viability was expressed as the percentage of untreated control (HBSS). Values are expressed as means ± SD, n = 5.
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