A Tf-modified tripterine-loaded coix seed oil microemulsion enhances anti-cervical cancer treatment

Abstract

PurposeA transferrin-modified microemulsion carrying coix seed oil and tripterine (Tf-CT-MEs) was developed for improved tumor-specific accumulation and penetration to enhance cervical cancer treatment.Materials and methodsTripterine-loaded coix seed oil microemulsion (CT-MEs) was prepared through one-step emulsion method. The morphology, size, and zeta potential of CT-MEs and Tf-CT-MEs were examined by transmission electron microscopy and dynamic light scattering. The cellular uptake and mechanisms of HeLa cells were investigated by flow cytometry. Intratumor penetration was investigated using a HeLa three-dimensional (3D) tumor spheroid as the model. The cytotoxicity of the CT-MEs and Tf-CT-MEs against HeLa cells were evaluated by the MTT assay. Additionally, the apoptotic rate of CT-MEs and Tf-CT-MEs inducing apoptosis in HeLa cells was evaluated.ResultsIn the physicochemical characterization, coix seed oil and CT-MEs exhibited a small size (32.47±0.15 nm) and nearly neutral surface charge (−0.36±0.11 mV). After modification with transferrin, the particle size of Tf-CT-MEs slightly increased to 40.02±0.21 nm, but the zeta potential decreased remarkably to -13.63±1.31 mV. The IC50 of Tf-CT-MEs against HeLa cells was 0.7260 µM, which was 2.58-fold lower than that of CT-MEs. In cellular studies, the intracellular fluorescence intensity of fluorescein isothiocyanate (FITC)-labeled Tf-CT-MEs (FITC/Tf-CT-MEs) was 2.28-fold higher than that of FITC-labeled CT-MEs (FITC/CT-MEs). The fluorescence signal of Tf-CT-MEs was observed at 350 µm below the surface of the 3D tumor spheroid. The apoptotic rate of cells treated with Tf-CT-MEs was 1.73- and 2.77-fold higher than that of cells treated with CT-MEs and tripterine, respectively, which was associated with mitochondrial-targeted delivery of tripterine. Moreover, Tf-CT-MEs was capable of significantly downregulating the cellular level of antiapoptotic proteins and arrested cell proliferation in the G2/M phase.ConclusionTaken together, Tf-CT-MEs holds promising potential to be an efficient drug delivery system for combinational therapy of cervical cancer.

Furin-responsive triterpenine-based liposomal complex enhances anticervical cancer therapy through size modulation

“…For small-sized Tf-CTM, we developed a dual-component microemulsion delivery system (Tf-CTM) comprising tripterine (anticancer drug 1) and coix seed oil (anticancer drug 2, oil phase). As previously reported, it has been verified that after transferrin modification, Tf-CTM exhibited enhanced anti-cervical cancer treatment (Qu et al, 2015(Qu et al, , 2017Chen et al, 2018;Qu et al, 2018).…”

“…The intracellular fluorescence of the FITC/Tf-C-MEs was more intense than that of various treatments group (Figure 2(A,B)), suggesting the enhancement of endocytosis after transferrin modification ( ÃÃ p < .01) (Chen et al, 2018). The intracellular fluorescence of the 42 C group was more intensive compared with that of the 37 C group ( Ã p < .05), suggesting that enhancement of endocytosis was triggered by temperature (Chen et al, 2018). In particular, the uptake fluorescence intensity of HeLa cells by the FITC/Tf-C-MEs was 568.97 ± 11.42, and that of FITC/PEGcleavable Tf-C-MEs/L-42 C was 271.68 ± 11.58, indicating an inherent advantage of small-sized nanoparticles on internalization.…”

“…PEGcleavable Tf-CTM/L coated with thermo-sensitive lipid and a kind of PEG shell modified with furin-cleavable peptide was developed for improved tumor-specific accumulation and penetration to enhance cervical cancer treatment). (Chen et al, 2018).…”

“…As previously reported, tripterine released from PEGcleavable Tf-CTM/L was determined via dialysis method (Qu et al, 2015(Qu et al, , 2017Chen et al, 2018;Qu et al, 2018). 1 mL of PEGcleavable Tf-CTM/L was firstly transferred to a dialysis bag (10 kDa MWCO), and then followed by incubation within 120 mL of PBS (pH 7.4) with 0.5% (wt%) Tween 80, under pH 7.4 at 37 C and 42 C. During the 0-24 h period, 50 lL of PEGcleavable Tf-CTM/L solution was taken at the predetermined time intervals with rotary shaking at 60 rpm.…”

“…HeLa cells were cultured in Dulbecco's modified Eagle's medium (DMEM, 10% FBS, 100 lg/mL streptomycin/penicillin) under 5% CO 2 . HeLa cells (1 Â 10 3 ) were seeded in the 96well plates with the surface of an agarose-based culture medium, under an atmosphere of 5% CO 2 at 37 C. HeLa 3 D tumor spheroids with an appropriate size ($300 nm) were selected and then transferred to confocal dishes, for study after 10 days of incubation (Qu et al, 2015(Qu et al, , 2017Chen et al, 2018;Qu et al, 2018). HeLa 3D tumor spheroids were treated with CTM, Tf-CTM with small size and Tf-CTM/L, PEGcleavable Tf-CTM/L with large size at fluorescein isothiocyanate (FITC, 10 mM) for 8 h and then fixed with 4% (v%) paraformaldehyde and then observed via CLSM (Z-stack tool, 5 mm interval/scan).…”