Paclitaxel and curcumin coadministration in novel cationic PEGylated niosomal formulations exhibit enhanced synergistic antitumor efficacy

Abstract

Background: The systemic administration of cytotoxic chemotherapeutic agents for cancer treatment often has toxic side effects, limiting the usage dose. To increase chemotherapeutic efficacy while reducing toxic effects, a rational design for synergy-based drug regimens is essential. This study investigated the augmentation of therapeutic effectiveness with the co-administration of paclitaxel (PTX; an effective chemotherapeutic drug for breast cancer) and curcumin (CUR; a chemosensitizer) in an MCF-7 cell line.

Results: We optimized niosome formulations in terms of surfactant and cholesterol content. Afterward, the novel cationic PEGylated niosomal formulations containing Tween-60: cholesterol:DOTAP:DSPE-mPEG (at 59.5:25.5:10:5) were designed and developed to serve as a model for better transfection efficiency and improved stability. The optimum formulations represented potential advantages, including extremely high entrapment efficiency (~ 100% for both therapeutic drug), spherical shape, smooth-surface morphology, suitable positive charge (zeta potential ~ + 15 mV for both CUR and PTX), sustained release, small diameter (~ 90 nm for both agents), desired stability, and augmented cellular uptake. Furthermore, the CUR and PTX kinetic release could be adequately fitted to the Higuchi model. A threefold and 3.6-fold reduction in CUR and PTX concentration was measured, respectively, when the CUR and PTX was administered in nano-niosome compared to free CUR and free PTX solutions in MCF-7 cells. When administered in nano-niosome formulations, the combination treatment of CUR and PTX was particularly effective in enhancing the cytotoxicity activity against MCF-7 cells.

Conclusions: Most importantly, CUR and PTX, in both free form and niosomal forms, were determined to be less toxic on MCF-10A human normal cells in comparison to MCF-7 cells. The findings indicate that the combination therapy of PTX with CUR using the novel cationic PEGylated niosome delivery is a promising strategy for more effective breast cancer treatment.

Keywords: Chemotherapy; Combination therapy; Curcumin; Niosome; Paclitaxel.

Fig. 1

Morphological assessment: a niosomal paclitaxel; b niosomal curcumin by cryogenic transmission electron microscopy (Cryo-TEM). Scanning electron microscopy (SEM) of c curcumin niosome; and d paclitaxel niosome

Fig. 2

The in vitro release profile of curcumin and paclitaxel from niosomal optimum formula

Fig. 3

Curcumin and paclitaxel comparative plots. a Zero order release kinetics; b first order release kinetics; c Higuchi (SQRT) release kinetics and d Hixson–Crowell model

Fig. 4

FTIR spectra. a Free paclitaxel; b free curcumin; c blank noisome; d niosomal paclitaxel; e niosomal; curcumin; f comparison blank noisome and niosomal paclitaxel; g comparison blank noisome and niosomal curcumin

Fig. 5

Inhibition of cell growth by curcumin (CUR) and paclitaxel (PTX) individual as a drug free form and drug niosomal form in MCF-7 and MCF-10A cell. a Free CUR; b Free PTX; c Nio CUR; d Nio PTX for MCF-7 (filled square) and MCF-10A (filled triangle) cells

Fig. 6

Analysis of synergy between curcumin and paclitaxel for MCF-7 (filled triangle) and MCF-10A (filled square) cells. a Dose–response curve of free CUR + Free PTX; b dose–response curve of Nio CUR + Nio PTX. CI values at different levels of growth inhibition effect (fraction affected, FA; c Free CUR + Free PTX in MCF-7 cells; d Nio CUR + Nio PTX in MCF-7 cells; e Free CUR + Free PTX in MCF-10A cells, f Nio CUR + Nio PTX in MCF-10A cell

Fig. 7

Cellular uptake of F6 and F7 CUR/PTX loaded niosomes formulations on MCF-7cell line. MCF-7cell line [a1 F6 Nio CUR Nucleus, a2 F6 Nio CUR, a3 F6 Nio CUR merged; b1 F7 Nio CUR Nucleus, b2 F7 Nio CUR, b3 F& Nio CUR merged; c1 F6 PTX CUR Nucleus, c2 F6 Nio PTX, c3 F6 Nio CUR PTX; d1 F7 Nio PTX Nucleus, d2 F7 Nio PTX, d3 F& Nio PTX merged]

Fig. 8

Cellular uptake of F6 and F7 CUR/PTX loaded niosomes formulations on MCF-7cell line. MCF-10A cell line [a1 F6 Nio CUR Nucleus, a2 F6 Nio CUR, a3 F6 Nio CUR merged; b1 F7 Nio CUR Nucleus, b2 F7 Nio CUR, b3 F& Nio CUR merged; c1 F6 PTX CUR Nucleus, c2 F6 Nio PTX, c3 F6 Nio CUR PTX; d1 F7 Nio PTX Nucleus, d2 F7 Nio PTX, d3 F& Nio PTX merged]

Fig. 9

Apoptosis assay using flow cytometry following the treatment of cells for 24 h. a Control; b free curcumin + free paclitaxel; c free curcumin; d free paclitaxel; e niosomal curcumin; f niosomal paclitaxel; g niosomal curcumin + niosomal paclitaxel