Efficient PEGylated magnetic nanoniosomes for co-delivery of artemisinin and metformin: a new frontier in chemotherapeutic efficacy and cancer therapy

Abstract

Two strategies were employed to modify the performance of the nano-niosome drug delivery system. Initially, the surface of the nano-niosomes underwent modification through the inclusion of polyethylene glycol, thereby altering its properties. Additionally, the core of the nano-niosomes was equipped with Fe₃O₄ magnetic nanoparticles to impart magnetic characteristics to the system. This study presents the development of PEGylated magnetic nanoniosomes (PMNios) for the co-delivery of artemisinin (ART) and metformin (MET) in cancer therapy, highlighting significant advancements in chemotherapeutic efficacy. The magnetization of the nano-niosomes facilitated the targeted delivery of drugs to specific tissues, while PEGylation improved the bioavailability of the nano-niosomes. These PEGylated magnetic niosomes (PMNios) were then loaded with artemisinin and metformin drugs. The synthesized PMNios were thoroughly evaluated in terms of zeta potential, size, morphology, and entrapment efficiency. The PMNios achieved a drug loading efficiency of 88%. They exhibited an average size of 298 nm, a polydispersity index of 0.32, and a zeta potential of - 19 mV, indicating the complete stability. SEM and TEM images of the PMNios revealed a spherical morphology. Subsequently, the PMNios were compared with other forms of nano-niosomes, including empty niosomes, non-magnetic niosomes, and non-PEGylated niosomes. The encapsulation of the nano-niosomes with magnetic nanoparticles allows for faster delivery of the encapsulated drugs to the tumor site, while PEGylation improved the stability, bioavailability, and controlled release of the PMNios. Furthermore, the in-vitro effectiveness of various formulations of the PMNios against A549, a lung cancer cell line, demonstrated that the PMNios exhibited appropriate toxicity towards cancer cell lines in the presence of an external magnetic field. Gene expression level of Bcl2 were lower for the PMNios-ART-MET system, whereas the level of Bax were higher than the other group. The PMNios-ART-MET system also demonstrated well internalization into the A549 cells and preponderant endocytosis. These findings underscore the novelty and potential of PMNios as a robust platform for the targeted co-delivery of hydrophilic and hydrophobic drugs, promising a new frontier in cancer therapy by enhancing the therapeutic index and minimizing side effects.

Keywords: Artemisinin; Lung cancer; Magnetic noisome; Metformin; Targeted drug delivery system.

Fig. 1

Schematic synthesis procedure of the PMNios-ART-MET.

Fig. 2

(a) X-ray diffraction (XRD) patterns of the PMNios-ART-MET; (b) the transmission electron microscopy of the synthesized Fe₃O₄ nanoparticles; (c) Vibrating-sample magnetometer curve of the Fe₃O₄ nanoparticles.

Fig. 3

FT-IR spectra of (a) span 60, (b) cholesterol, (c) ART, (d) MET, (e) Blank Nio, (f) Nio-ART-MET, (g) PNio-ART-MET, (h) PMNios-ART-MET, (i) PEG and (j) Fe₃O₄ nanoparticles.

Fig. 4

(a) The field emission scanning electron microscopy; (b) the transmission electron microscopy of the prepared PMNios-ART-MET; (c) microscopic images using atomic force microscopy of the PMNios-ART-MET; (d) size distribution by intensity.

Fig. 5

In vitro drugs release of the PNios-ART, PNios-MET, PNios-ART-MET and PMNios-ART-MET.

Fig. 6

Cell viability of A549 lung cancer cells and control after treatment with various concentrations of free ART, free MET, free ART/MET, Nio-ART, Nio-MET, Nio-ART/MET, PNios-ART-MET and PMNios-ART-MET after 48 h against A549 cells. Free ART/MET and niosomal ART/MET and PEGylated niosomal ART-MET have no cytotoxicity. Data are shown as Mean ± SD, n = 3 (* P < 0.05, ** P < 0.01 and *** p < 0.001).

Fig. 7

Cell viability of HBE cells and control after treatment with various concentrations of free ART, free MET, free ART/MET, Nio-ART, Nio-MET, Nio-ART/MET, PNios-ART-MET and PMNios-ART-MET after 48 h against HBE cells. Free ART/MET and niosomal ART/MET and PEGylated niosomal ART-MET have no considerable cytotoxicity. Data are shown as Mean ± SD, n = 3 (* P < 0.05, ** P < 0.01 and *** p < 0.001).

Fig. 8

Apoptotic effect with or without the presence of an external magnetic field in the various niosomal formulations (all data showing p < 0.05 considered significant). EMF-: no external magnetic field, EMF+: presence of an external magnetic field.

Fig. 9

The expression rate of Bcl2 and Bax in A549 lung cancer cells treated with free ART, Nios-ART, free MET, Nios-MET, free ART-MET, Nios-ART-MET and PMNios-ART-MET after 72 h incubation time. (***p < 0.001, **p < 0.01, and *p < 0.05). Results are mean ± SD (n = 3).

Fig. 10

Cellular Uptake of FITC-Labeled Nanoparticles in A549 Cells. Confocal microscopy images showing the uptake of FITC-labeled nanoparticles (PMNios-MET, PMNios-ART, and PMNios-ART-MET) at a concentration of 15 µM by A549 cells after 1, 4, and 8 h of incubation.