Liposomal formulation of model pentathiepin improves solubility and stability toward glutathione while preserving anticancer activity

Abstract

The biological properties of pentathiepins have been attracting increased attention in recent years. Experiments have shown a wide range of effects of pentathiepins in vitro, such as induction of apoptosis and alteration of mitochondrial membrane potential in cancer cells, and inhibition of antioxidant enzymes, for example, glutathione peroxidase 1 (GPx1). Biological evaluation is sometimes limited due to low aqueous solubility, high lipophilicity, and poor stability toward thiols, for example, glutathione (GSH). To assess whether liposomes are suitable as drug carriers to overcome these drawbacks, a model pentathiepin was formulated in a liposomal preparation. The success of loading liposomes with pentathiepins was evaluated by using ultraviolet‐visible light (UV‐Vis) spectroscopy, dynamic light scattering (DLS), and high‐performance liquid chromatography (HPLC). Through inclusion into 100‐nm‐sized 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine liposomes, the aqueous solubility of a representative pentathiepin could be increased by several orders of magnitude to ca. 400 µM. The stability of the pentathiepin in the presence of GSH was increased fourfold as determined by UV‐Vis spectroscopy. In antiproliferation experiments with two human cancer cell lines, no decrease in potency in the liposomal loaded pentathiepin compared to the free pentathiepin was found. In conclusion, liposomes are a suitable carrier for pentathiepins and improve both solubility and stability in the presence of thiols without compromising anticancer activity.

Synthesis of Seven Indolizine-Derived Pentathiepines: Strong Electronic Structure Response to Nitro Substitution in Position C-9

“…Another important aspect in this regard is the fact that the literature-known pentathiepines are somehow limited in their number and variation, while a larger available library would broaden, for instance, their use as monomers in electrochemical polymerization applications [ 22 ] and thereby provide an access to polymers with a wide range of characteristics. The milder protocol has the potential to change the limits of the present situation quite dramatically as was already indicated [ 23 , 24 , 25 ], and as is currently being explored by us intensively.…”