Entrapment Into Nanoemulsions Potentiates the Anticancer Activity of Tocotrienols Against the Highly Malignant (+SA) Mouse Mammary Epithelial Cells

Abstract

The highly malignant +SA mouse mammary epithelial cells were used as the model cell line over the years to establish the anticancer activity of tocotrienols. Tocotrienols, however, have poor oral bioavailability and were therefore entrapped into parenteral nanoemulsions for parenteral administration. The objective of this work was to test whether the activity of tocotrienols in lipid nanoemulsions against the +SA cells was retained. A secondary objective was to test whether stabilizing the nanoemulsions with poloxamer or sodium oleate would affect their activity. Nanoemulsions were found to be significantly more potent than tocotrienol/albumin conjugate. The IC50 values of the poloxamer and sodium oleate nanoemulsions were 3 and 6 microM, respectively, whereas the IC50 value of the conjugate was 10 microM. The antiproliferative activity of the nanoemulsions was also found to inversely correlate with particle size. No activity was observed with nanoemulsions loaded with alpha-tocopherol or vehicle, which confirmed the cytotoxic activity of tocotrienols and the potential use of nanoemulsions in cancer therapy.

Enhanced effectiveness of tocotrienol-based nano-emulsified system for topical delivery against skin carcinomas

“…Based on previous reports of superior emulsification results of VE-enriched NEs, the basic composition ratio of test O/W formulations was kept constant (oil/surfactant blend/water as 25/8/67 wt %) (Jordan et al, 2012;Pham et al, 2013). Of which, the surfactant blend consisted of 60 wt% polyethoxylated Solutol-HS 15, as the primary non-ionic surfactant (Anton et al, 2007), mixed with 40 wt% VE-TPGS, which serves as co-surfactant and stabilizing agent (quite similar in role to poloxamer-188, highlighted in earlier reports of T3-NE) (Alayoubi et al, 2013a(Alayoubi et al, , 2014. This system was used as the starting point for the evaluation of the primary physico-chemical characteristics of NE approaches for Tocomin Õ .…”

“…High-energy emulsification methods (typically 20-30 cycles of microfluidizer/high-shear homogenization, or 30-60 min of ultrasonication) are often utilized (Kuo et al, 2007;Bose et al, 2013;Alayoubi et al, 2014) due to the relatively high viscosity of the T3-rich palm oil fraction. Even though such harsh methods generally yield VE-NEs with desired properties and have industrial scalability, they may not be suitable for thermo-sensitive biological compounds, such as vitamins (e.g.…”

“…In addition, the anti-proliferative effects elicited by tocotrienol analogues, within Tocomin Õ , gained them growing attention in cancer therapy Alayoubi et al, 2013b). Palm oil fraction rich in tocotrienols have exhibited marked anticancer activity against various types of tumor tissues, of murine and human origins, such as mammary, prostate, hepatic and gastric cancers (Rajendran et al, 2011;Patacsil et al, 2012;Alayoubi et al, 2014). Moreover, certain tocotrienols (g-tocotrienol, g-T3) have been investigated in combination treatments to sensitize cancer cells towards co-administered therapeutic drugs, consequently enhancing the overall anticancer efficacy (Kannappan et al, 2010;Rajendran et al, 2011).…”

“…For topical administration (Muller et al, 2007), NE formulations have been successfully developed for improved cutaneous tissue permeation and residence time of Tph compounds, serving mostly as skin antioxidants (Kuo et al, 2007), to ameliorate UV-induced oxidative cell damage (Cichewicz et al, 2013). The majority of NE formulations of vitamin E analogues depend on the high-energy emulsification methods, such as high-pressure homogenization and ultrasonic emulsification to create nano-droplets with high kinetic energy (Ng et al, 2013;Alayoubi et al, 2014). During these processes, several forces, such as hydraulic shear, intense turbulence and collision, sometimes along with cavitation, act together to yield NE with extremely small particle size.…”

Use of Lipid Nanocarriers to Improve Oral Delivery of Vitamins

“…Nanoemulsions and microemulsions are other approaches used to improve the solubility and GI transport of vitamins [114]. Vitamins that are formulated in nanoemulsions have better physical stability in electrolyte dispersions and plasma [115]. The group of Dr. McClements (University of Massachusetts) performed a series of experiments to investigate the effect of different nanoemulsion formulations on the GI bioaccessibility of β-carotene (a provitamin A).…”