Abstract
Avocado (Persea americana Mill.; Lauraceae) seed-derived polyhydroxylated fatty alcohols (PFAs) or polyols (i.e., avocadene and avocadyne) are metabolic modulators that selectively induce apoptosis of leukemia stem cells and reverse pathologies associated with diet-induced obesity. Delivery systems containing avocado polyols have not been described. Herein, natural surface active properties of these polyols are characterized and incorporated into self-emulsifying drug delivery systems (SEDDS) that rely on molecular self-assembly to form fine, transparent, oil-in-water (O/W) microemulsions as small as 20 nanometers in diameter. Mechanistically, a 1:1 molar ratio of avocadene and avocadyne (i.e., avocatin B or AVO was shown to be a eutectic mixture which can be employed as a novel, bioactive, co-surfactant that significantly reduces droplet size of medium-chain triglyceride O/W emulsions stabilized with polysorbate 80. In vitro cytotoxicity of avocado polyol-SEDDS in acute myeloid leukemia cell lines indicated significant increases in potency and bioactivity compared to conventional cell culture delivery systems. A pilot pharmacokinetic evaluation of AVO SEDDS in C57BL/6J mice revealed appreciable accumulation in whole blood and biodistribution in key target tissues. Lastly, incorporation of AVO in SEDDS significantly improved encapsulation of the poorly water-soluble drugs naproxen and curcumin.
Highlights
Avocado (Persea americana Mill.; Lauraceae) seed-derived polyhydroxylated fatty alcohols (PFAs) or polyols are metabolic modulators that selectively induce apoptosis of leukemia stem cells and reverse pathologies associated with diet-induced obesity
We examined if avocado polyol SEDDS have enhanced bioactivity in vitro and if they accumulate in blood and key target tissues when delivered orally to mice
This study highlights strong links between the physical properties of avocado polyols extracted from avocado seeds to: i) their behaviour in SEDDS, ii) in vitro bioactivity, and iii) in vivo pharmacokinetics
Summary
Avocado (Persea americana Mill.; Lauraceae) seed-derived polyhydroxylated fatty alcohols (PFAs) or polyols (i.e., avocadene and avocadyne) are metabolic modulators that selectively induce apoptosis of leukemia stem cells and reverse pathologies associated with diet-induced obesity. Natural surface active properties of these polyols are characterized and incorporated into self-emulsifying drug delivery systems (SEDDS) that rely on molecular self-assembly to form fine, transparent, oil-in-water (O/W) microemulsions as small as 20 nanometers in diameter. We demonstrated that avocatin B (AVO), a 1:1 mixture of two 17-carbon polyols (avocadyne and avocadene), target mitochondria and inhibit fatty acid oxidation (FAO) which selectively induces death in leukemia cells[5,6,7,8]. Use of avocado polyols is prominent in topical cosmetic formulations described briefly in patent literature[11,12] This is the first report that avocadene and avocadyne possess unique physicochemical properties ideal for SEDDS applications. We tested the ability of avocadene, avocadyne and their mixtures to spontaneously form O/W nano and microemulsions when incorporated with polysorbates and medium chain triglyceride oils.
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