Abstract
An ever-growing number of preclinical studies have investigated the tumoricidal activity of the milk thistle flavonolignan silibinin. The clinical value of silibinin as a bona fide anti-cancer therapy, however, remains uncertain with respect to its bioavailability and blood–brain barrier (BBB) permeability. To shed some light on the absorption and bioavailability of silibinin, we utilized the Caco-2 cell monolayer model of human intestinal absorption to evaluate the permeation properties of three different formulations of silibinin: silibinin-meglumine, a water-soluble form of silibinin complexed with the amino-sugar meglumine; silibinin-phosphatidylcholine, the phytolipid delivery system Siliphos; and Eurosil85/Euromed, a milk thistle extract that is the active component of the nutraceutical Legasil with enhanced bioavailability. Our approach predicted differential mechanisms of transport and blood–brain barrier permeabilities between the silibinin formulations tested. Our assessment might provide valuable information about an idoneous silibinin formulation capable of reaching target cancer tissues and accounting for the observed clinical effects of silibinin, including a recently reported meaningful central nervous system activity against brain metastases.
Highlights
Silymarin is an extract of Silybum marianum seeds that was classified by the World Health Organization in the 1970s as an official medicine with health-promoting properties
To shed some light on the absorption and bioavailability capabilities of different silibinin formulations with proven pre-clinical and clinical activity, we evaluated the permeation properties of three different silibinin formulations: silibinin-meglumine, a more water-soluble form of silibinin complexed with the excipient amino-sugar meglumine [19,20]; silibinin-phytosome (Siliphos), a silibinin–phosphatidylcholine (PC) complex that can be administered to humans at doses achieving micromolar concentrations with minimal or no side effects [21,22,23]; and Eurosil85/Euromed, a patented extract of milk thistle ETHIS-094 that is the active component of the nutraceutical Legasil with enhanced bioavailability [24,25]
We first established the Caco-2 cell monolayer on a permeable transwell filter support and tested its integrity and reliability by measuring the transepithelial electrical resistance (TEER) as a function of time, which remained stable during the assays irrespective of the silibinin formulation assayed (Supplementary Figure S1A)
Summary
Silymarin is an extract of Silybum marianum (milk thistle) seeds that was classified by the World Health Organization in the 1970s as an official medicine with health-promoting properties. Silibinin undergoes extensive phase II metabolism through the first liver passage after its absorption [11] These four factors (low water solubility, rapid excretion, inefficient intestinal absorption, and elevated metabolism) significantly decrease the hematic concentration of silibinin when combined, reducing its arrival at the target organ and, limiting its therapeutic efficiency [12,13,14]. Numerous approaches have been pursued to overcome the low bioavailability of silibinin through the development of an enormous number (>200) of silibinin modifications [8,15,16,17] These modifications can be grouped into four main categories, namely: complexation with -cyclodextrins, chemical modification to generate different derivatives with enhanced water-solubility profiles (e.g., phosphate and sulphate salts, glycol-conjugates [gluco-, manno-, galacto-, and lacto-conjugates]), incorporation into different delivery technologies (e.g., solid dispersions, floating tablets, softgel capsules, micronizated/nanonizated formulations, etc.), and self-microemulsifying drug delivery systems (e.g., microspheres, nanoparticles, micelles, and phytosomes). Intestinal permeability was evaluated using the Caco-2 cell monolayer model, a well-accepted model of human intestinal absorption [26,27,28,29,30]
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