Abstract
Suberoylanilide hydroxamic acid (SAHA) or vorinostat (VOR) is a potent inhibitor of class I histone deacetylases (HDACs) that is approved for the treatment of cutaneous T-cell lymphoma. However, it has the intrinsic limitations of low water solubility and low permeability which reduces its clinical potential especially when given orally. Packaging of drugs within ordered mesoporous silica nanoparticles (MSNs) is an emerging strategy for increasing drug solubility and permeability of BCS (Biopharmaceutical Classification System) class II and IV drugs. In this study, we encapsulated vorinostat within MSNs modified with different functional groups, and assessed its solubility, permeability and anti-cancer efficacy in vitro. Compared to free drug, the solubility of vorinostat was enhanced 2.6-fold upon encapsulation in pristine MSNs (MCM-41-VOR). Solubility was further enhanced when MSNs were modified with silanes having amino (3.9 fold) or phosphonate (4.3 fold) terminal functional groups. Moreover, permeability of vorinostat into Caco-2 human colon cancer cells was significantly enhanced for MSN-based formulations, particularly MSNs modified with amino functional group (MCM-41-NH2-VOR) where it was enhanced ~4 fold. Compared to free drug, vorinostat encapsulated within amino-modified MSNs robustly induced histone hyperacetylation and expression of established histone deacetylase inhibitor (HDACi)-target genes, and induced extensive apoptosis in HCT116 colon cancer cells. Similar effects were observed on apoptosis induction in HH cutaneous T-cell lymphoma cells. Thus, encapsulation of the BCS class IV molecule vorinostat within MSNs represents an effective strategy for improving its solubility, permeability and anti-tumour activity.
Highlights
The efficient oral delivery of hydrophobic molecules to target tissues represents a major clinical challenge [1,2]
We demonstrate that the ability of vorinostat to inhibit histone deacetylases (HDACs) activity, alter gene expression and induce apoptosis in colorectal cancer and cutaneous T-cell lymphoma cells is markedly enhanced compared to free drug, and are similar to the effects induced by vorinostat solubilised in dimethyl sulfoxide (DMSO)
While our findings revealed that encapsulation of vorinostat within NH2 functionalised particles increased permeability among the formulations tested, we did not see any effect of mesoporous silica-based nanoparticles (MSNs) on tight junction function
Summary
The efficient oral delivery of hydrophobic molecules to target tissues represents a major clinical challenge [1,2]. There has been growing interest in the use of porous nanomaterials for improving the oral delivery of small hydrophobic molecules and macromolecules [10,11] In this regard, mesoporous silica-based nanoparticles (MSNs) have strong potential as drug delivery vehicles due to their high and tuneable surface area (>1000 m2/g), good biocompatibility, uniform particle size, tuneable pore sizes, large pore volumes, thermal stability and ease of functionalisation [6,7,8,12,13,14]. We sought to determine the effect of encapsulation of the BCS class IV molecule vorinostat within functionalised MSNs on its solubility, permeability and anti-cancer activity. To the best of our knowledge this is the first study that demonstrates efficient encapsulation of vorinostat within highly ordered MSNs with marked improvement in physicochemical and anti-cancer activity
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