Enhanced Solubility, Permeability and Anticancer Activity of Vorinostat Using Tailored Mesoporous Silica Nanoparticles

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.

Development of Novel Silica-Based Formulation of α-Lipoic Acid: Evaluation of Photo and Thermal Stability of the Encapsulated Drug

“…In present time, a significant scientific and technological interest has focused on drug-silica materials, which have been identified as potentially effective drug delivery systems (DDS). Encapsulation of drugs in silica matrix and formation of composite material between drug and colloid silica can cardinally change some very important properties of the drug, e.g., enhance its solubility and dissolution rate [1,2], protect against decomposition under various environmental factors [3][4][5], modify release kinetics of the drug [6][7][8][9], etc. Thus, the DDS can improve the administration and efficacy of pharmaceutical compounds.…”

The Self-Assembly Phenomenon of Poloxamers and Its Effect on the Dissolution of a Poorly Soluble Drug from Solid Dispersions Obtained by Solvent Methods

“…Recently, nanotechnology has emerged as a technique that leads to the formation of robust delivery systems. Numerous attempts have been applied to obtain several types of delivery systems, i.e., micelles [5], liposomes [6], capsules [7,8], protein nanocontainers [9], and silica-based nanoparticles [10,11]. Poorly water-soluble drugs have been frequently processed with hydrophilic polymers, as the molecular dispersion of drug molecules within the matrix provides better dissolution of the drug.…”

Mesoporous silica nanoparticles for drug delivery—Recent advances

“…Moreover, the solubility was further enhanced when MSNs were modified with amino groups (3.9 fold) or phosphonate groups (4.3 fold). Furthermore, the permeability of vorinostat into Caco-2 human colon cancer cells was significantly improved for MSNs-based formulations, particularly in positively charged amino-modified MSNs (almost enhanced 4 fold) (20). The solubility and oral bioavailability of several BCS II drugs (low solubility and high permeability) can be improved when they were encapsulated within mesoporous structures of MSNs with different morphologies, surface charge, and functional groups.…”

“…When water-insoluble drug molecules are impregnated in the porous channel of MSNs, they would convert into their amorphous state, and the limited space within the mesopores can inhibit the recrystallization of the incorporated amorphous drug molecules. Compared with the crystalline state, the amorphous drugs, without ordered structure, show the higher apparent solubility as there is no crystal lattice to be broken during the dissolution process (20,21).…”