Exploring new therapeutic properties from the encapsulation of pharmaceutical compounds within mesoporous silica particles
Oxygen and nitrogen containing reactive species are biologically important molecules in a range of physiological systems. The heightened production of reactive species causes oxidative damage to key biomolecules that contribute to the pathogenesis of diseases such as diabetes, cardiovascular, cancer, and neurodegeneration. Disruption to the blood brain barrier integrity by oxidative stress and inflammation (neuroinflammation) is a key event that causes the infiltration of neurotoxins and the development of neurodegenerative diseases. Drug compounds with antioxidant/anti-inflammatory properties are ideal candidates for the treatment of neuroinflammation. However, the therapeutic effectivness of these drug compounds are limited by their poor aqueous solubility.
The aim of this thesis is to explore the solubility and pharmacological properties of drug compounds released from mesoporous silica particle (MSP) for potentially new thereaputic applications. In chapter 3, the local molecular structure of the amorphous drug loaded within MSPs are explored through the use of pair distribution function (PDF) analysis of high energy X-ray diffration (HE-XRD) scans in order to understand the effect of such differences on the in vitro drug release. While an enhancement in the dissolution rate was achieved for a range of poorly soluble drug compounds released from MSP, PDF analysis provided additional information on the local molecular ordering of the loaded drug, which other characterisation techniques such as differential scanning calorimetry (DSC), nitrogen sorption, and X-ray diffraction (XRD) could not.
In chapter 4, probucol (PB) a drug compound considered practically insoluble in biological media, was loaded within MSP to determine the effect of drug loading (wt%), textural properties of MSP and capsule dose on the solubility of PB as compared to crystalline PB. The encapsulation of PB in the amorphous form was achieved at an equivalent loading of 30 wt% in SBA-15, and AMS-6 with a significant enhancement in the solubility of PB released from MSP as compared to crystalline PB. Further in vivo studies in rats showed an enhancement in pharmacokinetic properties of PB released from AMS-6 was achieved compared to crystalline PB at the equivalent dose. Additional in vitro studies in cellular models of oxidative stress showed an enhancement in PB’s antioxidant properties released from AMS-6 was achieved as compared to crystalline PB.
In chapter 5, the pharmacological properties of probucol and indomethacin released from AMS-6 was further explored in an in vitro blood brain barrier (BBB) model of neuroinflammation, using lipopolysaccharide (LPS) as the pro-inflammatory stimulus. An enhancement in the pharmacological proeprties of the drug released from AMS-6 was achieved as compared to the crystalline drug. Of the test compounds, ascorbic acid which is a potent water soluble antioxidant, and PB released from AMS-6 reduced LPS mediated increase in the permeability of the blood brain barrier compared to INDO and AMS-6INDO, suggesting drug compounds with antioxidant properties are superior in the treatment of neuroinflammation. In the final chapter, the antioxidant properties of PB released from AMS-6 was further explored in vivo in a zebrafish model of oxidative stress. PB released from AMS-6 reduced levels of reactive species at a lower dose in comparison to ascorbic acid and crystalline PB. Overall, this thesis suggest the encapsulation of poorly soluble drug compounds within MSP is a viable strategy to unlock the pharmacological properties of the drug compounds for new therapeutic applications.