The protein corona of mesoporous materials as a platform in drug delivery
For a drug to achieve systemic absorption orally, it needs to be present in a soluble form in the gastrointestinal tract and to permeate across the intestinal wall. Low oral bioavailability remains a big problem in the pharmaceutical industry, especially for poorly soluble compounds. It is advantageous in terms of solubility and bioavailability to prepare amorphous drug forms that can be loaded and stabilised within mesoporous silica particles. It is vital to understand their interaction with physiological media. This occurs via the formation of protein layers on the particle surface, which is termed the biological protein corona. As particles travel through the gastrointestinal tract they will encounter different protein and enzymatic environments which can modify their size, composition and behaviour giving them a new biological identity and properties.
This thesis focuses on evaluating the protein corona of mesoporous silica particles with different morphology and mesopore structure. This thesis also aims to understand how the protein corona can influence the pharmacokinetics of drugs loaded within the mesopores. Advanced characterization is conducted using X-ray diffraction (XRD), differential scanning calorimetry (DSC), adsorption isotherms, a range of spectroscopic techniques, scanning and transmission electron microscopy (SEM and TEM), gel electrophoresis and proteomics to fully understand the nature of the corona. In vivo oral pharmacokinetics with protein corona-complexes using Testosterone and Probucol as poorly soluble drug compounds are also performed.
Proteomic analysis demonstrates large variations in the protein-particle complex as a function of morphology, pore size and serum incubation time. The hard corona surrounds the particles tightly on the external surface and forms a layer of proteins of approximately 10 nm in size, for spherical particles. It is possible to load pharmaceutical compounds within the mesopores and form a protein corona complex without loss of drug or potential to enhance the solubility. The pharmacokinetic parameters of Testosterone are altered both in vitro and in vivo in the presence of a protein corona, whose composition is dominated by serum albumin. Further control is obtained when the protein corona is composed of stronger affinity proteins such as lysozyme, as demonstrated with the compound Probucol. Overall this thesis suggests that the protein corona can be developed into a new formulation strategy to achieve specific physiological objectives such as the efficient release of poorly soluble compounds with desired pharmacokinetic profiles.