Design, Synthesis and Characterization of Porous Silica Nanoparticles and Application in Intracellular Drug Delivery

Nanoparticle mediated drug delivery approaches provide potential opportunities for targeting and killing of intracellular bacteria. Among them, the porous silica nanoparticles deserve special attention due to their multifunctional properties such as high drug loading, controlled drug release and targeting of organs/cells. A review of the functional requirements of an ideal drug delivery system is provided. A general comparison between different drug delivery carriers and key issues to be addressed for intracellular drug delivery is discussed. Acid catalyzed and acid-base catalyzed, sol-gel derived, silica xerogel systems were investigated for sustained release of an aminoglycosides antimicrobial against salmonella infection in a mouse model. The release of gentamicin from the inner hollow part of the carrier is delayed. Further, the higher porosity of the acid–base catalyzed silica xerogel allows for high drug loading compared to the acid catalyzed silica xerogel system. Efficacy of these particles in killing intracellular bacteria (salmonella) was determined by administering three doses of porous silica loaded gentamicin. This proved to be useful in reducing the salmonella in the liver and spleen of infected mice. Furthermore, the presence of silanol groups provides the ability to functionalize the silica xerogel system with organic groups, poly (ethylene glycol) (PEG), to further increase the hydrophilicity of the silica xerogel matrix and to modify the drug release properties. Increase in the hydrophilicity of the matrix allows for faster drug release rate.

In order to facilitate controlled drug release, magnetic porous silica xerogels were fabricated by incorporating iron particles within the porous silica. The particles were fabricated using an acid-base catalyzed sol-gel technique. The in-vitro drug release studies confirm that the release rate can be changed by the magnetic field "ON-OFF" mechanism. This novel drug release methodology combined with the property of high drug loading capacity proves to be influential in treating salmonella intracellular bacteria. The potential application of any drug delivery carrier relies on the ability to deliver the requisite drug without adversely affecting the cells over the long term. We have developed silica/calcium nanocomposites and evaluated their solubility behavior. The solubility of particles was characterized by particle size measurements for different periods of time. It was found that the solubility behaviour of the silica/calcium particles was dependent on their calcium content. The results obtained demonstrate the potential to use mesoporous silica/calcium nano-composites for drug delivery applications.

The significant contribution of this research to drug delivery technology is on design and development of the novel porous core-shell silica nano-structures. This new core-shell nano-structure combines all the above mentioned properties (high drug loading, magnetic field controlled drug release, and solubility). The main aim of preparing these porous core-shell particles is to have a control over the solubility and drug release property, which is a significant phenomenon, which has not been achieved in any other drug delivery systems. The shell layer acts as a capping agent which dissolves at a controllable rate. The rate at which the shell layer dissolves depends on the composition of the particles. This shell prevents the drug "leakage" from the particles before reaching the target site. The core layer drug loading and release rate was modified by application of a magnetic field. Additionally, inclusion of the calcium ions in the core layer destabilizes the silica network and allows the particles to dissolve at an appropriate rate (which can be controlled by the concentration of the calcium ions).