F-radiolabeled Porous Silicon Particles for Drug Delivery Tracer Development and Evaluation in Rats

Poor biopharmaceutical properties such as low solubility and low permeability in the gastrointestinal (GI) tract plight many existing drugs and new chemical entities, presenting an impediment for efficient drug therapy. Incorporation of the drug to a delivery system based on a nanostructured material is increasingly investigated as a strategy to overcome these limitations and to achieve controlled and targeted delivery. Porous silicon (PSi) is a promising material for carrier-mediated drug delivery because of its biocompatibility, high chemical stability, and facile elimination from the body. Moreover, the physicochemical properties of PSi can be tailored by variation of the fabrication parameters and surface modifications to suit diverse payloads. Positron emission tomography (PET), a sensitive and quantitative method of molecular imaging, is a potent tool for drug delivery system development. Already at the preclinical stage PET can be employed for the investigation of drug delivery carrier biodistribution in vivo, thereby facilitating the selection of the most promising material candidates for further development and future drug delivery studies. In this dissertation, a direct nucleophilic radiolabeling method with a short-lived positron emitter fluorine-18 (18F) was developed for three different surface-modified PSi materials: thermally hydrocarbonized PSi (THCPSi), thermally carbonized PSi (TCPSi), and thermally oxidized PSi (TOPSi). Out of the investigated materials, nanosized [18F]THCPSi emerged as the one with the highest potential for imaging and drug delivery in terms radiolabeling yield, label stability, and bio­ compatibility in cell models in vitro, and was therefore forwarded to bio­ distribution studies in rats. After oral administration, [18F]THCPSi nanoparticles were shown to pass intact through the GI tract in 4 to 6 hours. Modification of [18F]THCPSi with a self-assembled layer of a fungal hydrophobin (HFBII) changed the hydrophilicity of the material bringing about bioadhesive properties that promoted gastric retention of the protein-coated nanoparticles. Intravenous delivery of [18F]THCPSi nanoparticles resulted in their rapid accumulation to the liver and spleen alluding to rapid immune recognition and removal of the particles from the bloodstream by macrophages of the mononuclear phagocyte system (MPS). HFBII-coating of the nanoparticles altered the adsorption of plasma proteins to the particle surface, which translated also to a change in the biodistribution pattern in vivo. In conclusion, the present work establishes 18F-radiolabeled particle tracers as useful means for the evaluation of new PSi-based drug delivery systems with PET.