Electronic Thesis/Dissertation


Applications of Micro- and Nanoparticles in Activating Photodynamic Therapeutic Agents within Deep-seated Targets Open Access

Photodynamic Therapy (PDT) is a therapeutic method that uses photo-sensitizers that can be preferentially localized in pathological tissue [1-3]. The dominant mode of photodynamic therapy (PDT) action is through the generation of reactive oxygen species (ROS). When the photo-sensitizer in tissue is excited by light, it interacts with molecular oxygen and transfers its energy to molecular oxygen to create highly reactive oxygen in its singlet state in tissues. Despite being non-invasive and having excellent selectivity for diseased tissue, PDT has not yet gained general clinical acceptance, largely due to the inherent limitations of light transport and penetration which restrict external light from activating photo-agents within target volumes deep inside the body. The photo-sensitizers that are approved for PDT treatment in oncology are found to maximally absorb light in the violet region of the visible spectrum, around 400 nm, and blood is a very strong absorber at this wavelength. Thus, the photo-agent's absorption characteristics inherently limit the effectiveness of PDT applications to target-sites that are shallow in depth, 2 - 3mm. For this reason, the clinical application of PDT has been limited to skin lesions, superficial solid tumors, or endoscopically-accessible regions [5].One of the worldwide approved photo-sensitizers in oncology, Photofrin II, is known to have good selectivity towards diseased tissue, and its major sub-cellular target is known to be mitochondria [1-3]. In this work, both X-ray down-converting (DC) and Infrared up-converting (UC) particles were studied as platforms to generate visible luminescence to activate the photo-sensitizer Photofrin II. Specifically, I have investigated DC particles composed of gadolinium oxysulfide doped with terbium (GdO2S: Tb) and UC particles composed of sodium yttrium fluoride co-doped with ytterbium and thulium (NaYF4: Yb/Tm).The DC and UC particles were tested in a cellular-like medium; the test tube with the DC particles was then irradiated with 120 keV X-rays, while the test tube with the UC particles was irradiated with a 980 nm laser. The ROS generation for each test tube was quantified by measuring the change in the absorbance of Vitamin C. In vitro studies on human glioblastoma cell lines were then conducted to investigate the possible cellular toxicity of these DC and UC particles through cell viability assays and an endotoxin detection assay. The therapeutic effectiveness of these particles via Photofrin II activation was also evaluated on in vitro human cancer cells through measurement of ROS levels and cell viability assays. Theoretical modeling of the experiment was generated using both analytical technique and Monte Carlo Modeling of light transport. The results obtained from cellular-like medium showed that both submicron- to micron-sized DC and UC particles have great potential to activate Photofrin II and to generate substantial levels of ROS. Specifically, the results on in vitro cellular studies have shown that 20 micron-sized DC particles have great potential to activate Photofrin II in deep seated targets and to generate substantial levels of ROS and no potential cell toxicity was observed. However, the UC particles tested (50 nm) were shown to be toxic to the cell lines. The cell killing does not appear to be due to the particles' efficiency in activating the photo-sensitizer, but rather appears to be due to toxicity of the particles.

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