Assessment of radiotherapy of cancer by apoptosis imaging with F-18 ML-10

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Zhou, Kedi
Ren, Qiushi
Nie, Shuming
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Cancer, currently the second leading cause of death in the United States, is expected to become the first killer in the near future by surpassing heart diseases. Molecular imaging has become a key tool in the biomedical research and clinical diagnosis. By employing specific imaging probes, molecular imaging traces various biological processes at the molecular level in living tissues with high resolution and specificity. In this dissertation, the early assessment of clinical radiotherapy effects has been carried by positron emission tomography (PET) imaging with F-18 labeled 2-(5-fluoropentyl)-2-methyl malonic acid (F-18 ML-10). However, most of the researches on application of F-18 ML-10 are preclinical studies. Currently, the clinical assessment of radiotherapy effects is based on the measurement of tumor size by magnetic resonance imaging (MRI) 2-4 months post radiotherapy. However, several months’ late assessment caused many patients who is bearing malignant tumor to lose the chance of surrogate therapy. This has caused an impediment for the management of therapy plan. Therefore, there is a great demand for early assessment of radiotherapy of cancer in the clinic. As apoptosis of tumor cells is one of the early events that occurred after radiotherapy, therefore monitoring of apoptotic cells by F-18 ML-10 PET imaging can be used for the early assessment. However, there are many challenges for its clinical use. As is produced through F-18 fluoride labelling via nucleophilic substitution reaction, Kryptofix 2.2.2 (K2.2.2) is one of the most widely used phase-transfer reagents for F-18 nucleophilic substitution reaction. Due to the toxicity of K2.2.2, its residue in F-18 radiopharmaceuticals should not exceed 50 g/mL, as required by the United States Pharmacopeia 40. However, false-positive or false-negative results of K2.2.2 detection affects the safety of F-18 pharmaceuticals. In this dissertation, we have overturned the hypothesis that amine compounds caused the false positive results. Moreover, we also proposed and tested the effect of reductive stabilizer and pH value on the false negative results. In the investigation on safety assessment of radiotherapy, a special clinical case for therapeutic assessment on lung cancer after CK treatment has been investigated. After CK treatment, there was no significant change in the apoptosis of tumor. However, the apoptosis in heart tissue and aortic arch increased significantly, indicating injuries in adjacent tissue by CK treatment caused by a rapid apoptotic response. The late return visit indicated that the cancer recurred, this is coincident with the F-18 ML-10 imaging results. This finding was verified by following preclinical studies on rabbits. Thus, this case study suggested that this method has the potential for the assessment of subsidiary-injury of lung cancer radiotherapy. In the investigation on efficacy assessment of radiotherapy, in the clinical applications, 29 clinical cases of different types of brain tumor have been included, and the PET image has been analyzed volume-by-volume in assessment of response of different types of tumors to CyberKnife (CK) radiotherapy. There are many challenges for quantitative analysis of therapeutic assessment by using apoptosis imaging. As apoptosis is essentially a transient process, it is necessary to standardize the imaging method and time point, and to make quantitative analysis based on “volume-by-volume” of the image, to distinguish between cell apoptosis and spontaneous apoptosis. Furthermore, correlation between the result of this early assessment and subsequent anatomic change in tumor determined by MRI was also investigated. The results show a high correlation between the F-18 ML-10 imaging results and the tumor volume changes evaluated by MRI. This research has provided a clinical method for the early evaluation of tumor radiotherapy. The applicability of this method has been discussed by analyses on different brain tumor types. In addition, two other imaging related projects which I have done during my PhD period are also included in this dissertation. For the application of spectroscopic molecular imaging to real-time surgery guidance, the sensitivity of a novel surface enhanced Raman spectroscopy (SERS) hand-held spectroscopic device for intraoperative tumor detection has been investigated. The SERS gold nanoparticles have been proved to be ultra-high sensitive for in vitro detection with wide dynamic range, thus could distinguish the signal of tumor tissue from that of normal tissue. Furthermore, the differentiation of tumor tissue from inflammatory tissue has also been investigated by a preclinical quad-modality imaging with multiple probes.
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