Abstract
Malignant glioma, including glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), is the most frequently relapsed cancer in the primary brain and central nervous system. High morbidity and mortality make it as the fourth most serious death-leading cancer worldwide. In this study, the 188Re-labeled PEGylated nanoliposomes (188Re-liposomes) were fabricated and evaluated as novel theranostic agents in an orthotopic glioma-bearing rat model (Fischer344/F98 or F98luc). The orthotopic glioma-bearing rats were carefully prepared and subsequently administered with 188Re-liposomes via single intravenous injection. Non-invasive bioluminescence imaging (BLI) was used to monitor tumor growth progress on Fischer344/F98luc model. For diagnostic evaluation, a series of experiments including biodistribution, pharmacokinetics, autoradiography, histopathology, and SPECT/CT imaging were conducted. A therapeutic evaluation, supported with pathological examination, was followed by monitoring the survivals of the 188Re-liposomes-treated rats together with non-treated group along with the reared time. Meanwhile, the dosimetry for the radiotherapeutic study was assessed. It is indicated from the diagnostic study that 188Re-liposomes could be efficiently and increasingly accumulated in the brain tumor from 0.28±0.09 %ID/g at 1 h to a maximum of 1.95±0.35 %ID/g at 24 h postinjection, with the tumor-to-normal brain uptake ratio (T/N ratio) from 3.5 at 1 h to 32.5 at 24 h. Both autoradiography and histopathological examination gave correlative informations for the diagnostic study. In addition, the tumors implanted in the rats could be obviously observed via SPECT/CT imagings in the growth period from 4 h till 48 h. For therapeutic study, the reporter cell line F98luc could afford a good relationship between the cell number and the bioluminescent intensity (R2 = 0.99) in vitro and the BLI could be used as a non-invasive imaging system to clearly monitor the brain tumor growth in vivo. It is demonstrated from the therapeutic study that the 188Re-liposomes-treated rats not only had the tumor growth inhibited but also had the survival with 10.67% prolonged as compared with the control group (treated with normal saline), with significance P<0.05. In dosimetry, the relative high radiation doses were found in the spleen (6.96 mSv/MBq) and kidney (1.20 mSv/MBq) whereas very less doses were found in the normal brain (2.75×10-2 mSv/MBq), red marrow (5.13×10-2 mSv/MBq), and thyroid (7.04×10-2 mSv/MBq); the maximum tolerated dose of 188Re-liposomes in Fischer344 rats was estimated to be 333 MBq. In summary, this work has revealed the potentiality of the role of 188Re-liposomes acted as a theranostic pharmaceutical and it is worthy to further evaluate the agent clinically for brain tumor therapy.