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The 188 Re-labeled pegylated nanoliposome (abbreviated as 188 Re-Liposome) was prepared and evalu... more The 188 Re-labeled pegylated nanoliposome (abbreviated as 188 Re-Liposome) was prepared and evaluated for its potential as a theragnostic agent for glioma. 188 Re-BMEDA complex was loaded into the pegylated liposome core with pH 5.5 ammonium sulfate gradient to produce 188 Re-Liposome. Orthotopic Fischer344/F98 glioma tumor-bearing rats were prepared and intravenously injected with 188 Re-Liposome. Biodistribution, pharmacokinetic study, autoradiography (ARG), histopathology, and nano-SPECT/CT imaging were conducted for the animal model. The result showed that 188 Re-Liposome accumulated in the brain tumor of the animal model from 0.28%-0.09% injected dose (ID)/g (n = 3) at 1 hour to a maximum of 1.95%-0.35% ID/g (n = 3) at 24 hours postinjection. The tumor-to-normal brain uptake ratio (T/N ratio) increased from 3.5 at 1 hour to 32.5 at 24 hours. Both ARG and histopathological images clearly showed corresponding tumor regions with high T/N ratios. Nano-SPECT/CT detected a very clear tumor image from 4 hours till 48 hours. This study reveals the potential of 188 Re-Liposome as a theragnostic agent for brain glioma.

Applied Radiation and Isotopes, 2009

Changes in regional metabolic activities induced by middle cerebral artery occlusion (MCAO) can i... more Changes in regional metabolic activities induced by middle cerebral artery occlusion (MCAO) can influence patient outcome. Our aim was to demonstrate in a rat model that 18F-FDG with positron emission tomography (PET) imaging is a quantitative, reproducible approach for identifying acute and sub-acute metabolic variations in infarct regions. We found that imaging with 18F-FDG/PET enabled detection and quantification of ischemia-induced metabolic deficits and provided a sensitive and reliable means of assessing cerebral ischemic lesions compared with conventional neurological scoring systems in rodents.

International journal of nanomedicine, 2015

Nuclear Medicine and Biology, 2008

The pharmacokinetics and internal radionuclide therapy of intraperitoneally administrated 188 Re-... more The pharmacokinetics and internal radionuclide therapy of intraperitoneally administrated 188 Re-N,N-bis(2-mercaptoethyl)-N′,N′diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin ( 188 Re-DXR-liposome) were investigated in the C26 murine colon carcinoma ascites mouse model. After intraperitoneal administration of the nanotargeted bimodality 188 Re-DXR-liposome, the ascites and tumor accumulation of the radioactivity were observed, the levels of radioactivity within the ascites were maintained at relatively higher levels before 48 h and the levels of radioactivity in the tumor were maintained at steady levels after 4 h. The AUC (o→∞) of 188 Re-DXRliposome in blood, ascites and tumor was 9.3-, 4.2-and 4.7-fold larger than that of 188 Re-BMEDA, respectively. The maximum tolerated dose of intraperitoneally administrated 188 Re-DXR-liposome was determined in normal BALB/c mice. The survival, tumor and ascites inhibition of mice after 188 Re-DXR-liposome (22.2 MBq of 188 Re, 5 mg/kg of DXR) treatment were evaluated. Consequently, radiochemotherapeutics of 188 Re-DXR-liposome attained better survival time, tumor and ascites inhibition (decreased by 49% and 91% at 4 days after treatment; Pb.05) in mice than radiotherapeutics of 188 Re-liposome or chemotherapeutics of Lipo-Dox did. Therefore, intraperitoneal administration of novel 188 Re-DXR-liposome could provide a benefit and promising strategy for delivery of passive nanotargeted bimodality radiochemotherapeutics in oncology applications.

Nuclear Medicine and Biology, 2007

Nanoliposomes are important carriers capable of packaging drugs for various delivery applications... more Nanoliposomes are important carriers capable of packaging drugs for various delivery applications through passive targeting tumor sites by enhanced permeability and retention effect. Radiolabeled liposomes have potential applications in radiotherapy and diagnostic imaging. The purpose of this study was to investigate the biodistribution, pharmacokinetics and imaging of nanotargeted (188)Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (RBLPL) and unencapsulated (188)Re-BMEDA after intraperitoneal (ip) injection in a C26 colon carcinoma ascites mouse model. The nanopegylated liposomes were labeled with (188)Re-BMEDA. The labeling efficiency of RBLPL was 82.3+/-4.5%. In vitro stability of RBLPL in normal saline at room temperature and in rat plasma at 37 degrees C for 72 h was 92.01+/-1.31% and 82.4+/-1.64%, respectively. The biodistribution studies indicated that the radioactivity in ascites was 69.96+/-14.08 percentage injected dose per gram (% ID/g) at 1h to 5.99+/-1.97% ID/g at 48 h after ip administration of RBLPL. The levels of radioactivity in tumor were progressive accumulation to a maximum of 6.57+/-1.7% ID/g at 24 h. The radioactivity of (188)Re-BMEDA in ascites reached the maximum level of 54.89+/-5.91% ID/g at 1 h and declined rapidly with time. Pharmacokinetic studies revealed that the terminal half-life, total body clearance and area under the curve of RBLPL were 5.3-, 9.5- and 9.4-fold higher than that of (188)Re-BMEDA in blood, respectively. These results suggested that the long circulation, bioavailability and localization of RBLPL in tumor and ascites sites, which also demonstrate that the ip administration of RBLPL is a potential multifunctional nanoradiotherapeutics and imaging agents on a C26 colon carcinoma ascites mouse model.

Molecules, 2014

The pharmacokinetics of N,N-bis(2-mercapatoethly)-N',N'-diethylenediamine (BMEDA), a molecule tha... more The pharmacokinetics of N,N-bis(2-mercapatoethly)-N',N'-diethylenediamine (BMEDA), a molecule that can form a chelate with rhenium-188 ( 188 Re) to produce the 188 Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles' plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC 0-t and AUC 0-∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.

IEEE Transactions on Medical Imaging, 2005

Micro positron emission tomography (PET) and micro single-photon emission computed tomography (SP... more Micro positron emission tomography (PET) and micro single-photon emission computed tomography (SPECT), used for imaging small animals, have become essential tools in developing new pharmaceuticals and can be used, among other things, to test new therapeutic approaches in animal models of human disease, as well as to image gene expression. These imaging techniques can be used noninvasively in both detection and quantification. However, functional images provide little information on the structure of tissues and organs, which makes the localization of lesions difficult. Image fusion techniques can be exploited to map the functional images to structural images, such as X-ray computed tomography (CT), to support target identification and to facilitate the interpretation of PET or SPECT studies. Furthermore, the mapping of two functional images of SPECT and PET on a structural CT image can be beneficial for those in vivo studies that require two biological processes to be monitored simultaneously. This paper proposes an automated method for registering PET, CT, and SPECT images for small animals. A calibration phantom and a holder were used to determine the relationship among three-dimensional fields of view of various modalities. The holder was arranged in fixed positions on the couches of the scanners, and the spatial transformation matrix between the modalities was held unchanged. As long as objects were scanned together with the holder, the predetermined matrix could register the acquired tomograms from different modalities, independently of the imaged objects. In this work, the PET scan was performed by Concorde's microPET R4 scanner, and the SPECT and CT data were obtained using the Gamma Medica's X-SPECT/CT system. Fusion studies on phantoms and animals have been successfully performed using this method. For microPET-CT fusion, the maximum registration errors were 0.21 mm ± 0.14 mm, 0.26 mm ± 0.14 mm, and 0.45 mm ± 0.34 mm in the X (right-left), Y (upper lower), and Z (rostral-caudal) directions, respectively; for the microPET-SPECT fusion, they were 0.24 mm ± 0.14 mm, 0.28 mm ± 0.15 mm, and 0.54 mm ± 0.35 mm in the X, Y, and Z directions, respectively. The results indicate that thi- s simple method can be used in routine fusion studies.

Cancer Biotherapy & Radiopharmaceuticals, 2012

Nanoliposomes are important carriers capable of packaging drugs for various delivery applications... more Nanoliposomes are important carriers capable of packaging drugs for various delivery applications. Rhenium-188-radiolabeled liposome ((188)Re-liposome) has potential for radiotherapy and diagnostic imaging. To evaluate the targeting of (188)Re-liposome, biodistribution, microSPECT/CT, whole-body autoradiography (WBAR), and pharmacokinetics were performed in LS-174T human tumor-bearing mice. The comparative therapeutic efficacy of (188)Re-liposome and 5-fluorouracil (5-FU) was assessed according to inhibition of tumor growth and the survival ratio. The highest uptake of (188)Re-liposome in LS-174T tumor was found at 24 hours by biodistribution and microSPECT/CT imaging, showing a positive correlation for tumor targeting of (188)Re-liposome using the Pearson's correlation analysis (r=0.997). Pharmacokinetics of (188)Re-liposome showed the properties of high circulation time and high bioavailability (mean residence time [MRT]=18.8 hours, area under the curve [AUC]=1371%ID/g·h). For therapeutic efficacy, the tumor-bearing mice treated with (188)Re-liposome (80% maximum tolerated dose [MTD], 23.7 MBq) showed better tumor growth inhibition and longer survival time than those treated with 5-FU (80% MTD, 144 mg/kg). The median survival time for mice treated with (188)Re-liposome (58.5 days; p<0.05) was significantly better than those of 5-FU (48.25 days; p>0.05) and normal saline-treated mice (43.63 days). Dosimetry study revealed that the (188)Re-liposome did not lead to high absorbed doses in normal tissue, but did in small tumors. These results of imaging and biodistribution indicated the highly specific accumulation of tumor after intravenous (i.v.) injection of (188)Re-liposome. The therapeutic efficacy of radiotherapeutics of (188)Re-liposome have been confirmed in a LS-174T solid tumor animal model, which points to the potential benefit and promise of passive nanoliposome delivered radiotherapeutics for cancer treatment.

Annals of Nuclear Medicine, 2012

Objective The OLINDA/EXM computer code was created as a replacement for the widely used MIRDOSE3 ... more Objective The OLINDA/EXM computer code was created as a replacement for the widely used MIRDOSE3 code for radiation dosimetry in nuclear medicine. A dosimetric analysis with these codes was performed to evaluate nanoliposomes as carriers of radionuclides ( 188 Re-liposomes) in colon carcinoma-bearing mice. Methods Pharmacokinetic data for 188 Re-N, N-bis (2-mercaptoethyl)-N 0 ,N 0 -diethylethylenediamine ( 188 Re-BMEDA) and 188 Re-liposome were obtained for estimation of absorbed doses in normal organs. Radiation dose estimates for normal tissues were calculated using the MIRDOSE3 and OLINDA/ EXM programs for a colon carcinoma solid tumor mouse model.

The 188 Re-labeled pegylated nanoliposome (abbreviated as 188 Re-Liposome) was prepared and evalu... more The 188 Re-labeled pegylated nanoliposome (abbreviated as 188 Re-Liposome) was prepared and evaluated for its potential as a theragnostic agent for glioma. 188 Re-BMEDA complex was loaded into the pegylated liposome core with pH 5.5 ammonium sulfate gradient to produce 188 Re-Liposome. Orthotopic Fischer344/F98 glioma tumor-bearing rats were prepared and intravenously injected with 188 Re-Liposome. Biodistribution, pharmacokinetic study, autoradiography (ARG), histopathology, and nano-SPECT/CT imaging were conducted for the animal model. The result showed that 188 Re-Liposome accumulated in the brain tumor of the animal model from 0.28%-0.09% injected dose (ID)/g (n = 3) at 1 hour to a maximum of 1.95%-0.35% ID/g (n = 3) at 24 hours postinjection. The tumor-to-normal brain uptake ratio (T/N ratio) increased from 3.5 at 1 hour to 32.5 at 24 hours. Both ARG and histopathological images clearly showed corresponding tumor regions with high T/N ratios. Nano-SPECT/CT detected a very clear tumor image from 4 hours till 48 hours. This study reveals the potential of 188 Re-Liposome as a theragnostic agent for brain glioma.

Applied Radiation and Isotopes, 2009

Changes in regional metabolic activities induced by middle cerebral artery occlusion (MCAO) can i... more Changes in regional metabolic activities induced by middle cerebral artery occlusion (MCAO) can influence patient outcome. Our aim was to demonstrate in a rat model that 18F-FDG with positron emission tomography (PET) imaging is a quantitative, reproducible approach for identifying acute and sub-acute metabolic variations in infarct regions. We found that imaging with 18F-FDG/PET enabled detection and quantification of ischemia-induced metabolic deficits and provided a sensitive and reliable means of assessing cerebral ischemic lesions compared with conventional neurological scoring systems in rodents.

International journal of nanomedicine, 2015

Nuclear Medicine and Biology, 2008

The pharmacokinetics and internal radionuclide therapy of intraperitoneally administrated 188 Re-... more The pharmacokinetics and internal radionuclide therapy of intraperitoneally administrated 188 Re-N,N-bis(2-mercaptoethyl)-N′,N′diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin ( 188 Re-DXR-liposome) were investigated in the C26 murine colon carcinoma ascites mouse model. After intraperitoneal administration of the nanotargeted bimodality 188 Re-DXR-liposome, the ascites and tumor accumulation of the radioactivity were observed, the levels of radioactivity within the ascites were maintained at relatively higher levels before 48 h and the levels of radioactivity in the tumor were maintained at steady levels after 4 h. The AUC (o→∞) of 188 Re-DXRliposome in blood, ascites and tumor was 9.3-, 4.2-and 4.7-fold larger than that of 188 Re-BMEDA, respectively. The maximum tolerated dose of intraperitoneally administrated 188 Re-DXR-liposome was determined in normal BALB/c mice. The survival, tumor and ascites inhibition of mice after 188 Re-DXR-liposome (22.2 MBq of 188 Re, 5 mg/kg of DXR) treatment were evaluated. Consequently, radiochemotherapeutics of 188 Re-DXR-liposome attained better survival time, tumor and ascites inhibition (decreased by 49% and 91% at 4 days after treatment; Pb.05) in mice than radiotherapeutics of 188 Re-liposome or chemotherapeutics of Lipo-Dox did. Therefore, intraperitoneal administration of novel 188 Re-DXR-liposome could provide a benefit and promising strategy for delivery of passive nanotargeted bimodality radiochemotherapeutics in oncology applications.

Nuclear Medicine and Biology, 2007

Nanoliposomes are important carriers capable of packaging drugs for various delivery applications... more Nanoliposomes are important carriers capable of packaging drugs for various delivery applications through passive targeting tumor sites by enhanced permeability and retention effect. Radiolabeled liposomes have potential applications in radiotherapy and diagnostic imaging. The purpose of this study was to investigate the biodistribution, pharmacokinetics and imaging of nanotargeted (188)Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (RBLPL) and unencapsulated (188)Re-BMEDA after intraperitoneal (ip) injection in a C26 colon carcinoma ascites mouse model. The nanopegylated liposomes were labeled with (188)Re-BMEDA. The labeling efficiency of RBLPL was 82.3+/-4.5%. In vitro stability of RBLPL in normal saline at room temperature and in rat plasma at 37 degrees C for 72 h was 92.01+/-1.31% and 82.4+/-1.64%, respectively. The biodistribution studies indicated that the radioactivity in ascites was 69.96+/-14.08 percentage injected dose per gram (% ID/g) at 1h to 5.99+/-1.97% ID/g at 48 h after ip administration of RBLPL. The levels of radioactivity in tumor were progressive accumulation to a maximum of 6.57+/-1.7% ID/g at 24 h. The radioactivity of (188)Re-BMEDA in ascites reached the maximum level of 54.89+/-5.91% ID/g at 1 h and declined rapidly with time. Pharmacokinetic studies revealed that the terminal half-life, total body clearance and area under the curve of RBLPL were 5.3-, 9.5- and 9.4-fold higher than that of (188)Re-BMEDA in blood, respectively. These results suggested that the long circulation, bioavailability and localization of RBLPL in tumor and ascites sites, which also demonstrate that the ip administration of RBLPL is a potential multifunctional nanoradiotherapeutics and imaging agents on a C26 colon carcinoma ascites mouse model.

Molecules, 2014

The pharmacokinetics of N,N-bis(2-mercapatoethly)-N',N'-diethylenediamine (BMEDA), a molecule tha... more The pharmacokinetics of N,N-bis(2-mercapatoethly)-N',N'-diethylenediamine (BMEDA), a molecule that can form a chelate with rhenium-188 ( 188 Re) to produce the 188 Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles' plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC 0-t and AUC 0-∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.

IEEE Transactions on Medical Imaging, 2005

Micro positron emission tomography (PET) and micro single-photon emission computed tomography (SP... more Micro positron emission tomography (PET) and micro single-photon emission computed tomography (SPECT), used for imaging small animals, have become essential tools in developing new pharmaceuticals and can be used, among other things, to test new therapeutic approaches in animal models of human disease, as well as to image gene expression. These imaging techniques can be used noninvasively in both detection and quantification. However, functional images provide little information on the structure of tissues and organs, which makes the localization of lesions difficult. Image fusion techniques can be exploited to map the functional images to structural images, such as X-ray computed tomography (CT), to support target identification and to facilitate the interpretation of PET or SPECT studies. Furthermore, the mapping of two functional images of SPECT and PET on a structural CT image can be beneficial for those in vivo studies that require two biological processes to be monitored simultaneously. This paper proposes an automated method for registering PET, CT, and SPECT images for small animals. A calibration phantom and a holder were used to determine the relationship among three-dimensional fields of view of various modalities. The holder was arranged in fixed positions on the couches of the scanners, and the spatial transformation matrix between the modalities was held unchanged. As long as objects were scanned together with the holder, the predetermined matrix could register the acquired tomograms from different modalities, independently of the imaged objects. In this work, the PET scan was performed by Concorde's microPET R4 scanner, and the SPECT and CT data were obtained using the Gamma Medica's X-SPECT/CT system. Fusion studies on phantoms and animals have been successfully performed using this method. For microPET-CT fusion, the maximum registration errors were 0.21 mm ± 0.14 mm, 0.26 mm ± 0.14 mm, and 0.45 mm ± 0.34 mm in the X (right-left), Y (upper lower), and Z (rostral-caudal) directions, respectively; for the microPET-SPECT fusion, they were 0.24 mm ± 0.14 mm, 0.28 mm ± 0.15 mm, and 0.54 mm ± 0.35 mm in the X, Y, and Z directions, respectively. The results indicate that thi- s simple method can be used in routine fusion studies.

Cancer Biotherapy & Radiopharmaceuticals, 2012

Nanoliposomes are important carriers capable of packaging drugs for various delivery applications... more Nanoliposomes are important carriers capable of packaging drugs for various delivery applications. Rhenium-188-radiolabeled liposome ((188)Re-liposome) has potential for radiotherapy and diagnostic imaging. To evaluate the targeting of (188)Re-liposome, biodistribution, microSPECT/CT, whole-body autoradiography (WBAR), and pharmacokinetics were performed in LS-174T human tumor-bearing mice. The comparative therapeutic efficacy of (188)Re-liposome and 5-fluorouracil (5-FU) was assessed according to inhibition of tumor growth and the survival ratio. The highest uptake of (188)Re-liposome in LS-174T tumor was found at 24 hours by biodistribution and microSPECT/CT imaging, showing a positive correlation for tumor targeting of (188)Re-liposome using the Pearson's correlation analysis (r=0.997). Pharmacokinetics of (188)Re-liposome showed the properties of high circulation time and high bioavailability (mean residence time [MRT]=18.8 hours, area under the curve [AUC]=1371%ID/g·h). For therapeutic efficacy, the tumor-bearing mice treated with (188)Re-liposome (80% maximum tolerated dose [MTD], 23.7 MBq) showed better tumor growth inhibition and longer survival time than those treated with 5-FU (80% MTD, 144 mg/kg). The median survival time for mice treated with (188)Re-liposome (58.5 days; p<0.05) was significantly better than those of 5-FU (48.25 days; p>0.05) and normal saline-treated mice (43.63 days). Dosimetry study revealed that the (188)Re-liposome did not lead to high absorbed doses in normal tissue, but did in small tumors. These results of imaging and biodistribution indicated the highly specific accumulation of tumor after intravenous (i.v.) injection of (188)Re-liposome. The therapeutic efficacy of radiotherapeutics of (188)Re-liposome have been confirmed in a LS-174T solid tumor animal model, which points to the potential benefit and promise of passive nanoliposome delivered radiotherapeutics for cancer treatment.

Annals of Nuclear Medicine, 2012

Objective The OLINDA/EXM computer code was created as a replacement for the widely used MIRDOSE3 ... more Objective The OLINDA/EXM computer code was created as a replacement for the widely used MIRDOSE3 code for radiation dosimetry in nuclear medicine. A dosimetric analysis with these codes was performed to evaluate nanoliposomes as carriers of radionuclides ( 188 Re-liposomes) in colon carcinoma-bearing mice. Methods Pharmacokinetic data for 188 Re-N, N-bis (2-mercaptoethyl)-N 0 ,N 0 -diethylethylenediamine ( 188 Re-BMEDA) and 188 Re-liposome were obtained for estimation of absorbed doses in normal organs. Radiation dose estimates for normal tissues were calculated using the MIRDOSE3 and OLINDA/ EXM programs for a colon carcinoma solid tumor mouse model.