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Objective:To label mesenchymal stem cells (MSCs) with 89Zr-oxine complex, and assess its characteristics of PET imaging in systemic lupus erythematosus (SLE) model (MRL/lpr mice). Methods:SLE mice were screened by 18F-FDG PET imaging. 89Zr-oxine was prepared and used for labeling MSCs (10 6 MSCs and 1 MBq 89Zr-oxine). 89Zr-oxine-labeled MSCs (0.2 MBq) were injected into MRL/lpr mice and BALB/c mice (each n=5) via tail vein at a dose of 1.2×10 6 cells per mouse, and followed with microPET imaging in vivo at 2 h, 6 h, 1 d, 3 d, 7 d, 10 d and 14 d after injection. The percentage activity of injection dose per gram of tissue (%ID/g) was calculated. Independent-sample t test was used to analyze the data. Results:MSCs was successfully labeled with 89Zr-oxine, with the labeling efficiency of 20% and cell viability >90%. MicroPET imaging showed that MSCs were mainly distributed in lungs and the liver sites at 2 h after injection. The number of MSCs homing to kidneys of MRL/lpr mice ( n=5) increased significantly 24 h after the injection, and the renal uptake of MSCs in MRL/lpr mice was much higher than that in BALB/c mice ((8.28±1.27) vs (4.33±0.94) %ID/g; t=3.54, P=0.024). The renal uptake increased firstly and then decreased and then leveled off, indicating MSCs homing to kidneys. Conclusions:A method for 89Zr-oxine labeling of MSCs is successfully established. 89Zr-labeled MSCs can home to kidneys of SLE mice. PET imaging of 89Zr-labeled MSCs can be effectively used to explore the in vivo distribution and migration behavior of transplanted MSCs during the treatment of diseases such as SLE.
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Objective:To synthesize N- 18F-fluoroethyl-tofacitinib, and explore its feasibility in the diagnosis of rheumatoid arthritis (RA). Methods:The " two-step method" was used to modify tofacitinib with 18F-fluoroethyl, and the labeling rate and radiochemical purity of the probe were measured by high performance liquid chromatography (HPLC), and the stabilities of the probe in vivo and in vitro were investigated. BALB/c mice (normal group; n=3) and collagen-induced arthritis (CIA) model mice (CIA group; n=3) were injected with N- 18F-fluoroethyl-tofacitinib and CIA model mice injected with tofacitirrib and N- 18F-fluoroethyl-tofacitinib were as blocking group ( n=3). All mice underwent microPET imaging and the percentage injection dose per gram of tissue (%ID/g) and the uptake ratio of inflamed joints to muscle (T/M) were calculated. One-way analysis of variance and the least significant difference (LSD) t test were used to analyze the data. Results:The synthesis time of N- 18F-fluoroethyl-tofacitinib was about 120 min, with the yield approximately 1%, the specific activity >13.6 GBq/μmol, and the radiochemical purity >99%. After the probe incubated with PBS, plasma or in vivo for 2 h, the radiochemical purity was still more than 95%. MicroPET imaging showed that 30 min after injection, the uptake of N- 18F-fluoroethyl-tofacitinib in the inflamed joints of CIA group was higher than that of normal group and blocking group ((10.22±1.64), (2.71±0.26) and (2.81±0.33) %ID/g; F=58.26, t values: 7.83, 7.67, P values: 0.001, 0.002). The T/M of CIA group was also higher than that of normal group and blocking group (24.73±5.77, 2.75±1.36 and 2.89±0.54; F=40.64, t values: 6.42, 6.53, P values: 0.003, 0.003). Conclusions:N- 18F-fluoroethyl-tofacitinib is successfully prepared and it is stable in vitro with good imaging performance in vivo. It may be used in clinic for the diagnosis of RA.
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Objective:To prepare a 68Ga labeled human epidermal growth factor receptor 2 (HER2) affibody 68Ga-1, 4, 7-triazacylononane-1, 4, 7-triacetic acid (NOTA)-maleimide (MAL)-Cysteine (Cys)-Glycine-Glycine-Glycine-Arginine-Aspartic acid-asparagine-HER 2: 342 affibody (GGGRDN-ZHER 2: 342)( 68Ga-MZHER), and evaluate its biodistribution and microPET characteristics. Methods:NOTA-MAL-Cys-GGGRDN-ZHER 2: 342 conjugate was labeled with 68Ga in one step. Radiochemical purity, radiolabeling yield and stability in vitro were analyzed. Normal mice ( n=24) were scarified at 15, 30, 60 and 120 min postinjection (1.85 MBq 68Ga-MZHER) to measure radioactive counts (percentage activity of injection dose per gram of tissue (%ID/g)) in main organs. Biodistribution and kinetics were evaluated by dynamic microPET in mice. Ovarian cancer (SKOV-3) models were established and microPET was performed at 30, 60 and 120 min postinjection of radiotracer. After administration of unlabeled Cys-ZHER 2: 342 peptide (10 mg/kg body weight) for 30 min, 68Ga-MZHER was injected into mice and PET images were acquired at 60 min postinjection. Region of interest (ROI) was drawn to access time-activity curve (TAC) in main organs and tumor. Six normal mice were used for the safety study. Results:68Ga-MZHER was synthesized in about 15 min with the yields more than 90%, and radiochemical purity more than 95%. The radiochemical purity was also determined to be more than 95% after being stored for 120 min at room temperature. Predominant uptake of 68Ga-MZHER was in the kidneys, and was cleared rapidly in normal tissues except the kidney. At 15 min postinjection, the renal uptake value was (106.36±15.74) %ID/g, then gradually increased with time, up to (145.15±28.04) %ID/g (60 min), and decreased to (86.12±22.75) %ID/g after 120 min postinjection. The blood pharmacokinetic of the probe in mice was fit with the two-compartment model. MicroPET imaging in mice bearing HER2 positive SKOV-3 tumors showed that the xenografts were clearly visualized with good contrast to normal tissue. The uptakes in tumors was determined to be (11.26±0.50), (12.27±1.13) and (12.65±0.89) %ID/g at 30, 60 and 120 min postinjection. Block experiment showed that the corresponding values decreased to (1.25±0.28) %ID/g at 60 min postinjection. Safety studies showed that after injection of 68Ga-MZHER for 30 d, the mice survived and no obvious abnormalities were observed in the main organs as shown in pathological results. Conclusions:68Ga-MZHER can be successfully labeled by one-step method. The 68Ga-MZHER probe owns the advantages of favorable imaging properties, convenient preparation, excellent stability, safety, rapid clearance in the blood, which support its application for further research.
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Objective:To prepare 18F-Alfatide Ⅱ automatically based on the improved CFN-100 fluorine multifunctional module and assess its PET/CT imaging in prostate cancer patients. Methods:A certain volume (200-500 μl) of fluoride ion was separated into the reaction tube by a fluoride ion separator and reacted with the labeled precursor l, 4, 7-triazacylononane-1, 4, 7-triacetic acid-E[(polyethylene glycol) 4-cyclo(Arg-Gly-Asp- D-Phe-Tyr)] 2(NOTA-E[PEG 4-c(RGDfk)] 2) (lyophilized kit). In the aqueous phase, 18F was chelated with aluminum. After being separated and purified by C18 column, 18F-Alfatide Ⅱ was prepared automatically. The radiochemical yield and its quality were analyzed. Quality control was carried out and 18F-Alfatide Ⅱ PET/CT imaging was performed in 2 patients (72 and 66 years old)with prostate cancer. Results:18F-Alfatide Ⅱ was prepared automatically by the improved CFN-100 fluorine multifunctional module combined with a double channel-fluorine ion separation device. 18F-Alfatide Ⅱ was synthetized in about 30 min, with radiochemical yield of (28±3)% (non-decay corrected, n=6). The radiochemical purity of the product was more than 98%, the specific activity was 2.8×10 7 MBq/mmol and the nuclear purity was >99%. PET/CT imaging of 2 patients showed that 18F-Alfatide Ⅱ were highly concentrated in prostate cancer lesions with the maximum standardized uptake value (SUV max) of 35.6 and 5.0, respectively. Conclusion:18F-Alfatide Ⅱ can be prepared successfully by improved CFN-100 fluorine multifunctional module with stable synthesis method, short synthesis time and high radiochemical yield, which can be highly concentrated in prostate cancer.
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Objective To investigate the characteristics of 18F-Alfatide II PET/CT imaging in normal breasts and breast cancer lesions.Methods From March 2016 to August 2017,22 female patients(age:(52±10)years)with suspected breast malignant nodules or masses were prospectively enrolled.All patients underwent 18F-Alfatide II PET/CT imaging prior to biopsy or surgery.The imaging characteristics of normal breasts were assessed visually and the difference of maximum standardized uptake value(SUVmax)in normal breasts and uterus between patients with and without menopause was compared,SUVmax of cancer lesions and normal breasts was also compared.Breast cancer lesions were classified according to the distribution characteristics of radioactive uptake,and molecular subtypes ware determined by immunohistochemistry and fluorescence in situ hybridization.The SUVmax of different morphological and molecular subtypes were analyzed.Two-sample t test and Pearson or Spearman correlation analysis were used to analyze the data.Results There were 23 breast cancer lesions(one patient had bilateral breast cancer lesions and one had a history of one-side breast resection),20 normal breasts and 21 normal uteruses.Those normal breasts and uteruses didn't show any malignant change after being followed up for more than 1 year(one patient had uterine fibroids resection).There was a slight increase of radioactivity uptake in the cord-like connective tissue region at the margin of the gland in 11 mammary glands,and the SUVmax was higher than that of glandular tissue in the central region(1_81±0.67 vs 0.79±0.37;t = 6.771,P<0.00l).Of the 11 cases,except for one patient whose uterus was removed,the other 10 patients were accompanied by increased diffuse radioactivity of the uterus.SUVmax of 19 normal breast connective tissues(1.31±0.80)and uterus(3.80+1.79)were positively correlated(r = 0.785,P<0.05).For patients with/without menopause(n= 11 each group),the SUVmax of normal breast connective tissues(0.72±0.39 vs 1.81±0.67)and uterus(2.04±0.39 vs 5.11 + 1.06)were significantly different(t values:4.42 and 8.66,both P<0.01).Different levels of radioactive uptake were observed in all 23 breast cancer lesions,with SUVmax of 6.93±3.97,which was significantly higher than the nipple,connective tissue and glandular tissue of normal breasts(t values:6.784-7.559,all P<0.05).According to the characteristics of the radioactivity uptake distribution of the lesion,among the 23 breast cancer lesions,5 were mass type,3 were nodular type,4 were diffuse type,and 11 were multi-focal/multi-center type,and the SUVmax of multi-focal/multi-center type was the highest(F=3.55,P<0.05).The SUVmax of basal-like breast cancer lesions(2.49±1.67)was lower than the other three molecular subtypes.Lesions with high level human epidermal growth factor receptor 2(HER2)positive expression had higher SUVmax.Conclusions 18F-Alfatide II PET/CT imaging shows that normal breasts have a slight radioactive distribution,mainly concentrate in the nipple and connective tissues around the glandular,and the uptake have a positive correlation with the radioactive uptake of the uterus.The degree of radioactive uptake of breast cancer lesions is significantly higher than that of normal breasts.Breast cancer lesions with different moqjhological features all have obvious radioactive uptake,especially the multi-focal/multi-center type.Different molecular subtypes have different radioactive uptake levels.SUVmax is lower in basal-like breast cancer lesions,and higher in HER2 positive expression lesions.
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Objective To synthesize 18F-AlF-1,4,7-triazacyclononane-l,4,7-triacetic acid (NOTA)-c (CGRRAGGSC),which could specifically bind to the α chain of interleukin (IL)-11 receptor (IL-11 R),and evaluate its targeting potential to IL-11 R-positive tumors.Methods Polypeptide c (CGRRAGGSC) was first coupled with NOTA and then labeled with 18F by AlF labeling method.The radiochemical purity and radiochemical yield of 18F-AlF-NOTA-c(CGRRAGGSC) were analyzed by high performance liquid chromatography,and the stability in vitro was evaluated.The tracer biodistribution in tumor-bearing mice (cell line SKOV3) was evaluated by the dynamic imaging with microPET 30 min,1 h,2 h after injection of 18F-AlF-NOTA-c (CGRRAGGSC).The tracer kinetics was performed in normal mice.Pharmacokinetics parameters were calculated using DAS2.0 software.Results The radiochemical purity of 18F-AlF-NOTA-c(CGRRAGGSC) was higher than 95％ and the radiochemical yield was (30.0±7.4)％.It could be stably maintained in phosphatebuffered solution and plasma for at least 2 h.MicroPET imaging showed that 18F-AlF-NOTA-c(CGRRAGGSC)had a good affinity to SKOV3 tumor.The tumor/muscle ratios at 30 min,1 h,2 h after the injection of 18F-AlF-NOTA-c(CGRRAGGSC) were 6.26±2.98,7.19±3.63 and 9.05±4.30,respectively.The tracer was cleared rapidly in blood and mainly excreted by the liver and kidneys.The T1/2α and T1/2β were (0.38±0.14) h and (2.64±0.28) h,respectively.Conclusions 18F-AlF-NOTA-c(CGRRAGGSC) is easy to be synthesized and has a good affinity to IL-11R-positive tumors.It will be a potential IL-11R-targeting imaging agent.
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Objective To synthesize 18 F-DPA-714 and to study its labeling rate, radiochemical purity, stability and biological characteristics. Methods 18F-was reacted with K2CO3/K2.2.2 and then en-gaged in nucleophilic substitution with DPA-714. The crude product was purified by aluminum column and semi-preparation HPLC. The stability of 18 F-DPA-714 was identified in PBS and plasma. The lipid-water partition coefficient (LogP) was determined. Biodistribution analysis and microPET imaging were performed on mice and rats respectively. Results It took about 25 min for synthesizing 18 F-DPA-714, the radiochemi-cal yield was 31.6% (decay not corrected), and the radiochemical purity was ≥99%. The product re-mained stable within 4 h. The LogP of 18 F-DPA-714 was 2.71. Pharmacokinetics of 18 F-DPA-714 was more in line with the two compartment model, with the distribution half-life ( T1/2α) of 2.40 min and the elimina-tion half-life( T1/2β) of 69.15 min. 18 F-DPA-714 was quickly uptaken by tissues after the tail vein injection. It mainly distributed in the lungs, kidneys, and heart, with the radioactive uptake values of (17.85±7.52)%ID/g, (15.41±1.80) %ID/g and (10.56±0.94) %ID/g at 30 min post-injection, respectively. 18F-DPA-714 was mainly metabolized through the liver, and excreted by the kidneys. The uptake in bones was stable. PET dynamic scanning showed that 18 F-DPA-714 accumulated in the brain of aged rats and cleared slowly within 60 min. Conclusions 18 F-DPA-714 prepared in this study has high labeling rate, short synthesis time and small precursor dosage. It displays good biological distribution and blood-brain barrier permeability characteristics.
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Objective To synthesize 18 F-DPA-714 and to study its labeling rate, radiochemical purity, stability and biological characteristics. Methods 18F-was reacted with K2CO3/K2.2.2 and then en-gaged in nucleophilic substitution with DPA-714. The crude product was purified by aluminum column and semi-preparation HPLC. The stability of 18 F-DPA-714 was identified in PBS and plasma. The lipid-water partition coefficient (LogP) was determined. Biodistribution analysis and microPET imaging were performed on mice and rats respectively. Results It took about 25 min for synthesizing 18 F-DPA-714, the radiochemi-cal yield was 31.6% (decay not corrected), and the radiochemical purity was ≥99%. The product re-mained stable within 4 h. The LogP of 18 F-DPA-714 was 2.71. Pharmacokinetics of 18 F-DPA-714 was more in line with the two compartment model, with the distribution half-life ( T1/2α) of 2.40 min and the elimina-tion half-life( T1/2β) of 69.15 min. 18 F-DPA-714 was quickly uptaken by tissues after the tail vein injection. It mainly distributed in the lungs, kidneys, and heart, with the radioactive uptake values of (17.85±7.52)%ID/g, (15.41±1.80) %ID/g and (10.56±0.94) %ID/g at 30 min post-injection, respectively. 18F-DPA-714 was mainly metabolized through the liver, and excreted by the kidneys. The uptake in bones was stable. PET dynamic scanning showed that 18 F-DPA-714 accumulated in the brain of aged rats and cleared slowly within 60 min. Conclusions 18 F-DPA-714 prepared in this study has high labeling rate, short synthesis time and small precursor dosage. It displays good biological distribution and blood-brain barrier permeability characteristics.
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Objective To prepare a specific integrin αvβ3 probe 18F-Al-1,4,7-triacetic acid-1,4,7-triazacyclononane-2-(4-amino benzyl) thioamide-(3,6,9-trioxaundecanoic acid-11-amide)-(glutamic acid-cyclo(arginine-glycine-aspartic acid-phenylalanine-lysine) dimeric peptide) (18 F-Al-NOTA-PRGD2) and evaluate its feasibility for PET imaging in papillary thyroid carcinoma (PTC).Methods 18F-Al-NOTA-PRGD2 was synthesized by a novel Al18F complex strategy.Human PTC tissues were implanted into nude mice.Immunohistochemistry staining was performed to detect αvβ3 expression in human PTC tissues,xenografts in mice and adjacent normal tissues respectively.18F-Al-NOTA-PRGD2 with or without blocking agent of PRGD2 was injected via the tail vein into tumor-bearing mice (n =5) for microPET imaging.The radioactivity uptake in the tumor and major organs were measured via ROI technology.Biodistribution studies were also performed in tumor bearing mice (n=15) 30,60,120 min postinjection respectively.The two sample t test was used for statistical analysis.Results The labeling yield of 18F-Al-NOTA-PRGD2 was over 45％ (no attenuation correction) and the radiochemical purity was above 95％.The integrin αvβ3 expression was observed in human PTC both in situ specimens and xenograft in mice,while no expression was shown in the adjacent normal tissues.MicroPET imaging revealed that tumors were clearly visible with good tumor-to-background contrast.The radioactive uptake by tumor was (2.81 ±0.35) ％ ID/g,(2.45±0.27) ％ID/g and (1.80±0.21) ％ID/g at 30,60 and 120 min postinjection,respectively.In the presence of unradiolabeled PRGD2,the corresponding tumor uptake decreased to (0.51±0.05) ％ID/g at 60 min postinjection.High tumor uptake was also shown in the biodistribution studies,which was (3.09±0.25) ％ID/g,(2.75±0.37) ％ID/g and (1.90±0.16) ％ID/g at 30,60 and 120 min postinjection,respectively.The results were consistent with the microPET imaging results (t=1.456,1.465 and 0.847,respectively,all P＞0.0.5).18F-Al-NOTA-PRGD2 was rapidly cleared in blood and muscles,and the tumor to blood and muscle uptake ratios were 6.15±0.45 and 7.86±0.56 respectively.Conclusions 18 F-Al-NOTA-PRGD2 could be labeled easily and quickly with good labeling yield and radiochemical purity.Overexpressed integrin αvβ3 in PTC can be proved by both immunostaining and microPET imaging.18F-A1-NOTA-PRGD2 PET imaging might be a novel in vivo method for investigation of molecular mechanism in PTC.
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Objective To study the preparation of 131 I-nalepride and its characters in small animal in vivo ,and to evaluate the feasibility for its application in diagnosing neuropsychiatric disease .Methods s-5-(tributyltin)-N-[(1-ethyl-2-pyrrolidinyl) meth-yl]-2 ,3-dimethoxy-benzamide was used as the labeled precursor .The hydrogen peroxide method was adopted to label131 I-nalepride . The bio-distribution character test in ICR mice was performed .SD rats were performed the blocking experiment and the cerebral au-toradiography .Results The radiolabeled yield and radiochemical purity were over 95% .The results of the bio-distribution character test showed that the striatum had the highest uptake .The striatum to cerebellum uptake radio(ST/CB) reached 111 .87 at 4 h after injection and the maximum ST/CB value of 416 .97 at 12 h after injection .Regional brain autoradiography showed that the optical densities were significantly decreased from 7 .43 ± 0 .86 to 1 .07 ± 0 .18 after injection of 131 I-naleprid(P<0 .05) .These results indi-cated that 131 I-nalepride had specific binding to the dopamine D2 receptor .131 I-nalepride was rapidly uptaken by organs after injec-tion .The initial uptake in liver and kidney were higher and the % ID/g values were 14 .82 ± 3 .88 and 10 .28 ± 1 .65 receptively .The tracer was cleared out from the organ quite rapidly .Conclusion 131 I-nalepride has the high affinity and specificity to dopamine D2 receptor ,which could be used as the EPECT imaging agent of dopamine D2 receptors and as a tool drug to screen and evaluate the affinity of other antipsychotic agents to dopamine D2 receptors .
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Objective To study the therapeutic and toxic effects of 32 P-chromic phosphate-poly (L-lactic) acid (32p-CP-PLLA) microparticle intratumoral administration into BALB/c nude mice bearing BxPc-3 human pancreatic carcinoma.Methods Twenty four nude mice bearing tumors were injected with 0,9.3,18.5 and 37.0 M Bq 32p-CP-PLLA microparticle,respectively.The relative tumor growth rates were observed every day,and white blood cells,platelets and body weight were measured.At 14 d after administration,the tumors were removed,histological examination and immunohistochemical analysis were performed.Results The relative tumor growth rates of each treatment group was lower than 40％.Histological examination showed the degenerative necrosis at the site nearby the mircoparticle.Immunohistochemical analysis showed that the Microvessel density (MVD) and the expression of Bcl-2 in treated group were lower than those in control group.In contrast,the expression of bax in treated group were higher than those in control group.The ratio of Bcl-2/Bax protein significantly decreased in the treatment group,which were 3.83 ± 0.43,0.47 ± 0.13,1.10 ± 0.32,2.19 ± 0.57 for 0,9.3,18.5 and 37.0 MBq 32 P-CP-PLLA microparticle,respectively ( t =2.36 - 2.77,P ＜ 0.05).MVD were 31.2 ± 2.3,23.8 ± 1.5,14.8 ±0.8,11.0 ± 1.2,respectively.Dose dependence was observed in both HE and IHC staining after 14 d treatment ( t =2.30 - 2.57,P ＜ 0.05 ).Conclusions Intratumoral injection of 32p-CP-PLLA microparticle might be a safe,easy and effective radionuclide interventional therapy for pancreatic carcinoma.
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<p><b>OBJECTIVE</b>To investigate the effect of betulinic acid (BA) on the proliferation, migration, apoptosis and cell cycle of pancreatic cancer cells (BxPC-3) in vitro and elucidate the underlying.</p><p><b>METHOD</b>The effect of BA on the proliferation of BxPC-3 was measured by using sulforhodamine B (SRB) assay. Migratory ability of BxPC3 cells were detected by wound healing assay, and the morphological change was observed with light microscope. The influence of BA on cell cycle of BxPC-3 cells was tested by flow cytometry (FCM). Apoptosis was analyzed by using Hochest33342-PI double staining. Western blot technologies were applied to detect the expression of Bcl-2 and Bax.</p><p><b>RESULT</b>BA exhibited significant cell proliferation and migration inhibition, as well as its potency of inducing apoptosis in BxPC-3 cells in vitro in a dose-dependent manner. The IC50 value for 72 h was 16.54 mg x L(-1). Cell migration was significantly inhibited at 5 mg x L(-1) of BA. Cells treated with BA showed increased cell population in G0 phase, with decreased G2/M phase population. The expression of Bax and Bcl-2 was up and down-regulated respectively in BA-treated BxPC-3 cells in a dose-dependent manner.</p><p><b>CONCLUSION</b>BA exerted potent effect on growth inhibition, G0 cell cycle arrest and induction of apoptosis in BxPC-3 cells in vitro, possibly associated with the down-regulation of Bcl-2 and up-regulation of Bax expression. The potent antitumor capacity of BA suggested that it could be a promising new anticancer agent in human pancreatic cancer treatment.</p>