Zhi Yang

A Novel Type of Dual-Modality Molecular Probe for MR and Nuclear Imaging of Tumor: Preparation, Characterization and in Vivo Application

A novel dual-modality molecular probe composed of biocompatible Fe(3)O(4) nanocrystal, monoclonal antibody and radionuclide was designed and prepared. All functional components in the dual-modality molecular probe, i.e., Fe(3)O(4), PEG, mAb 3H11 and (125)I, were chemically bonded together for forming a stable molecular probe. Systematic in vitro experiments were carried out for evaluating the biological activity of the antibody in the targeting probe. A series of in vivo experiments were performed based on the dual-modality imaging probe for detecting xenografted tumors in nude mice by MRI and gamma-imaging techniques. The pharmacokinetics of the dual-modality molecular probe in tumor-bearing nude mice was studied.

99mTc-Labeled Bombesin(7-14)NH2 with Favorable Properties for SPECT Imaging of Colon Cancer

In this report, we present the synthesis and evaluation of the (99m)Tc-labeled beta-Ala-BN(7-14)NH2 (ABN = beta-Ala-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) as a new radiotracer for tumor imaging in the BALB/c nude mice bearing HT-29 human colon cancer xenografts. The gastrin releasing peptide receptor binding affinity of ABN and HYNIC-ABN (6-hydrazinonicotinamide) was assessed via a competitive displacement of (125)I-[Tyr4]BBN bound to the PC-3 human prostate carcinoma cells. The IC 50 values were calculated to be 24 +/- 2 nM and 38 +/- 1 nM for ABN and HYNIC-ABN, respectively. HYNIC is the bifunctional coupling agent for (99m)Tc-labeling, while tricine and TPPTS (trisodium triphenylphosphine-3,3,3-trisulfonate) are used as coligands to prepare the ternary ligand complex [(99m)Tc(HYNIC-ABN)(tricine)(TPPTS)] in very high yield and high specific activity. Because of its high hydrophilicity (log P = -2.39 +/- 0.06), [(99m)Tc(HYNIC-ABN)(tricine)(TPPS)] was excreted mainly through the renal route with little radioactivity accumulation in the liver, lungs, stomach, and gastrointestinal tract. The tumor uptake at 30 min postinjection (p.i.) was 1.59 +/- 0.23%ID/g with a steady tumor washout over the 4 h study period. As a result, it had the best T/ B ratios in the blood (2.37 +/- 0.68), liver (1.69 +/- 0.41), and muscle (11.17 +/- 3.32) at 1 h p.i. Most of the injected radioactivity was found in the urine sample at 1 h p.i., and there was no intact [(99m)Tc(HYNIC-ABN)(tricine)(TPPTS)] detectable in the urine, kidney, and liver samples. Its metabolic instability may contribute to its rapid clearance from the liver, lungs, and stomach. Despite the steady radioactivity washout, the tumors could be clearly visualized in planar images of the BALB/c nude mice bearing the HT-29 human colon xenografts at 1 and 4 h p.i. The favorable excretion kinetics from the liver, lungs, stomach, and gastrointestinal tract makes [(99m)Tc(HYNIC-ABN)(tricine)(TPPTS)] a promising SPECT radiotracer for imaging colon cancer.

in vivo gamma imaging of the secondary tumors of transplanted human fetal striatum neural stem cells-derived primary tumor cells

This study describes &ggr;-imaging of the secondary tumors from the transplanted human fetal striatum neural stem cells-derived primary tumor cells in nude mice. The subcutaneous primary tumors were detected to express integrin &agr;v&bgr;3, and the corresponding cells were isolated and enriched in vitro, then transplanted to the nude mice. The technetium-99m-labeled Arg-Gly-Asp peptide, with high affinity to integrin &agr;v&bgr;3, was prepared for biodistribution and &ggr;-imaging. The secondary tumors were readily visualized at 1-h postinjection, and the tumor uptake of radiotracer was similar to that of positive control animals transplanted with U87MG human glioma cells. The tumor specificity of radiotracer was demonstrated by blocking experiment. We concluded that &ggr;-imaging is a promising approach in imaging the tumorigenesis of transplanted stem cells in vivo.

Advantages of positron emission tomography-computed tomography imaging in esophageal squamous cell carcinoma.

To explore the value of positron emission tomography-computed tomography (PET-CT) scan in esophageal squamous cell carcinoma (ESCC), we retrospectively summarize the results of PET-CT scan from 118 patients, with ESCC who underwent PET-CT scan in the different courses during treatment. Then, the results of PET-CT scan plus other conventional methods were analyzed to identify the value of PET-CT scan in diagnosis, staging, response evaluation, monitoring recurrence, and metastasis following treatment. It is suggested that PET-CT scan possess high value in diagnosis and gives more favorable indication in N and M staging. PET-CT scan should be translated into routine surveillance for postoperation follow up and is one of more helpful evaluators of response to chemoradiotherapy or chemotherapy.

Prognostic value of interim (18)F-FDG PET/CT in diffuse large B-cell lymphoma.

OBJECTIVEnDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. The prognostic factor currently used is not accurate enough to predict the outcomes of patients with DLBCL. The prognostic significance of interim PET/CT in DLBCL remains controversial. The aim of this study is to determine the predictive value of interim (18)F-FDG PET/CT after first-line treatment in patients with DLBCL.nnnMETHODSnThirty-two patients with DLBCL underwent baseline, interim and post-treatment (18)F-FDG PET/CT scans. Imaging results were analyzed for the survival of patients via software SPSS 13.0, retrospectively.nnnRESULTSnThirty-one of the 32 patients were treated with R-CHOP regimen, and interim (18)F-FDG PET/CT of 24 patients was performed after 2 cycles of treatment. After a median follow-up period of 16.7 months, the 2-year progression-free survival (PFS) rates were significantly different between the groups above and below SUV(max) cut-off value of 2.5 (P=0.039). No significant differences were found in the 2-year PFS rates if SUV(max) cut-off values were set as 2.0 and 3.0, respectively (P=0.360; P=0.113).nnnCONCLUSIONSnInterim PET/CT could predict the prognosis of DLBCL patients with the SUV(max) cut-off value of 2.5, but more clinical data should be concluded to confirm this conclusion.nnnKEY WORDSnFludeoxyglucose F18; lymphoma; large cell; diffuse; prognosis; standard utility value.

Noninvasive small-animal imaging of galectin-1 upregulation for predicting tumor resistance to radiotherapy

Increasing evidence indicates that the overexpression of galectin-1, a member of the galectin family, is related to tumor progression and invasion, as well as tumor resistance to therapies (e.g., radiotherapy). Herein, we investigated whether near-infrared fluorescence (NIRF) imaging and positron-emission tomography (PET) were sensitive approaches for detecting and quantitating galectin-1 upregulation inxa0vivo. An anti-galectin-1 antibody was labeled with either an NIRF dye or 64Cu, and NIRF and PET imaging using the resulting probes (Dye-αGal-1 and 64Cu- 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-αGal-1) were performed in 4T1 breast cancer-bearing mice treated with several rounds of sorafenib. Radiotherapy was performed inxa0vitro and inxa0vivo to identify the role of galectin-1 in radioresistance. NIRF and PET imaging both revealed significantly increased upregulation of galectin-1 in the hypoxic tumors after sorafenib treatment, which was verified by exxa0vivo biodistribution, western blotting, and enzyme-linked immunosorbent assays. Galectin-1 specific inhibition by thiodigalactoside dramatically improved the efficacy of radiotherapy, and overcame sorafenib-induced radiotherapy resistance. Taken together, galectin-1 is a key mediator of tumor resistance to radiotherapy. Targeted molecular imaging allows for real-time, noninvasive, and quantitative detection of the dynamic changes in galectin-1 levels inxa0vivo; this introduces the possibility of early detection of tumor resistance to therapies.

Clinical Evaluation of 99mTc-Rituximab for Sentinel Lymph Node Mapping in Breast Cancer Patients

The metastatic status of sentinel lymph nodes (SLNs) might be the most important prognostic factor in breast cancer. In this paper, we report to our knowledge the first study of 99mTc-rituximab as a radiotracer for imaging of SLNs using lymphoscintigraphy in both preoperative and intraoperative breast cancer patients. Methods: 99mTc-rituximab was designed as an SLN tracer targeting the CD20 antigen, which expresses extensively in LNs. A retrospective study was performed on 2,317 patients with primary breast cancer who underwent lymphoscintigraphy and sentinel lymph node biopsy (SLNB). Before imaging, all patients were administered a preoperative peritumoral injection of 37 MBq of 99mTc-rituximab. Results: 99mTc-rituximab was synthesized in both high radiolabeling yield and high radiochemical purity (>95%), with molecular integrity and immune activity well maintained. The initial study of 100 breast cancer patients showed that the success rate of SLN lymphoscintigraphy by injection of 99mTc-rituximab, as compared with SLNB, was 100%, and the sensitivity, specificity, accuracy, and false negative rate were 97.4%, 100%, 98.0%, and 2.60%, respectively. Of the following 2,217 patients studied, the success rate of lymphoscintigraphy and SLNB was 98.8% and 99.9%, and the average number of SLN was 1.78 (range, 1–10) and 2.85 (range, 1–15). Age was an independent predictor of the number of SLNs identified by lymphoscintigraphy and intraoperative handheld γ-probe (P < 0.05), and other factors—such as sex, imaging time, primary tumor site, histopathologic subtype, clinical T stage, and immunochemistry—were not (P > 0.05). However, the SLN metastatic rates were different in patients with different histopathologic subtype, clinical T stage, and immunochemistry (P < 0.05). Conclusion: Here we report the first study of the new radiotracer 99mTc-rituximab for breast cancer lymphoscintigraphy. This tracer showed great feasibility, safety, and effectiveness for SLN mapping in breast cancer patients.

Can the SUVmax-liver-based interpretation improve prognostic accuracy of interim and posttreatment 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma?

Abstract In order to investigate whether the SUVmax-liver-based interpretation could improve prognostic accuracy of interim (PET-4) and posttreatment PET/CT (PET-end), 115 patients with newly diagnosed DLBCL were recruited in the study. ROC analysis revealed the optimal threshold is 1.6-fold of SUVmax-liver for PET-4 and 1.4-fold of SUVmax-liver for PET-end. The SUVmax-liver-based interpretation had a perfect interobserver agreement, higher prognostic accuracy and positive predictive value than 5-point scale and %ΔSUVmax criteria in both PET-4 and PET-end. Dramatic differences in the outcome between patients with positive and negative PET-4/PET-end were demonstrated using Kaplan–Meier survival curves (pu2009<u2009.05). Univariate and multifactor analysis found PET-4 and PET-end were independent prognostic factors for the outcome of DLBCL. In conclusion, the SUVmax-liver-based interpretation were superior to 5-point scale and %ΔSUVmax criteria in analyzing the PET-4 and PET-end for the prognosis of DLBCL patients.

Evaluating early interim fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography with the SUVmax-liver-based interpretation for predicting the outcome in diffuse large B-cell lymphoma

Abstract Interim 18F-FDG PET/CT is an effective predictor in patients with DLBCL, but the standard evaluating criteria were controversial. In this study, investigators tried to investigate whether the liver SUVmax (SUVmax-liver)-based interpretation could improve the accuracy of predicting the outcomes, comparing with the Deauville five-point scale (5-PS) and the reduction rate of the maximum standardized uptake value (ΔSUVmax) criteria. In 119 patients, PET/CT after two chemotherapy cycles (PET2) were evaluated with the SUVmax-liver-based interpretation, 5-PS, and ΔSUVmax criteria. Uni- and multivariate analyses were performed. The optimal threshold for the SUVmax-liver-based interpretation was 1.6 fold of SUVmax-liver. Using the SUVmax-liver-based interpretation, the 3-year PFS and OS were 19.9% and 33.0% for patients with a positive residue while 78.2% and 86.4% for patients with negative results (pu2009<u2009.001). SUVmax-liver-based interpretation demonstrated slightly superior accuracy, and was independent predictor for PFS and OS (pu2009≤u2009.001). Thus, early interim 18F-FDG PET/CT effectively predicts the outcome in patients with DLBCL using SUVmax-liver-based interpretation.

Synthesis and evaluation of Cy5.5-Rit tracer for specific near-infrared fluorescence imaging of sentinel lymph node

Sentinel lymph nodes biopsy (SLNB) is a critically important technique to determine the metastatic status of primary breast cancer. Here we reported the new use of a conjugate, Cy5.5-Rituximab (Cy5.5-Rit), which is specific toward the CD20 receptor, as an imaging agent for non-invasive near-infrared fluorescence (NIRF) imaging of sentinel lymph nodes (SLN). The conjugate, Cy5.5-Rit, was synthesized with the ratio of dye to Rituximab close to 1.0. Both gel electrophoresis and mass spectrometry analysis confirmed the molecular integrity of Cy5.5-Rit. For in vivo NIRF imaging, the conjugate stayed in SLN as long as 9days post injection. The in vivo imaging results of SLN targeting were also confirmed by in vitro HE stain. In addition, the direct fluorescence signal of dissected lymph node demonstrated that Cy5.5-Rit binds to the surface of lymph node cells. All of these results showed that the conjugate Cy5.5-Rit has potential for non-invasive optical imaging of SLN.